USMLE Preparatory Online Resource_ Effective Biochemistry and Genetics Teaching Relatively Short...

Know the: Know the:

1.Urea Cycle: Reaction and Significance.1.Urea Cycle: Reaction and Significance.2.The Importance of the Cytosol and Mitochondria.2.The Importance of the Cytosol and Mitochondria.3.Enzyme Defect and Subsequent Clinical Diagnosis. 3.Enzyme Defect and Subsequent Clinical Diagnosis.

Lecture outline…Lecture outline…

Learning Learning ObjectivesObjectives

II.Urea CycleII.Urea Cycle

A.Reactions of the urea cycle.A.Reactions of the urea cycle. 1.Synthesis of carbamoyl phosphate.1.Synthesis of carbamoyl phosphate. 2. Production of arginine by urea cycle.2. Production of arginine by urea cycle. 3. Cleavage of arginine to produce urea.3. Cleavage of arginine to produce urea.

B. Origin of ornithine.B. Origin of ornithine.

C. Regulation of the urea cycle. C. Regulation of the urea cycle.

D. Function of the urea cycle during fasting.D. Function of the urea cycle during fasting.

III. Disorders of the Urea Cycle. III. Disorders of the Urea Cycle. http://www.wiley.com/college/fob/quiz/quiz20/20-8.html

What is What is UreaUrea

Urea is a diamide, chiefUrea is a diamide, chief nitrogenous waste nitrogenous waste product. product.

Ammonia +COAmmonia +CO22 + Aspartate are the + Aspartate are the precursors of Urea.precursors of Urea.

Other nitrogenous waste products Other nitrogenous waste products which which includes includes uric acid & creatinineuric acid & creatinine..

What are the Precursors of What are the Precursors of UreaUrea

H2N C

O

NH2

Urea

HH22N-C-NHN-C-NH22

UreaUrea

OO

CarbonCarbon NitrogenNitrogen

Other Other N-N-Containing Containing CompoundsCompounds

Dietary ProteinsDietary ProteinsSummary of Amino Acid MetabolismSummary of Amino Acid Metabolism

Amino Acids in Amino Acids in BloodBlood

Amino AcidsAmino Acids

COCO22 + H + H22OOEnergy ATPEnergy ATP

ProteinProteinss

Digestion (Stomach Digestion (Stomach Intestine)Intestine)

MembranMembranee

-Aminobutyrate-AminobutyrateDopamineDopamineNorepinephrineNorepinephrineEpinephrineEpinephrineSerotoninSerotonin

-C--C-

UreaUrea

OO

CarboCarbonn

NitrogeNitrogenn

Fate of Amino Acid Nitrogen: Urea CycleFate of Amino Acid Nitrogen: Urea CycleAmino Amino AcidsAcids

AspartateAspartate

COCO22+H+H22OO

COO-COO-

H C-H C-

COO-COO-

StoragStoragee

EnergEnergyy

ATPATP

NHNH44++

+CO+CO22

----

--

NHNH22 Urea Urea

CycleCycleNHNH22

NHNH

22

What are the source of amino groups and carbonyl group for the biosynthesis of Urea?.

NH4+

Ammonium ion

Uric acidH2N-C-NH2

Urea

O

NH4+

O

O

HN

NH

NH

NH

O

Most terrestrial vertebrates Birds & reptiles

Fish & other aquatic

vertebrates

Some animals excrete NH4

+ or uric acid.

Amino Amino acidsacids

The carbon chains are broken down to molecules that feed into the TCA cycle.

Most mammals convert amino-acid nitrogen to urea for excretion

Excretion of Nitogenous Waste ProductsExcretion of Nitogenous Waste Products

An Overview of Urea An Overview of Urea CycleCycle

Urea biosynthesis occurs Urea biosynthesis occurs partly in the cytosol and partly in the cytosol and partly in the mitochondria of partly in the mitochondria of the liver.the liver.

What Are The Sites & The What Are The Sites & The Organ In Which Organ In Which

Biosynthesis Of Urea Biosynthesis Of Urea Occurs?Occurs?

Net reaction:

NH3 + CO2 + 2 ATP(HCO3)

Carbamoyl-Phosphate + 2 ADP + Pi

NH4+ + HCO3

- + 2 ATP

UreaArginine

Argininosuccinate

Citrulline

Carbamoyl phosphate

Mitochondrial Matrix

Cytoplasm

Arginase

Carbamoyl phosphate synthase I (CPS-I)

Ornithine Transcarbamoylase (OTC)

Argininosuccinate Synthetase

Argininosuccinate Lyase

Fumerate

The Urea Cycle in the LiverThe Urea Cycle in the Liver

Ornithine

Citrulline

Ornithine

Hep

ato

cyte

Aspartate

ATP

AMP+ Pi

1

2

3

45

What is Normal Value of UreaWhat is Normal Value of Urea Serum urea concentration is 15-40 Serum urea concentration is 15-40 mg/dL.mg/dL.

Accumulation of urea more than normal Accumulation of urea more than normal value in blood is referred asvalue in blood is referred as’””UremiaUremia”.”.

Urea Excretion: 20–30 gm / day.Urea Excretion: 20–30 gm / day.

Not yet identified, but probably may Not yet identified, but probably may involve ininvolve in ‘’’’’the maintenance of osmotic the maintenance of osmotic balance as abalance as a ‘’’’’crystalloid.crystalloid.

Is there any Specific functions of Is there any Specific functions of UreaUrea

Osmolality of Plasma: 285-295 milliosmoles / Kg.Osmolality of Plasma: 285-295 milliosmoles / Kg.

OsmolalityOsmolality is a measure of the solute particles is a measure of the solute particles present in the fluid medium.present in the fluid medium.

Plasma Osmolality Plasma Osmolality can be computed fromcan be computed from the the concentrations concentrations (mmol/l) of Na(mmol/l) of Na++, K, K++, urea, & glucose, urea, & glucoseas follows.as follows. 2(Na2(Na++) + 2(K) + 2(K++) + Urea + Glucose) + Urea + Glucose

The factor 2 is used for NaThe factor 2 is used for Na++ & K & K++ ions for the ions for theassociated anion concentration.associated anion concentration.

Plasma OsmolalityPlasma Osmolality will be altered in lipidaemias, ESRD, will be altered in lipidaemias, ESRD, hyperproteinaemia, ketoacidosis, diabetes insipidus,chronichyperproteinaemia, ketoacidosis, diabetes insipidus,chronicalcohol intoxication, diuretics & in chronic diarrhoea.alcohol intoxication, diuretics & in chronic diarrhoea.

Osmolality of PlasmaOsmolality of Plasma

Is any Clinical Conditions Are Is any Clinical Conditions Are related with Low Urea Levelrelated with Low Urea Level

Impairment of liver functions and Impairment of liver functions and congenital deficiencies of urea cycle congenital deficiencies of urea cycle enzymes will impair the biosynthesis of enzymes will impair the biosynthesis of urea, which ultimately leads to urea, which ultimately leads to accumulation of ammonia in blood and CSF accumulation of ammonia in blood and CSF causes “causes “azotemia”azotemia”..

What Is Meant By AzotemiaWhat Is Meant By Azotemia Accumulation of nitrogenous materials Accumulation of nitrogenous materials includingincludingammonia due to impairment in urea ammonia due to impairment in urea biosynthesis due to,biosynthesis due to, Urea cycle enzyme deficiencies,Urea cycle enzyme deficiencies,

Gastrointestinal tract (GI) bleeding, Gastrointestinal tract (GI) bleeding,

Valproic acid therapy andValproic acid therapy and

Renal impairments ect.,.Renal impairments ect.,.

What Are The Consequences of What Are The Consequences of UremiaUremia

Uremia will leads to ammonia toxicity, Uremia will leads to ammonia toxicity, hypercapnia & alkalosis which may leads to hypercapnia & alkalosis which may leads to neurotoxicity depending on the severity.neurotoxicity depending on the severity.

Impaired renal function leads to Impaired renal function leads to erythropoietinerythropoietin deficiency and hence deficiency and hence accumulation of COaccumulation of CO22..

Ureamia may occur as a result of Ureamia may occur as a result of impairment in impairment in ‘’’’’the the renal functionsrenal functions, , which occur as a result ofwhich occur as a result of nephrotic syndrome,nephrotic syndrome, heavy metal toxicities, heavy metal toxicities, ESRD and ESRD and

nitrogen load due to high protein diet. nitrogen load due to high protein diet.

What Are The Causes of What Are The Causes of UremiaUremia

Importance of Urea CycleImportance of Urea Cycle

Removal of CORemoval of CO22..

Removal of Ammonia.Removal of Ammonia.

Recycling of TCA cycle Recycling of TCA cycle intermediates.intermediates.

Recycling of amino acids & Recycling of amino acids & ketoacids.ketoacids.

Involvement of Peripheral Tissues And Liver in the Ammonia Metabolism

α-KG = α-Ketoglutaratee GDH = Glutamate Dehydrogenase.

α-Ketoglutarate

Glutamate Dehydrogenase

Glutamine Synthetase

Molecualr Interconversions in Handling of AmmoniaMolecualr Interconversions in Handling of Ammonia

NH4+

ATP

Alanine

Glutamate

Pyruvate

Glutamine

AST

ADP+Pi

Aspartate

Oxaloacetate

NADH+H+

NAD

NADPH+H+

NADPH+

ALT

NH4+

H2O

The major enzyme responsible for the interconversion of Glutamate into α-KG isGlutamate Dehydrogenase. ALT= Alanine aminotransferaseAST= Aspartate aminotransferase.

Reactions of the Urea CycleReactions of the Urea Cycle

1.1. Synthesis of Carbomoyl Phosphate.Synthesis of Carbomoyl Phosphate.2.2. Production of Arginine by the Urea Production of Arginine by the Urea

Cycle.Cycle.3.3. Cleavage of Arginine to Produce Urea.Cleavage of Arginine to Produce Urea.

Most terrestrial land animals convert excess nitrogen to urea, prior to excreting it.

Urea is less toxic than ammonia.

The Urea Cycle occurs mainly in liver.

The 2 nitrogen atoms of urea derived from NH3 and the amino nitrogen of aspartate.

H2N C

O

NH2

Urea

Carbamoyl Phosphate SynthaseCarbamoyl Phosphate Synthase is the is the committed committed stepstep of the Urea Cycle, and is subject to of the Urea Cycle, and is subject to regulationregulation. .

The NH3 and HCO3- that will be part of urea are

incorporated first into carbamoyl phosphate (CP).

H2N C OPO32

O

HCO3 + NH3 + 2 ATP

+ 2 ADP + Pi

Carbamoyl Phosphate Synthase-I

Carbamoyl phosphate

Carbamoyl Phosphate Synthase-ICarbamoyl Phosphate Synthase-I has an has an absolute requirement for an absolute requirement for an allostericallosteric activatoractivator NN-acetylglutamate-acetylglutamate..

This derivative of glutamate is synthesized from This derivative of glutamate is synthesized from acetyl-CoA & glutamate when cellular [glutamate] acetyl-CoA & glutamate when cellular [glutamate] is high, signaling an is high, signaling an excess of free amino acidsexcess of free amino acids due to protein breakdown or dietary intake. due to protein breakdown or dietary intake.

H3N+ C COO

CH2

CH2

COO

H

Glutamate (Glu)

NH

C COO

CH2

CH2

COO

H

CH3C

O

N-Acetylglutamate

Formation & Degradation of N-Formation & Degradation of N-Acetylglutamate (NAG)Acetylglutamate (NAG)

NAG NAG

NAG, is an allosteric activator of CPS-NAG, is an allosteric activator of CPS-I.I.

N-Acetyl glucoseamine (NAG)N-Acetyl glucoseamine (NAG) serves as an serves as an allosteric activatorallosteric activator for the enzyme CPS-I for the for the enzyme CPS-I for the biosynthesis of carbamoyl phosphate (CP) with the biosynthesis of carbamoyl phosphate (CP) with the help of HCOhelp of HCO33

- - and ATP.and ATP.

The The ReactionsReactions

of the Urea of the Urea CycleCycle

NAG:NAG:N-acetyl N-acetyl glutamate; (in the glutamate; (in the formation of urea, formation of urea, one amino group one amino group is derived from is derived from free NHfree NH44

++ ion, ion, while the other is while the other is from aspartate. from aspartate. Carbon is obtained Carbon is obtained from COfrom CO22. (*) . (*) mitochondrial mitochondrial enzymes, the restenzymes, the restof the enzymes of the enzymes are cytosolic).are cytosolic).

NAG*

*Cytosol

Mitochondria

Role of Glutamate in Urea Role of Glutamate in Urea ProductionProduction

TransaminationTransamination

GlutamateGlutamate

OxalaoacetateOxalaoacetate

AspartateAspartate

αα-Ketoacids-Ketoacids

UreaUrea

NHNH44++

Amino acidsAmino acids


αα-Ketoglutarate-Ketoglutarate


Urea Urea CycleCycle

Other reactionsOther reactions

Role of Glutamate in Amino Acid Role of Glutamate in Amino Acid SynthesisSynthesis

PLPPLP

Glutamate Glutamate

Glutamate transfers Nitrogen by means of Glutamate transfers Nitrogen by means of transamination reactions to transamination reactions to αα–ketoacids to form AAs. –ketoacids to form AAs. The nitrogen is obtained by glutamate either from The nitrogen is obtained by glutamate either from transamination of other AAs or from NHtransamination of other AAs or from NH44

++ by means by means of the of the glutamate dehydrogenaseglutamate dehydrogenase (GDH) reaction (GDH) reaction


Amino acidsAmino acids


αα-Ketoacid-Ketoacid

PLPPLP GDHGDH


PLP= Pyridoxal phosphatePLP= Pyridoxal phosphate

OxaloacetateOxaloacetate is converted to is converted to aspartateaspartate via via transamination (e.g., from glutamate). transamination (e.g., from glutamate). Aspartate then reenters Urea Cycle, carrying an Aspartate then reenters Urea Cycle, carrying an amino group derived from another amino acid.amino group derived from another amino acid.

Aspartate -Ketoglutarate Oxaloacetate Glutamate

Aminotransferase (Transaminase)

COO

CH2

CH2

C

COO

O

COO

CH2

HC

COO

NH3+

COO

CH2

CH2

HC

COO

NH3+

COO

CH2

C

COO

O + +

Regulation of the Urea CycleRegulation of the Urea Cycle

Liver has a vast capacity to convert AA nitrogen Liver has a vast capacity to convert AA nitrogen to ureato urea

,thereby preventing toxic effects from ammonia.,thereby preventing toxic effects from ammonia. Urea cycle is regulated by substrate (S) Urea cycle is regulated by substrate (S)

availability; the higher the rate of NHavailability; the higher the rate of NH33 production, the higher the rate of urea production, the higher the rate of urea formation.formation.

Regulation by the S availability is a general Regulation by the S availability is a general characteristics of disposal pathways, such as the characteristics of disposal pathways, such as the urea cycle, which remove toxic compounds from urea cycle, which remove toxic compounds from the body.the body.

This is a type of “feed-forward” regulation, in This is a type of “feed-forward” regulation, in contrast to the “feed-back” regulation contrast to the “feed-back” regulation characteristic of pathways that produce characteristic of pathways that produce functional endproducts. functional endproducts.

Regulation of the Urea Cycle…Regulation of the Urea Cycle… The other type of regulation control the urea The other type of regulation control the urea

cycle: cycle: Allosteric activationAllosteric activation of CPS-I by N- of CPS-I by N-acetylglutamate (NAG) and acetylglutamate (NAG) and induction/repressioninduction/repression of the synthesis of urea cycle enzymes.of the synthesis of urea cycle enzymes.

NAG is formed specifically to activate CPS-I; it NAG is formed specifically to activate CPS-I; it has no other known function in mammals.has no other known function in mammals.

The synthesis of NAG from acetyl CoA and The synthesis of NAG from acetyl CoA and glutamate is stimulated by arginine.glutamate is stimulated by arginine.

Thus, the arginine level increase within the liver, Thus, the arginine level increase within the liver, 2 important reactions are stimulated.2 important reactions are stimulated.

The first is the synthesis of NAG, which will The first is the synthesis of NAG, which will increase the rate at which CP is produced.increase the rate at which CP is produced.

The 2The 2ndnd is to produce more ornithine (via is to produce more ornithine (via arginase rxn), such that the cycle can operate arginase rxn), such that the cycle can operate more rapidly. more rapidly.

D. Functions of Urea Cycle During D. Functions of Urea Cycle During FastingFasting During fasting, the liver maintains blood glucose During fasting, the liver maintains blood glucose

by by gluconeogenesisgluconeogenesis by utilizing muscle protein by utilizing muscle protein AAs as a carbon source.AAs as a carbon source.

As AA carbons are converted to As AA carbons are converted to glucoseglucose, the , the nitrogens are converted to urea, thus the nitrogens are converted to urea, thus the urinary excretion of urea is high during fasting.urinary excretion of urea is high during fasting.

As fasting progresses, the brain begins to use As fasting progresses, the brain begins to use ketone bodies, sparing blood glucose.ketone bodies, sparing blood glucose.

Less muscle protein is cleaved to provide AAs for Less muscle protein is cleaved to provide AAs for gluconeogenesis,and decreased production of gluconeogenesis,and decreased production of glucose from AAs for gluconeogenesis.glucose from AAs for gluconeogenesis.

Hence, Decreased production of glucose from Hence, Decreased production of glucose from AAs is accompanied by decreased production of AAs is accompanied by decreased production of urea. urea.

D.Functions of Urea Cycle During D.Functions of Urea Cycle During Fasting…Fasting… The major AA substrate for gluconeogenesis is The major AA substrate for gluconeogenesis is

AlanineAlanine, which is synthesized in peripheral , which is synthesized in peripheral tissues to act as a nitrogen carrier.tissues to act as a nitrogen carrier.

GlucagonGlucagon release, which is expected during release, which is expected during fasting, fasting, stimulates alanine transport into the stimulates alanine transport into the liverliver by activating the transcription of transport by activating the transcription of transport systems for alanine.systems for alanine.

Two molecules of alanine are required to Two molecules of alanine are required to generate one molecule of glucose.generate one molecule of glucose.

The nitrogen from 2 molecules of alanine is The nitrogen from 2 molecules of alanine is converted to one molecule of urea.converted to one molecule of urea.

Hereditary deficiencyHereditary deficiency of any of the Urea of any of the Urea Cycle enzymes leads to Cycle enzymes leads to hyperammonemiahyperammonemia - - elevated [ammonia] in blood. elevated [ammonia] in blood.

Total lack of any Urea Cycle enzyme is lethal. Total lack of any Urea Cycle enzyme is lethal.

Elevated ammonia is toxic, especially to the Elevated ammonia is toxic, especially to the brainbrain. .

If not treated immediately after birth, If not treated immediately after birth, severe severe mental retardationmental retardation results. results.

1.1.Ornithine Transcarbamylase Deficiency (OTC) Ornithine Transcarbamylase Deficiency (OTC) 2.2.Citrullinemia. Citrullinemia. 3.3.Arginase Deficiency Arginase Deficiency 4.4.Argininosuccinic Aciduria Argininosuccinic Aciduria 5.5.Carbamyl Phosphate Synthetase (CPS-I) Deficiency Carbamyl Phosphate Synthetase (CPS-I) Deficiency 6.6.N-Acetyl Glutamate Synthetase Deficiency (NAGS)N-Acetyl Glutamate Synthetase Deficiency (NAGS)

Genetic Deficiency of Urea SynthesisGenetic Deficiency of Urea Synthesis

May be caused by,

Genetic Deficiency of Urea SynthesisGenetic Deficiency of Urea Synthesis

Carbamoyl Phosphate Carbamoyl Phosphate Synthetase-ISynthetase-I

(CPS-I) Deficiency(CPS-I) Deficiency

Ornithine Ornithine Transcarbamylase Transcarbamylase

(OTC)(OTC)

↑↑[NH[NH44++]; hyperammonemia ]; hyperammonemia ↑↑[NH[NH44

++]; ];

hyperammonemiahyperammonemia

↑↑Blood GlutamineBlood Glutamine ↑↑Blood GlutamineBlood Glutamine

BUN is decreasedBUN is decreased BUN is decreasedBUN is decreased

No increase in uracil or orotic acidNo increase in uracil or orotic acid ↑↑Uracil & orotic acid in Uracil & orotic acid in blood & urineblood & urine

Cerbral edemaCerbral edema Cerebral edemaCerebral edema

Lethargy, convulsions, coma, Lethargy, convulsions, coma, deathdeath

Lethargy, convulsions, Lethargy, convulsions, coma, deathcoma, death

Disorders present in infants:Disorders present in infants:

Symptoms:Symptoms: Lethargy, swelling of the brain leads to Lethargy, swelling of the brain leads to mental retardation / brain damage.mental retardation / brain damage.

Diagnosis:Diagnosis: Low blood urea nitrogen (BUN) levels -high Low blood urea nitrogen (BUN) levels -high levels of ammonia in the blood elevated circulating levels of ammonia in the blood elevated circulating glutamine glutamine -other metabolites that accumulate depend on the -other metabolites that accumulate depend on the specific enzyme defect.specific enzyme defect.

Most common form:Most common form: Hyperammonemia Type II caused Hyperammonemia Type II caused by Ornithine Transcarbamylase (OTC) Deficiency by Ornithine Transcarbamylase (OTC) Deficiency elevated Carbamoyl-Phosphate (CP) levels in this elevated Carbamoyl-Phosphate (CP) levels in this deficiency causedeficiency causesecondary problems in pyrimidine metabolism.secondary problems in pyrimidine metabolism.

Metabolic Diseases of the Urea Cycle

Treatment:Treatment:

Long termLong term, dietary restriction., dietary restriction.Low protein diet. Supplemented with Arginine.Low protein diet. Supplemented with Arginine.

Short termShort termDialysis.Dialysis.Administration of Nitrogen “scavengers”.Administration of Nitrogen “scavengers”.

e.g. Phenylacetate.e.g. Phenylacetate.

Treatment of Hyperammonemia with Phenylacetate:Treatment of Hyperammonemia with Phenylacetate:taking advantage of metabolismtaking advantage of metabolism

PhenylbutyratePhenylbutyrate

Glycine + Benzoic Acid Hippuric Acid

Excreted in Urine

Transaminases

Urea Cycle

Protein Degradation

Heme & Biliribin

PKU

Sulphur

Tyrosine

Purines

Pyrimidines

Anticancer Drugs

Gout

Enzyme deficiencies

Anemia Folate

+ Modulators

Alllosteric inhibitors

Allopurinol

End pdt accumulation

Cofactors required

Lead

HGPRT

Albinism

Deficiencies / Genetics

Cofactors

Nutritional Deficiencies

Signs & Symptoms

Treatment /Management.

1.1. The rate-limiting step in the urea biosynthetic pathway isThe rate-limiting step in the urea biosynthetic pathway isCatalyzed by the enzyme,Catalyzed by the enzyme,

A. A. Carbamoyl phosphate synthetase-ICarbamoyl phosphate synthetase-I (CPS-I)(CPS-I)B. Ornithine transcarbamoyl trasferase (OTC)B. Ornithine transcarbamoyl trasferase (OTC)C. Argininosuccinate synthase.C. Argininosuccinate synthase.D. Argininosuccinate lyase.D. Argininosuccinate lyase.E. Arginase.E. Arginase.

Answer:Answer: A.A. The rate-limiting step (committed step) in the urea The rate-limiting step (committed step) in the urea biosynthetic pathway is catalyzed by the enzyme carbamoyl biosynthetic pathway is catalyzed by the enzyme carbamoyl phosphate synthase-I (CPS-I).phosphate synthase-I (CPS-I).

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Which biomolecule acts as a positive modulator for the first Which biomolecule acts as a positive modulator for the first step of the urea cycle which is catalyzed by carbamoyl step of the urea cycle which is catalyzed by carbamoyl phosphate synthetase-I (CPS-I). phosphate synthetase-I (CPS-I).

A. Gultamate.A. Gultamate.B. Glutamine. B. Glutamine. C. N-Acetyl Glutamate (NAG).C. N-Acetyl Glutamate (NAG).D. Aspartate.D. Aspartate.E. Ammonium ions (NHE. Ammonium ions (NH44

++).).

Answer:Answer: CC. N-Acetyl glutamate acts as a positive modulator for . N-Acetyl glutamate acts as a positive modulator for the first step of the urea cycle which is catalyzed by CPS-I.the first step of the urea cycle which is catalyzed by CPS-I.

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2. 2. Two days after a full-term normal delivery, a neonate beginsTwo days after a full-term normal delivery, a neonate beginsto hyperventilate, develops hypothermia and cerebral edema, to hyperventilate, develops hypothermia and cerebral edema, and becomes comatose. Urinalysis reveals high levels of and becomes comatose. Urinalysis reveals high levels of glutamineglutamine and and orotic acidorotic acid. The BUN is below normal. Which. The BUN is below normal. Whichenzyme is most likely to be deficient in this child?.enzyme is most likely to be deficient in this child?.

A.A. Cytoplasmic glutaminase.Cytoplasmic glutaminase.B.B. Cytoplasmic carbamoyl phosphate synthetase.Cytoplasmic carbamoyl phosphate synthetase.C.C. Cytoplasmic orotidylate decarboxylase.Cytoplasmic orotidylate decarboxylase.D.D. Mitochondrial carbamoyl phosphate synthetase.Mitochondrial carbamoyl phosphate synthetase.E.E. Mitochondrial ornitihine transcarbamoylase.Mitochondrial ornitihine transcarbamoylase.

Answer: E.Answer: E. Given these symptoms, the defect in the urea cycle Given these symptoms, the defect in the urea cycle and the elevated orotate suggests deficiency of ornithineand the elevated orotate suggests deficiency of ornithinetranscarbamoylase (OTC). transcarbamoylase (OTC).

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19.2. Which one of the following statements about the urea cycle is correct?

A. The two nitrogen atoms that are incorporated into urea enter the cycle as ammonia and alanine.

B. Urea is produced directly by the hydrolysis of ornithine. C.ATP is required for the reaction in which argininosuccinate is

cleaved to form arginine. D.Urinary urea is increased by a diet rich in protein. E. The urea cycle occurs exclusively in the cytosol.

Correct answer = D. The amino nitrogen of dietary protein is excreted as urea. The two nitrogens enter the urea cycle as ammonia and aspartate. Urea is produced by the hydrolysis of arginine. The cleavage of argininosuccinate does not require ATP. The urea cycle occurs partly in the mitochondria.

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Transamination reactions are essential for ammonia assimilation.Transamination reactions are essential for ammonia assimilation.What cofactor is required to catalyze transamination reactions?What cofactor is required to catalyze transamination reactions?

A.A. pyridoxal phosphate (PLP)pyridoxal phosphate (PLP)B.B. thiamin pyrophosphatethiamin pyrophosphateC.C. biotinbiotinD.D. NADNAD++

E.E. NADPHNADPH

Ans: A.Ans: A.

Which of the following enzymes function in the biological Which of the following enzymes function in the biological assimilation of ammonia?.assimilation of ammonia?.

A.A. glutamate dehydrogenase.glutamate dehydrogenase.B.B. glutamine synthetase.glutamine synthetase.C.C. glutamate synthase.glutamate synthase.D.D. all of the above.all of the above.

Ans: D.Ans: D.

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Which of the following protein modifications target a protein for Which of the following protein modifications target a protein for degradation?.degradation?.

A.A. Phosphorylation.Phosphorylation.B.B. Ubiquitination.Ubiquitination.C.C. Zymogen activation.Zymogen activation.D.D. Subunit aggregation.Subunit aggregation.E.E. All of the above.All of the above.

Ans: B.Ans: B.

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Specific amino acids associated with the ______ of Specific amino acids associated with the ______ of a protein a protein

determine its half life.determine its half life.

A.A. C-terminal.C-terminal.B.B. N-terminal.N-terminal.C.C. All of the above.All of the above.

Ans: B.Ans: B. (N-terminal / amino terminal). (N-terminal / amino terminal).

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Ubiquitin is covalently attached to a protein through Ubiquitin is covalently attached to a protein through an amide linkage to which specific amino acid?.an amide linkage to which specific amino acid?.

A.A. Aspartate.Aspartate.B.B. Glutamate.Glutamate.C.C. Lysine.Lysine.D.D. Arginine.Arginine.E.E. Histidine.Histidine.

Ans: C.Ans: C.

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What part of the 26S proteosome complex recognizes an What part of the 26S proteosome complex recognizes an ubiquitinated protein?.ubiquitinated protein?.

A.A. 20S proteosome core.20S proteosome core.B.B. 19S cap.19S cap.C.C. E3 subunit.E3 subunit.D.D. E2 subunit.E2 subunit.E.E. All of the above.All of the above.

Ans: B.Ans: B.

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In a patient with cystic fibrosis, the mutant cytosolic In a patient with cystic fibrosis, the mutant cytosolic transmembrane conductance regulator (CFTR) protein folds transmembrane conductance regulator (CFTR) protein folds incorrectly. The patients cells modify this abnormal proteins by incorrectly. The patients cells modify this abnormal proteins by attaching ubiquitin molecules to it. What is the fate of this modifiedattaching ubiquitin molecules to it. What is the fate of this modifiedCFTR protein?.CFTR protein?.

A.A. It performs its normal function, as the ubiquitin largely correctsIt performs its normal function, as the ubiquitin largely corrects for the effect of the mutation.for the effect of the mutation.B. It is secreted from the cell.B. It is secreted from the cell.C. It is placed into storage vesicles.C. It is placed into storage vesicles.D. It is degraded by the proteasome.D. It is degraded by the proteasome.E. It is repaired by cellular enzymes.E. It is repaired by cellular enzymes.

Ans: D.Ans: D. Ubiquitination usually marks old, damaged, or misfolded Ubiquitination usually marks old, damaged, or misfolded proteins for destruction by proteasome. There is no known cellular proteins for destruction by proteasome. There is no known cellular mechanism for repair of damaged proteins.mechanism for repair of damaged proteins.

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A young boy has cystic fibrosis, which is due to a mutation A young boy has cystic fibrosis, which is due to a mutation resulting in misfolded protein. The protein is degraded very quickly resulting in misfolded protein. The protein is degraded very quickly inside the cell. This protein degradation is most probably inside the cell. This protein degradation is most probably undertaken by:undertaken by:

A. lipoic acid.A. lipoic acid.B. acetyl CoA.B. acetyl CoA.C. C. ubiquitin. ubiquitin. E. linoleoic acid.E. linoleoic acid.E. linolenic acid. E. linolenic acid.

Ans: C.Ans: C.

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After proteins are synthesized, their lifespan is regulated by After proteins are synthesized, their lifespan is regulated by proteolytic degradation. Some proteins are degraded by proteolytic degradation. Some proteins are degraded by lysosomal enzymes. The process of _________ allows lysosomal enzymes. The process of _________ allows subcellular material, including organelles, to be enclosed by a subcellular material, including organelles, to be enclosed by a membrane and subjected to lysosomal action. membrane and subjected to lysosomal action.

A.A. autophagy.autophagy.B.B. phylogeny.phylogeny.C.C. phagocytosis.phagocytosis.D.D. pinocytosis.pinocytosis.E.E. exocytosis.exocytosis.

Ans: C.Ans: C.

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What part of the 26S proteosome complex contains the What part of the 26S proteosome complex contains the protease function?.protease function?.

A.A. 26S proteosome core.26S proteosome core.B.B. 19S cap.19S cap.C.C. E3 subunit.E3 subunit.D.D. E2 subunit.E2 subunit.E.E. All of the above.All of the above.

Ans: A.Ans: A.

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What is the fate of excess amino acids in animals and humans?.What is the fate of excess amino acids in animals and humans?.

A.A. they are recycled for the synthesis of new proteins.they are recycled for the synthesis of new proteins.B.B. they are stored for future use.they are stored for future use.C.C. they are catabolized to free ammonia and carbon skeletons.they are catabolized to free ammonia and carbon skeletons. D.D. a and b.a and b.E.E. a and c.a and c.

Ans: C.Ans: C.

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Fish dispose of toxic ammonia by ___________.Fish dispose of toxic ammonia by ___________.

A.A. converting it to uric acid, which is subsequently secreted.converting it to uric acid, which is subsequently secreted.B.B. converting it to urea, which is subsequently secreted.converting it to urea, which is subsequently secreted.C.C. releasing it directly to the environment.releasing it directly to the environment.D.D. all of the above.all of the above.E.E. none of the above.none of the above.

Ans: C.Ans: C.

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The enzyme of the urea cycle are localized within __________.The enzyme of the urea cycle are localized within __________.

A.A. the mitochondria..the mitochondria..B.B. the cytosol.the cytosol.C.C. the chloroplast.the chloroplast.D.D. a and b.a and b.E.E. all of the above.all of the above.

Ans: D.Ans: D.

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Which amino acid participates as a pathway intermediate in the Which amino acid participates as a pathway intermediate in the urea cycle?.urea cycle?.

A.A. Lysine.Lysine.B.B. Arginine.Arginine.C.C. Glutamine.Glutamine.D.D. Histidine.Histidine.E.E. Tyrosine.Tyrosine.

Ans: B.Ans: B.

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In humans, the urea cycle functions primarily in the ___________.In humans, the urea cycle functions primarily in the ___________.

A.A. muscle tissue.muscle tissue.B.B. heart.heart.C.C. brain.brain.D.D. liver.liver.E.E. adipose tissue.adipose tissue.

Ans: D.Ans: D.

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Muscle tissue gets rid of toxic ammonia _________________.Muscle tissue gets rid of toxic ammonia _________________.

A.A. by running the urea cycle in its cells.by running the urea cycle in its cells.B.B. through the glucose / alanine cycle.through the glucose / alanine cycle.C.C. through the Cori cycle.through the Cori cycle.D.D. through the Bohr Effect.through the Bohr Effect.E.E. none of the above.none of the above.

Ans: B.Ans: B.

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A patient presents with Hemolytic Anemia. Which of the followingA patient presents with Hemolytic Anemia. Which of the followingshould be elevated in the BLOOD?.should be elevated in the BLOOD?. A.A. Bilirubin Bilirubin B.B. Ammonia Ammonia C.C. UreaUreaD.D. MitochondriaMitochondriaE.E. RiboseRibose

Ans: A.Ans: A.

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Your patient is a 60-year-old male who has a long history ofYour patient is a 60-year-old male who has a long history ofalcohol abuse. He is confused, has an enlarged liver, and a alcohol abuse. He is confused, has an enlarged liver, and a flapping tremor at the wrist (asterixis). Your diagnosis is hepatic flapping tremor at the wrist (asterixis). Your diagnosis is hepatic encephalopathy. A treatment is a diet of branched-chain amino encephalopathy. A treatment is a diet of branched-chain amino acids. Which one of the following sets of amino acids is acids. Which one of the following sets of amino acids is composed of branched-chain amino acids?.composed of branched-chain amino acids?.

A. Methionine, proline, and cysteine.A. Methionine, proline, and cysteine.B. Glycine, alanine, and serine.B. Glycine, alanine, and serine.C. Valine, leucine, isoleucine.C. Valine, leucine, isoleucine.D. D. Aspartate, glutamate, and asparagine.Aspartate, glutamate, and asparagine.E.E. Tryptophan, phenylalanine, and tyrosine.Tryptophan, phenylalanine, and tyrosine.

Ans: C. Ans: C. Only valine, leucine, and isoleucine compose the only Only valine, leucine, and isoleucine compose the only set of branched-chain amino acids.set of branched-chain amino acids.

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3. A 49-year-old man with a rare recessive condition is at high3. A 49-year-old man with a rare recessive condition is at highrisk deep vein thrombosis and stroke and has had replacementrisk deep vein thrombosis and stroke and has had replacementof ectopic lenses. He has a normal hematocrit and no of ectopic lenses. He has a normal hematocrit and no evidence of megaloblastic anemia.evidence of megaloblastic anemia.

A mutation in the gene encoding which of the following is A mutation in the gene encoding which of the following is Most likely to cause this disease?. Most likely to cause this disease?.

A.A. Cystathionine synthase.Cystathionine synthase.B.B. Homocysteine methyltransferase. XXXHomocysteine methyltransferase. XXXC.C. Fibrillin.Fibrillin.D.D. Lysyl oxidase.Lysyl oxidase.E.E. Branched chain α-ketoacid dehydrogenase.Branched chain α-ketoacid dehydrogenase.

Answer: A.Answer: A. Homocysteine, the substrate for enzyme, accumulates Homocysteine, the substrate for enzyme, accumulates Increasing the risk of deep thrombosis and disrupting the normal Increasing the risk of deep thrombosis and disrupting the normal crosslinking of fibrillin. Deficiency of homocysteine crosslinking of fibrillin. Deficiency of homocysteine methyltransferase would cause homocysteineuria, but would alsomethyltransferase would cause homocysteineuria, but would alsopredispose to megaloblastic anemia.predispose to megaloblastic anemia.

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Have a Have a BreakBreak

5. A-56-year-old man with a history of genetic disease undergoes 5. A-56-year-old man with a history of genetic disease undergoes hip replacement surgery for arthritis. During the operation the hip replacement surgery for arthritis. During the operation the surgeon notes a dark pigmentation (ochronosis) in the man’s surgeon notes a dark pigmentation (ochronosis) in the man’s cartilage. His ochronotic arthritis is most likely caused by oxidationcartilage. His ochronotic arthritis is most likely caused by oxidationand polymerization of excess tissueand polymerization of excess tissue

A.A. Homogentisic acid.Homogentisic acid.B.B. Orotic acid.Orotic acid.C.C. Methylmalonic acid.Methylmalonic acid.D.D. Uric acid.Uric acid.E.E. Ascorbic acid.Ascorbic acid.

Answer: A.Answer: A. Adults with alkaptonuria show a high prevalence of Adults with alkaptonuria show a high prevalence of ochronotic arthritis due to deficiency of homogentisate oxidase.ochronotic arthritis due to deficiency of homogentisate oxidase.

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6. A woman 7 months pregnant with her first child develops anemia.6. A woman 7 months pregnant with her first child develops anemia.laboratory evaluation indicates an increased mean cell volume laboratory evaluation indicates an increased mean cell volume (MCV), hypersegmented neutrophils, and altered morphology of(MCV), hypersegmented neutrophils, and altered morphology ofseveral other cell types. The most likely underlying cause of this several other cell types. The most likely underlying cause of this woman’s anemia is, woman’s anemia is,

A.A. Folate deficiency.Folate deficiency.B.B. Iron deficiency.Iron deficiency.C.C. Glucose-6-phosphate dehydrogenase deficiency.Glucose-6-phosphate dehydrogenase deficiency.D.D. Cyanocabalamin (vitamin BCyanocabalamin (vitamin B1212) deficiency.) deficiency.

E.E. Lead poisoning.Lead poisoning.

Answer: A.Answer: A. Pregnant woman with megaloblastic anemia and Pregnant woman with megaloblastic anemia and elevated serum homocysteine strongly suggest folate deficiency.elevated serum homocysteine strongly suggest folate deficiency.iron deficiency presents as microcytic, hypochromic anemia and iron deficiency presents as microcytic, hypochromic anemia and would not elevate homocysteine. Bwould not elevate homocysteine. B1212 deficiency is not most deficiency is not most

In this presentation. In this presentation. ?

7. A 62-year-old man being treated for tuberculosis develops a 7. A 62-year-old man being treated for tuberculosis develops a microcytic, hypochromic anemia. Ferritin levels are increased, andmicrocytic, hypochromic anemia. Ferritin levels are increased, andmarked sideroblastosis is present. A decrease in which of the marked sideroblastosis is present. A decrease in which of the following enzyme activities is most directly responsible for the following enzyme activities is most directly responsible for the Anemia in this man?.Anemia in this man?.

A.A. Cytochrome oxidase.Cytochrome oxidase.B.B. Cytochrome PCytochrome P450450 oxidase. oxidase.

C.C. Pyruvate kinase.Pyruvate kinase.D.D. δ-aminolevulinate synthase.δ-aminolevulinate synthase.E.E. Lysyl oxidase.Lysyl oxidase.

Answer: D.Answer: D. Sideroblastic anemia in a person being treated for Sideroblastic anemia in a person being treated forTuberculosis (with Tuberculosis (with isoniazidisoniazid) is most likely due to vitamin B) is most likely due to vitamin B66

deficiency. δdeficiency. δ-Aminolevulinate synthase, the first enzyme in hemeAminolevulinate synthase, the first enzyme in hemesynthesis, requires vitamin Bsynthesis, requires vitamin B66 (pyridoxine). (pyridoxine).

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2. Patients with Lesch-Nyhan syndrome have hyperuricemia, 2. Patients with Lesch-Nyhan syndrome have hyperuricemia, indicating an increased biosynthesis of purine nucleotides, and indicating an increased biosynthesis of purine nucleotides, and markedly decreased levels of hypoxanthine phosphoribosyl markedly decreased levels of hypoxanthine phosphoribosyl transferase (HPRT). The hyperuricemia can be explained on the transferase (HPRT). The hyperuricemia can be explained on the basis of a decrease in which regulator of purine biosynthesis?.basis of a decrease in which regulator of purine biosynthesis?.

A.A. ATP.ATP.B.B. GDP.GDP.C.C. Glutamine.Glutamine.D.D. IMP.IMP.E.E. PRPP.PRPP.

Answer: D.Answer: D. IMP is a feedback inhibitor of PRPP amidophospho- IMP is a feedback inhibitor of PRPP amidophospho--ribosyl transferase, the first reaction in the biosynthesis of purines.-ribosyl transferase, the first reaction in the biosynthesis of purines.IMP is formed by the HPRT reaction in the salvage of hypoxanthine.IMP is formed by the HPRT reaction in the salvage of hypoxanthine.

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3. A 12-week-old infant with a history of 3. A 12-week-old infant with a history of persistent diarrheapersistent diarrhea and and CandidiasisCandidiasis is seen for a respiratory tract infection with is seen for a respiratory tract infection with Pneumocystis cariniiPneumocystis carinii. A chest X-ray confirms . A chest X-ray confirms pneumoniapneumonia and and reveals absence of a thymic shadow. The IgG is present in his reveals absence of a thymic shadow. The IgG is present in his serum, but IgA and IgM are absent. His RBCs completely lack anserum, but IgA and IgM are absent. His RBCs completely lack anessential enzymeessential enzyme in purine degradation. The product normally in purine degradation. The product normally formed by this enzyme is, formed by this enzyme is,

A.A. Guanine monophosphate.Guanine monophosphate.B.B. Hypoxanthine.Hypoxanthine.C.C. Inosine.Inosine.D.D. Xanthine.Xanthine.E.E. Xanthine monophosphate.Xanthine monophosphate.

Answer: C.Answer: C. The child most likely has severe combined immuno- The child most likely has severe combined immuno--deficiencye caused by -deficiencye caused by adenosine deaminase (ADA) deficiencyadenosine deaminase (ADA) deficiency. . This enzyme deaminates adenosine) a nucleotide) to form inosine This enzyme deaminates adenosine) a nucleotide) to form inosine (another nucleoside). Hypoxanthine and xanthine are both purine (another nucleoside). Hypoxanthine and xanthine are both purine Bases, and the monophosphates are nucleotides..Bases, and the monophosphates are nucleotides..

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1.1. In the synthesis of cysteine, the carbon atoms (nearest In the synthesis of cysteine, the carbon atoms (nearest precursor) are provided by which of the following?. precursor) are provided by which of the following?.

A.A. Aspartic acid.Aspartic acid.B.B. Methionine.Methionine.C.C. Oxaloacetic acid.Oxaloacetic acid.D.D. Serine.Serine.E.E. Homocysteine.Homocysteine.

Answer: D.Answer: D. This question refers to the precursor of the carbon This question refers to the precursor of the carbonatoms of cysteine that are provided by serine. Homocystene, a atoms of cysteine that are provided by serine. Homocystene, a direct precursor, only supplies sulfur. These two molecules formdirect precursor, only supplies sulfur. These two molecules formcystathionine. Methionine is the precursor to homocysteine. cystathionine. Methionine is the precursor to homocysteine. Aspartate and oxaloacetate are involved in transamination and doAspartate and oxaloacetate are involved in transamination and donot directly affect cysteine synthesis.not directly affect cysteine synthesis.

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3. Which of the following is the correct enzyme-genetic defect 3. Which of the following is the correct enzyme-genetic defect disease pair?.disease pair?.

A.A. Argininosuccinate synthetase-Citrullinemia.Argininosuccinate synthetase-Citrullinemia.B.B. Arginase- Argininosuccinate aciduria.Arginase- Argininosuccinate aciduria.C.C. Ornithine transcarbomylase-Congenital hyperammonemia type-IOrnithine transcarbomylase-Congenital hyperammonemia type-ID.D. Argininosuccinate lyase-Arginemia.Argininosuccinate lyase-Arginemia.E.E. Carbamoyl phosphate synthetase-Congental hyperammonemiaCarbamoyl phosphate synthetase-Congental hyperammonemia type-II.type-II.

Answer: A.Answer: A. Defective argininosuccinate synthetase yields Defective argininosuccinate synthetase yields citrullinemia. Defective arginase yields mild hyperammonemia.citrullinemia. Defective arginase yields mild hyperammonemia.ornithine transcarbamoylase and carbamoyl phosphate synthetaseornithine transcarbamoylase and carbamoyl phosphate synthetaseyield congenital hyperammonemia type II and I, respectively.yield congenital hyperammonemia type II and I, respectively.Defective argininosuccinate lyase yields hyperammonemia. Defective argininosuccinate lyase yields hyperammonemia.

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4. Which of the following is a common compound shared by 4. Which of the following is a common compound shared by The TCA cycle and the urea cycle?.The TCA cycle and the urea cycle?.

A.A. α-ketoglutarate.α-ketoglutarate.B.B. Succcinyl Coenzyme A (CoA).Succcinyl Coenzyme A (CoA).C.C. Oxaloacetate.Oxaloacetate.D.D. Fumarate.Fumarate.E.E. Arginine.Arginine.

Answer: D.Answer: D. Fumarate is in both the urea and TCA cycles. Fumarate is in both the urea and TCA cycles. α-ketoglutarate, succinyl CoA, and oxaloacetate (OAA) are only inα-ketoglutarate, succinyl CoA, and oxaloacetate (OAA) are only inthe TCA cycle. Arginine is only in the urea cycle.the TCA cycle. Arginine is only in the urea cycle.

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5. Which of the following enzymes requires adenosine 5. Which of the following enzymes requires adenosine Triphosphate (ATP) to mediate its reactions?.Triphosphate (ATP) to mediate its reactions?.

A.A. Argininosuccinate lyase.Argininosuccinate lyase.B.B. Argininosuccinate synthetase.Argininosuccinate synthetase.C.C. Arginase.Arginase.D.D. Glutaminase.Glutaminase.E.E. Ornitine transcarbamoylase.Ornitine transcarbamoylase.

Answer: B.Answer: B. Argininosuccinate synthetase requires ATP. All of the Argininosuccinate synthetase requires ATP. All of theother enzymes listed do not require energy and are exergonic other enzymes listed do not require energy and are exergonic reactions; remember, ∆G is negative.reactions; remember, ∆G is negative.

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6. Which of the following is the common nitrogen acceptor 6. Which of the following is the common nitrogen acceptor for for

all reactions involving transaminase?. all reactions involving transaminase?.

A.A. α-ketoglutarate.α-ketoglutarate.B.B. α-ketobutyrate.α-ketobutyrate.C.C. Pyruvate.Pyruvate.D.D. Oxaloacetate.Oxaloacetate.E.E. Acetoacetate.Acetoacetate.

Answer: A.Answer: A. All transaminases have All transaminases have α-ketoglutarate as the α-ketoglutarate as the common nitrogen acceptorcommon nitrogen acceptor. Serine is deaminated to pyruvate, and. Serine is deaminated to pyruvate, and threonine is deaminated to α-ketobutyrate. Other amino acids arethreonine is deaminated to α-ketobutyrate. Other amino acids areconverted to acetoacetate.converted to acetoacetate.

#124. Slide 124?

11. A 55-year-old man suffers from cirrhosis of the liver. Toxins 11. A 55-year-old man suffers from cirrhosis of the liver. Toxins such as ammonia are not properly metabolized by the liver and cansuch as ammonia are not properly metabolized by the liver and cannow damage structures such as the brain. Which of the followingnow damage structures such as the brain. Which of the followingamino acids covalently binds ammonia and transports and storesamino acids covalently binds ammonia and transports and storesIt in a nontoxic form?.It in a nontoxic form?. A.A. Aspartate.Aspartate.B.B. Glutamate.Glutamate.C.C. Serine.Serine.D.D. Cysteine.Cysteine.E.E. Histidine.Histidine.

Answer: B.Answer: B. Glutamate and ammonia from glutamine, as catalyzed Glutamate and ammonia from glutamine, as catalyzed by glutamine synthetase at the cost of 1 ATP. Cysteine is not by glutamine synthetase at the cost of 1 ATP. Cysteine is not directly involved with ammonia. Aspartate and ammonia both directly involved with ammonia. Aspartate and ammonia both donate a nitogen to form urea (along with ammonia). Histidine anddonate a nitogen to form urea (along with ammonia). Histidine andserine are deaminated, forming ammonia. Central nervous systemserine are deaminated, forming ammonia. Central nervous systemdysfunction due to high ammonia-level hepatic encephalopathy dysfunction due to high ammonia-level hepatic encephalopathy results in a sequelae of symptoms such as asterixis, confusion andresults in a sequelae of symptoms such as asterixis, confusion andcoma.coma.

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14. A 2-year-old girl was seen in the emergency room for vomiting14. A 2-year-old girl was seen in the emergency room for vomitingand tremors. The elevated and tremors. The elevated plasma ammonium ion concentrationplasma ammonium ion concentration was 195 µM (normal, 11-50 µM). Metabolic screens of serum and was 195 µM (normal, 11-50 µM). Metabolic screens of serum and urine were ordered and were urine were ordered and were remarkable for an elevation in the remarkable for an elevation in the amino acid arginine in serumamino acid arginine in serum. You conclude that this patient may . You conclude that this patient may have a defect in the following enzymes?.have a defect in the following enzymes?.

A.A. Carbamoyl phosphate synthetase I.Carbamoyl phosphate synthetase I.B.B. Carbamoyl phosphate synthase II.Carbamoyl phosphate synthase II.C.C. Ornitine transcarbamoylase.Ornitine transcarbamoylase.D.D. Arginase.Arginase.E.E. Argininosuccinate lyase.Argininosuccinate lyase.

Answer: D.Answer: D. This is another case of hyperammonemia. The This is another case of hyperammonemia. The presence of elevated arginine indicates that the block is the presence of elevated arginine indicates that the block is the conversion to the next step. Arginase converts arginine to conversion to the next step. Arginase converts arginine to ornithine. Argininosuccinate lyase is the step to synthesize to ornithine. Argininosuccinate lyase is the step to synthesize to arginine. Ornithine transcarbamoylase converts ornithine to arginine. Ornithine transcarbamoylase converts ornithine to citrulline, and the carbamoyl phosphate synthetases are involvedcitrulline, and the carbamoyl phosphate synthetases are involvedin the beginning of the urea cycle.in the beginning of the urea cycle.

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20.2 Which one of the following statements concerning a one-week-old 20.2 Which one of the following statements concerning a one-week-old male infant with undetected classic phenylketonuria is correct?male infant with undetected classic phenylketonuria is correct?

A. Tyrosine is a nonessential amino acid for the infant.A. Tyrosine is a nonessential amino acid for the infant.B. High levels of phenylpyruvate appear in his urine. B. High levels of phenylpyruvate appear in his urine. C. Therapy must begin within the first year of life. C. Therapy must begin within the first year of life. D. A diet devoid of phenylalanine should be initiated immediately.D. A diet devoid of phenylalanine should be initiated immediately.E. When the infant reaches adulthood, it is recommended that diet therapy be E. When the infant reaches adulthood, it is recommended that diet therapy be discontinued.discontinued.

Correct answer = B.Correct answer = B. Phenyllactate, phenylacetate, and phenylpyruvate, which Phenyllactate, phenylacetate, and phenylpyruvate, which are not nor mally produced in significant amounts in the presence of functional are not nor mally produced in significant amounts in the presence of functional phenylalanine hydroxylase, are elevated in PKU, and appear in the urine. In phenylalanine hydroxylase, are elevated in PKU, and appear in the urine. In patients with PKU, tyrosine cannot be synthesized from phenylalanine and, patients with PKU, tyrosine cannot be synthesized from phenylalanine and, hence, becomes essential and must be supplied in the diet. Treatment must hence, becomes essential and must be supplied in the diet. Treatment must begin during the first seven to ten days of life to prevent mental retardation. begin during the first seven to ten days of life to prevent mental retardation. Discontinuance of the phenylalanine-restricted diet before eight years of age is Discontinuance of the phenylalanine-restricted diet before eight years of age is associated with poor performance on IQ tests. Adult PKU patients show associated with poor performance on IQ tests. Adult PKU patients show deterioration of attention and speed of mental processing after discontinuation deterioration of attention and speed of mental processing after discontinuation of the diet. Life-long restriction of dietary pheny lalanine is, therefore, of the diet. Life-long restriction of dietary pheny lalanine is, therefore, recommended.recommended.

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20.3 A four-year-old boy of a first-degree consanguineous couple was 20.3 A four-year-old boy of a first-degree consanguineous couple was noted by the parents to have darkening of the urine to an almost black noted by the parents to have darkening of the urine to an almost black color when it was left standing. He had a normal sibling, and there were color when it was left standing. He had a normal sibling, and there were no other medical problems. Childhood growth and development were no other medical problems. Childhood growth and development were normal. Which of the following is most likely to elevated in this patient?normal. Which of the following is most likely to elevated in this patient?

A.A. Methylmalonate Methylmalonate B.B. Homogentisate Homogentisate C.C. Phenylpyruvate Phenylpyruvate D.D. αα-Ketoisovalerate -Ketoisovalerate E.E. HomocystineHomocystine

Correct answer = B.Correct answer = B. Alkaptonuria is a rare metabolic disease involving Alkaptonuria is a rare metabolic disease involving a deficiency in homogentisic acid oxidase, and the subsequent a deficiency in homogentisic acid oxidase, and the subsequent accumulation of homogentisic acid in the urine, which turns dark upon accumulation of homogentisic acid in the urine, which turns dark upon standing. The elevation of methylmalonate (due to methylmalonyl CoA standing. The elevation of methylmalonate (due to methylmalonyl CoA mutase deficiency), phenylpyruvate (due to phenylalanine hydroxlyase mutase deficiency), phenylpyruvate (due to phenylalanine hydroxlyase deficiency), deficiency), αα-ketoisovalerate (due to branched-chain -ketoisovalerate (due to branched-chain αα-ketoacid -ketoacid dehydrogenase deficiency), and homocystine (due to cystathionine dehydrogenase deficiency), and homocystine (due to cystathionine synthase deficiency) are inconsistent with a healthy child with darkening synthase deficiency) are inconsistent with a healthy child with darkening of the urine.of the urine.

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15. A new test is developed that can non-radioactively “label” 15. A new test is developed that can non-radioactively “label” compounds in the human body. As a physician with a back-ground compounds in the human body. As a physician with a back-ground In the new field of metabolomics, you assess a 21-year-old withIn the new field of metabolomics, you assess a 21-year-old withclassical classical phenylketonuria (PKU).phenylketonuria (PKU). Phenylalanine is fed with a label Phenylalanine is fed with a labelin the phenyl ring. in the phenyl ring. In the urineIn the urine, in which of the following compounds, in which of the following compoundswould you expect to find the would you expect to find the greatest amount of label?greatest amount of label?..

A.A. Tyrosine.Tyrosine.B.B. Tryptophan.Tryptophan.C.C. Epinephrine.Epinephrine.D.D. Phenylketone.Phenylketone.E.E. Acetate.Acetate.

Answer: D.Answer: D. Phenylketonutria (PKU) is a defect in phenylalanine Phenylketonutria (PKU) is a defect in phenylalanine hydroxylase, resulting in a block in the conversion of phenylalaninehydroxylase, resulting in a block in the conversion of phenylalanineto tyrosine. to tyrosine. PhenylalaninePhenylalanine accumulates in in both disorders and to accumulates in in both disorders and toconverted to converted to phenylketonesphenylketones. Tyrosine is the product whose. Tyrosine is the product whoseformation is blocked, and epinephrine, a product of tyrosine, wouldformation is blocked, and epinephrine, a product of tyrosine, wouldnot be made or “labelled’. Acetate and tryptophan are very far not be made or “labelled’. Acetate and tryptophan are very far downstream from tyrosine. downstream from tyrosine.

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1.1. The biosynthetic pathway involves both BH4 and a The biosynthetic pathway involves both BH4 and a pyridoxal phosphate (PLP)-pyridoxal phosphate (PLP)-dependent decarboxylation dependent decarboxylation reaction to form which of the following?. reaction to form which of the following?.

A.A. Histamine.Histamine.B.B. .aminobutyric acid (GABA).-aminobutyric acid (GABA)-الالC.C. Creatine.Creatine.D.D. Epinephrine.Epinephrine.E.E. Carnitine.Carnitine.

Answer: D.Answer: D. Epinephrine synthesis requires both BH4 and a Epinephrine synthesis requires both BH4 and a pyridoxal phosphate (PLP)-dependent decaroxylation from pyridoxal phosphate (PLP)-dependent decaroxylation from Phenylalanine→ Tyrosine→DOPA→Dopamine→Epinephrine. BothPhenylalanine→ Tyrosine→DOPA→Dopamine→Epinephrine. BothHistidine→Histamine and Glutamate→Histidine→Histamine and Glutamate→الال-Aminobutyric acid (GABA) -Aminobutyric acid (GABA) require pyridoxal phosphate (PLP) for decarboxylation (but notrequire pyridoxal phosphate (PLP) for decarboxylation (but notBHBH44). Creatine is produced from glycine, arginine and S-adenosyl ). Creatine is produced from glycine, arginine and S-adenosyl

methionine (SAM).methionine (SAM).

3. Which of the following is a compound formed from both a 3. Which of the following is a compound formed from both a Hydroxylation with an enzyme requiring vitamin C and Hydroxylation with an enzyme requiring vitamin C and subsequent methylation?.subsequent methylation?.

A.A. Histamine.Histamine.B.B. Epinephrine.Epinephrine.C.C. GABA.GABA.D.D. Carnitine.Carnitine.E.E. Creainine.Creainine.

Answer: B.Answer: B. Epinephrine forms when dopamine is hydroxylated by Epinephrine forms when dopamine is hydroxylated by an enzyme that requires copper and vitamin C, to form an enzyme that requires copper and vitamin C, to form norepinephrine, which subsequently methylated. Histamine is norepinephrine, which subsequently methylated. Histamine is derived by decarboxylation of histidine. GABA is decarboxylatedderived by decarboxylation of histidine. GABA is decarboxylatedglutamate. Creatinine is formed by a SAM methylation, and glutamate. Creatinine is formed by a SAM methylation, and carnitine is an acyl group acceptor.carnitine is an acyl group acceptor.

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Excessive degradation of AMP and GMP would result in Excessive degradation of AMP and GMP would result in Increased urinary excretion of, ___________.Increased urinary excretion of, ___________.

A. creatineA. creatineB. ureaB. ureaC. uric AcidC. uric AcidD. thiamineD. thiamineE. thymineE. thymine

Answer:Answer: C.C. The purine bases, adenine (A) and guaninie (G), are The purine bases, adenine (A) and guaninie (G), are oxidized to oxidized to uric aciduric acid, which is excreted in the urine. Excessive , which is excreted in the urine. Excessive Production of uric acid can result in the condition known as Production of uric acid can result in the condition known as goutgout..

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Which of the following statement about heme and iron Which of the following statement about heme and iron metabolism is correct?.metabolism is correct?.

A. Iron is strored in the liver as transferrin.A. Iron is strored in the liver as transferrin.B. Iron (as FeB. Iron (as Fe2+2+) is inserted into protoporpyrin IX in the last step.) is inserted into protoporpyrin IX in the last step. of heme synthesisof heme synthesisC. C. δδ-ALA synthase catalyzes the regulated and rate-limiting -ALA synthase catalyzes the regulated and rate-limiting step in heme biosynthesis.step in heme biosynthesis.D. The major route for bilirubin excretion is via the urine.D. The major route for bilirubin excretion is via the urine.E. The iron produced by heme degradation is excreted in the feces.E. The iron produced by heme degradation is excreted in the feces.

Answer:Answer: C.C. The first rate-limiting step in heme biosynthesis The first rate-limiting step in heme biosynthesisInvolves the condensation of glycine and succinyl CoA to form Involves the condensation of glycine and succinyl CoA to form Delta-ALA. Iron is stored as ferritin & transported in the bloodDelta-ALA. Iron is stored as ferritin & transported in the bloodin transferrin. As Fein transferrin. As Fe2+2+, it is inserted into protoporpyrin IX to form, it is inserted into protoporpyrin IX to formheme. When heme is degraded to form bilirubin (which is excretedheme. When heme is degraded to form bilirubin (which is excretedMainly via the intestine), iron is returned to the body’s iron stores Mainly via the intestine), iron is returned to the body’s iron stores and is not excreted. Bleeding is the only significant means by and is not excreted. Bleeding is the only significant means by Which Iron is lost from the body.Which Iron is lost from the body.

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The component that would be elevated to the greatest extentThe component that would be elevated to the greatest extentin the blood of a person suffering from Gout is _________.in the blood of a person suffering from Gout is _________.

A. bilirubin.A. bilirubin.B. uric acid.B. uric acid. C. creatine kinase.C. creatine kinase.D. blood urea nitrogen (BUN).D. blood urea nitrogen (BUN).

Answer:Answer: B. B.

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The genetic defect in the hypoxanthine guanine The genetic defect in the hypoxanthine guanine phosphoribosyl transferse (HGPRT) will leads to,phosphoribosyl transferse (HGPRT) will leads to,

A.A. Parkinson’s disease.Parkinson’s disease.B.B. Cystinuria.Cystinuria.C.C. Pellagra.Pellagra.D.D. Lesch-Nyhan syndrome.Lesch-Nyhan syndrome.E.E. Hartnup’s disease.Hartnup’s disease.

Answer: D.Answer: D. The defect in the purine salvage enzyme HGPRT The defect in the purine salvage enzyme HGPRTcauses Lesch-Nyhan syndrome.causes Lesch-Nyhan syndrome.

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NoNo DisorderDisorder Answer Answer Enzyme DefectEnzyme Defect

11 Hyperammonemia type IHyperammonemia type I A. Argininosuccinate synthaseA. Argininosuccinate synthase

22 Hyperammonemia type IIHyperammonemia type II B. Ornithine transcarbomylase B. Ornithine transcarbomylase (OTC)(OTC)

33 CitrullinemiaCitrullinemia C. Argininosuccinate lyaseC. Argininosuccinate lyase

44 Argininosuccinic AciduriaArgininosuccinic Aciduria D. ArginaseD. Arginase

55 HyperargininemiaHyperargininemia E. Carbamoyl-P synthase-I (CPS-I)E. Carbamoyl-P synthase-I (CPS-I)

Answer:Answer: 1E; 2-B; 3-A; 4-C; 5-D.1E; 2-B; 3-A; 4-C; 5-D.

Match the Urea Cycle Disorders With Match the Urea Cycle Disorders With the Enzyme Defectthe Enzyme Defect

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Genetic Deficiencies in Some of the Urea Cycle Enzymes can Genetic Deficiencies in Some of the Urea Cycle Enzymes can be Treated Pharmacologically by eliminating the amino acids be Treated Pharmacologically by eliminating the amino acids such as glycine and glutamine by administering, such as glycine and glutamine by administering,

A. Aspartic acid.A. Aspartic acid.B. B. Benzoic acid and phenylacetate.Benzoic acid and phenylacetate.C. GABA.C. GABA.D. Pyridoxal phosphate.D. Pyridoxal phosphate.E. Methionine.E. Methionine.

Ans: B.Ans: B. The amide products of these reactions (hippurate and The amide products of these reactions (hippurate and phenylacetylglutamine) are excreted in the urine. Synthesizing phenylacetylglutamine) are excreted in the urine. Synthesizing the Glycine or Glutamine removes ammonia.the Glycine or Glutamine removes ammonia.

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The reaction catalyzed by glutamate dehydrogenase which The reaction catalyzed by glutamate dehydrogenase which reversibly converts glutamate to reversibly converts glutamate to αα-ketoglutarate require the -ketoglutarate require the cofactor,cofactor,

A.A. ATP.ATP.B.B. NAD.NAD.C.C. NAD(P)NAD(P)++ / NAD(P)H. / NAD(P)H. D.D. Biotin.Biotin.E.E. Pyridoxal phosphate.Pyridoxal phosphate.

Ans: C.Ans: C. The cofactors require by the glutamate dehydrogenase is The cofactors require by the glutamate dehydrogenase isNAD(P)NAD(P)++ / NAD(P)H. / NAD(P)H.

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4. Methotrexate is a potent anticancer agent that starves dividing cells of4. Methotrexate is a potent anticancer agent that starves dividing cells ofdeoxyribonucleotides through direct inhibition of which of the following deoxyribonucleotides through direct inhibition of which of the following enzymes?enzymes?

A. Ribonucleotide reductaseA. Ribonucleotide reductaseB. Xanthine oxidaseB. Xanthine oxidaseC. Carbamoyl phosphate synthetase IIC. Carbamoyl phosphate synthetase IID. Thymidylate synthetaseD. Thymidylate synthetaseE. Dihydrofolate reductaseE. Dihydrofolate reductase F. Adenosine deaminase.F. Adenosine deaminase.

4. The answer is E.4. The answer is E. Methotrexate is an analog of folic acid that binds Methotrexate is an analog of folic acid that binds with very high affinity to the substrate-binding site of dihydrofolate with very high affinity to the substrate-binding site of dihydrofolate reductase, the enzyme that catalyzes conversion of DHF to THF, which reductase, the enzyme that catalyzes conversion of DHF to THF, which is used in various forms by enzymes of both the purine and pyrimidine is used in various forms by enzymes of both the purine and pyrimidine de novo synthetic pathways. Thus, synthesis of dTMP from dUMP de novo synthetic pathways. Thus, synthesis of dTMP from dUMP catalyzed by thymldylate synthetase and several steps in purine catalyzed by thymldylate synthetase and several steps in purine synthesis cat alyzed by formytransferase are indirectly blocked by the synthesis cat alyzed by formytransferase are indirectly blocked by the action of methotrexate because both those enzymes require THF action of methotrexate because both those enzymes require THF coenzymes.coenzymes.

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A 2-year-old boy's mother is concerned about his tendency to bite himself to A 2-year-old boy's mother is concerned about his tendency to bite himself to the pointthe point of bleeding. The boy's ringers show scarring and several scabs, and of bleeding. The boy's ringers show scarring and several scabs, and his lips are swollen and bruised. He exhibits poor coordination, poor muscle his lips are swollen and bruised. He exhibits poor coordination, poor muscle tone, and frequent jerking movements of his arms and legs. He is significantly tone, and frequent jerking movements of his arms and legs. He is significantly delayed in speech. His urine is orange in color and "gritty.“delayed in speech. His urine is orange in color and "gritty.“

5. Which of the following is the most likely diagnosis?.5. Which of the following is the most likely diagnosis?.

A. Tay-Sachs disease A. Tay-Sachs disease B. GoutB. GoutC. Lesch-Nyhan syndromeC. Lesch-Nyhan syndromeD. Severe combined immunodeficiency D. Severe combined immunodeficiency E. Cerebral palsy.E. Cerebral palsy.

5. The answer is C.5. The answer is C. This patient's self-mutilation behavior, neurologic symptoms, This patient's self-mutilation behavior, neurologic symptoms, and de velopmental delay are all consistent with a diagnosis of Lesch-Nyhan and de velopmental delay are all consistent with a diagnosis of Lesch-Nyhan syndrome. This disorder is due to deficiency of HGPRT, which prevents salvage of syndrome. This disorder is due to deficiency of HGPRT, which prevents salvage of hypoxanthine and guanine to their respective nucleotides, IMP and GMP. This hypoxanthine and guanine to their respective nucleotides, IMP and GMP. This leads in turn to hyperactivlty of the purine synthesis pathway, excessive purine leads in turn to hyperactivlty of the purine synthesis pathway, excessive purine degradation, and overproduc tion of uric acid. The gritty substance and orange degradation, and overproduc tion of uric acid. The gritty substance and orange color of the patient's urine are due to excretion of both dissolved uric acid and color of the patient's urine are due to excretion of both dissolved uric acid and precipitated sodium urate. Gout might account for the excessive uric acid precipitated sodium urate. Gout might account for the excessive uric acid production but not the neurologic symptoms. Self-mutilation is not characteristic of production but not the neurologic symptoms. Self-mutilation is not characteristic of either Tay-Sach’s disease or cerebral palsy.either Tay-Sach’s disease or cerebral palsy.

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21.2 The catabolism of hemoglobin:

A. occurs in red blood cells. B. involves the oxidative cleavage of the porphyrin ring.C. results in the liberation of carbon dioxide. D. results in the formation of protoporphyrinogen. E. is the sole source of bilirubin.

Correct answer = B. The cyclic heme molecule is oxidatively cleaved to form biliverdin. The catabolism occurs in the cells of the reticulo-endothelial system, particularly the spleen, and resultsin the liberation of carbon monoxide. Protoporphyrinogen is an intermediate in the synthesis, not degradation, of heme.Hemoglobin and tissue cytochromes are precursors of bilirubin.

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CLINICAL PROBLEMS 135CLINICAL PROBLEMS 135

A 44-year-old woman is brought to the emergency department doubled over A 44-year-old woman is brought to the emergency department doubled over with abdominal pain. Her husband states that the pain began several hours with abdominal pain. Her husband states that the pain began several hours earlier, comes in waves, but has not really subsided completely even for brief earlier, comes in waves, but has not really subsided completely even for brief periods since then. Oral antacids have not helped the pain at all. Her periods since then. Oral antacids have not helped the pain at all. Her discomfort is not relieved by defecation. A stool sample is light gray or clay-discomfort is not relieved by defecation. A stool sample is light gray or clay-colored. Physical examination shows right upper quadrant abdominal pain. colored. Physical examination shows right upper quadrant abdominal pain. Her sclerae are slightly yellow in color. A sonogram shows a 2-cm mass in Her sclerae are slightly yellow in color. A sonogram shows a 2-cm mass in the region of the bile duct.the region of the bile duct.

Testing of her serum would be expected to reveal elevated levels of which of Testing of her serum would be expected to reveal elevated levels of which of the following?.the following?.

A. Albumin-bound bilirubin.A. Albumin-bound bilirubin.B. Porphobilinogen.B. Porphobilinogen.C. Free, unconjugated bilirubin.C. Free, unconjugated bilirubin.D. Conjugated bilirubin / Bilirubin Diglucuronide / Direct Bilirubin.D. Conjugated bilirubin / Bilirubin Diglucuronide / Direct Bilirubin.E. Biliverdin.E. Biliverdin.

Ans: D.Ans: D. ?

148148

CLINICAL PROBLEMSCLINICAL PROBLEMS

1.1. Severe combined immunodeficiency arises from inhibition of Severe combined immunodeficiency arises from inhibition of lymphocyte proliferation because B and T cells are particularlylymphocyte proliferation because B and T cells are particularlysensitive to allosteric inhibition of which of the following enzymes sensitive to allosteric inhibition of which of the following enzymes of purine nucleotide metabolism?.of purine nucleotide metabolism?.

A.A. Xanthine oxidase.Xanthine oxidase.B.B. Dihydrofolate reductase.Dihydrofolate reductase.C.C. Adenosine deaminase.Adenosine deaminase.D.D. Ribonucleotide reductase.Ribonucleotide reductase.E.E. Hypoxanthine-guanine phosphoribosyltransferase.Hypoxanthine-guanine phosphoribosyltransferase.

Ans: C.Ans: C.

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5. A 2-year-old boy's mother is concerned about his tendency to bite himself to 5. A 2-year-old boy's mother is concerned about his tendency to bite himself to the point of bleeding. The boy's fingers show scarring and several scabs, and the point of bleeding. The boy's fingers show scarring and several scabs, and his lips are swollen and bruised. He exhibits poor coordination, poor muscle his lips are swollen and bruised. He exhibits poor coordination, poor muscle tone, and frequent jerking movements of his arms and legs. He is significantly tone, and frequent jerking movements of his arms and legs. He is significantly delayed in speech. His urine is orange in color and "gritty.“delayed in speech. His urine is orange in color and "gritty.“

5. Which of the following is the most likely diagnosis?.5. Which of the following is the most likely diagnosis?. A.A. Tay-Sachs disease. Tay-Sachs disease. B.B. Gout.Gout.C. Lesch-Nyhan syndrome.C. Lesch-Nyhan syndrome. D. Severe combined immunodeficiency.D. Severe combined immunodeficiency.E. Cerebral palsy.E. Cerebral palsy.

5. The answer is C. This patient's self-mutilation behavior, neurologic symptoms,5. The answer is C. This patient's self-mutilation behavior, neurologic symptoms,and de velopmental delay are all consistent with a diagnosis of Lesch-Nyhan and de velopmental delay are all consistent with a diagnosis of Lesch-Nyhan syndrome. This disorder is due to deficiency of HGPRT, which prevents salvagesyndrome. This disorder is due to deficiency of HGPRT, which prevents salvageof hypoxanthine and guanine to their respective nucleorides, IMP and GMP. This of hypoxanthine and guanine to their respective nucleorides, IMP and GMP. This leads in turn to hyperac-tivity of the purine synthesis pathway, excessive purineleads in turn to hyperac-tivity of the purine synthesis pathway, excessive purinedegradation, and overproduction of uric acid. The gritty substance and orange degradation, and overproduction of uric acid. The gritty substance and orange color of the patient's urine are due to excretion of both dissolved uric acid and color of the patient's urine are due to excretion of both dissolved uric acid and precipitated sodium urate. Gout might account for the excessive uric acid precipitated sodium urate. Gout might account for the excessive uric acid production but not the neurologic symptoms. Self-mutilation is not characteristicproduction but not the neurologic symptoms. Self-mutilation is not characteristicof either of either

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4. Methotrexare is a potent anticancer agent that starves dividing4. Methotrexare is a potent anticancer agent that starves dividingcells of deoxyribonucleotides through direct inhibition of which of cells of deoxyribonucleotides through direct inhibition of which of the following enzymes?.the following enzymes?.

A.A. Ribonucleotide reductase Ribonucleotide reductase B.B. Xanthine oxidaseXanthine oxidaseC. Carbamoyl phosphate synthetase II C. Carbamoyl phosphate synthetase II D. Thymidylate synthetase.D. Thymidylate synthetase.

Ans: D.Ans: D.

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A 44-year-old woman is brought to the emergency department doubled over A 44-year-old woman is brought to the emergency department doubled over with abdominal pain. Her husband states that the pain began several hours with abdominal pain. Her husband states that the pain began several hours earlier, comes in waves, but has not really subsided completely even for brief earlier, comes in waves, but has not really subsided completely even for brief periods since then. Oral antacids have not helped the pain at all. Her periods since then. Oral antacids have not helped the pain at all. Her discomfort is not relieved by defecation. A stool sample is light gray or clay-discomfort is not relieved by defecation. A stool sample is light gray or clay-colored. Physical examination shows right upper quadrant abdominal pain. colored. Physical examination shows right upper quadrant abdominal pain. Her sclerae are slightly yellow in color. A sonogram shows a Her sclerae are slightly yellow in color. A sonogram shows a 2-cm mass in 2-cm mass in the region of the bile duct.the region of the bile duct.

Testing of her serum would be expected to reveal elevated levels of which of Testing of her serum would be expected to reveal elevated levels of which of the following?.the following?.

A. Albumin-bound bilirubin.A. Albumin-bound bilirubin.B. Porphobilinogen.B. Porphobilinogen.C. Free, unconjugated bilirubin.C. Free, unconjugated bilirubin.D. Conjugated bilirubin.D. Conjugated bilirubin.E. Biliverdin.E. Biliverdin.

Ans: D.Ans: D. ?

148148

CLINICAL PROBLEMSCLINICAL PROBLEMS

1.1. Severe combined immunodeficiency arises from inhibition of Severe combined immunodeficiency arises from inhibition of lymphocyte proliferation because B and T cells are particularlylymphocyte proliferation because B and T cells are particularlysensitive to allosteric inhibition of which of the following enzymes sensitive to allosteric inhibition of which of the following enzymes of purine nucleotide metabolism?.of purine nucleotide metabolism?.

A.A. Xanthine oxidase.Xanthine oxidase.B.B. Dihydrofolate reductase.Dihydrofolate reductase.C.C. Adenosine deaminase.Adenosine deaminase.D.D. Ribonucleotide reductase.Ribonucleotide reductase.E.E. Hypoxanthine-guanine phosphoribosyltransferase.Hypoxanthine-guanine phosphoribosyltransferase.

Ans: C.Ans: C.

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4. Methotrexare is a potent anticancer agent that starves dividing4. Methotrexare is a potent anticancer agent that starves dividingcells of deoxyribonucleotides through direct inhibition of which of cells of deoxyribonucleotides through direct inhibition of which of the following enzymes?.the following enzymes?.

A.A. Ribonucleotide reductase Ribonucleotide reductase B.B. Xanthine oxidaseXanthine oxidaseC. Carbamoyl phosphate synthetase II C. Carbamoyl phosphate synthetase II D. Thymidylate synthetase.D. Thymidylate synthetase.

Ans: D.Ans: D.

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5. A 2-year-old boy's mother is concerned about his tendency to bite himself to 5. A 2-year-old boy's mother is concerned about his tendency to bite himself to the point of bleeding. The boy's fingers show scarring and several scabs, and the point of bleeding. The boy's fingers show scarring and several scabs, and his lips are swollen and bruised. He exhibits poor coordination, poor muscle his lips are swollen and bruised. He exhibits poor coordination, poor muscle tone, and frequent jerking movements of his arms and legs. He is significantly tone, and frequent jerking movements of his arms and legs. He is significantly delayed in speech. His urine is orange in color and "gritty.“delayed in speech. His urine is orange in color and "gritty.“

5. Which of the following is the most likely diagnosis?.5. Which of the following is the most likely diagnosis?. A.A. Tay-Sachs disease. Tay-Sachs disease. B.B. Gout.Gout.C. Lesch-Nyhan syndrome.C. Lesch-Nyhan syndrome. D. Severe combined immunodeficiency.D. Severe combined immunodeficiency.E. Cerebral palsy.E. Cerebral palsy.

5. The answer is C. This patient's self-mutilation behavior, neurologic symptoms,5. The answer is C. This patient's self-mutilation behavior, neurologic symptoms,and de velopmental delay are all consistent with a diagnosis of Lesch-Nyhan and de velopmental delay are all consistent with a diagnosis of Lesch-Nyhan syndrome. This disorder is due to deficiency of HGPRT, which prevents salvagesyndrome. This disorder is due to deficiency of HGPRT, which prevents salvageof hypoxanthine and guanine to their respective nucleorides, IMP and GMP. This of hypoxanthine and guanine to their respective nucleorides, IMP and GMP. This leads in turn to hyperac-tivity of the purine synthesis pathway, excessive purineleads in turn to hyperac-tivity of the purine synthesis pathway, excessive purinedegradation, and overproduction of uric acid. The gritty substance and orange degradation, and overproduction of uric acid. The gritty substance and orange color of the patient's urine are due to excretion of both dissolved uric acid and color of the patient's urine are due to excretion of both dissolved uric acid and precipitated sodium urate. Gout might account for the excessive uric acid precipitated sodium urate. Gout might account for the excessive uric acid production but not the neurologic symptoms. Self-mutilation is not characteristicproduction but not the neurologic symptoms. Self-mutilation is not characteristicof either of either

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For which of the following reactions S-adenosyl methionineFor which of the following reactions S-adenosyl methionine(SAM), serve as a methylating agent?.(SAM), serve as a methylating agent?.

A. Conversion of dopamine to norepinephrine.A. Conversion of dopamine to norepinephrine.B. Synthesis of creatine from ceratine P.B. Synthesis of creatine from ceratine P.C. C. Synthesis of phosphatidylcholine from phosphatidylethanolamine.Synthesis of phosphatidylcholine from phosphatidylethanolamine.D. Conversion of dUMP to dTMP.D. Conversion of dUMP to dTMP.E. Formation of methionine fro homosycteine.E. Formation of methionine fro homosycteine.

Answer:Answer: C.C. The The conversion of dopamine to norepinephrine The The conversion of dopamine to norepinephrineInvolved in the hydroxylation reaction. (SAM methylatesInvolved in the hydroxylation reaction. (SAM methylatesnorepinephrine to form epinephrine). The synthesis of creatine norepinephrine to form epinephrine). The synthesis of creatine requires SAM, not The conversion conversion of creatine requires SAM, not The conversion conversion of creatine phosphate to creatine.phosphate to creatine.

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X

Pregnant women frequently suffer from folate deficiencies. Pregnant women frequently suffer from folate deficiencies. A deficiency of folate would decrease the production of ,A deficiency of folate would decrease the production of ,

A. Creatine phosphate from creatine.A. Creatine phosphate from creatine.B. All of the pyrimidines required for RNA synthesis.B. All of the pyrimidines required for RNA synthesis.C. C. The thymine nucleotide required for DNA synthesis.The thymine nucleotide required for DNA synthesis.D. Phosphatidylcholimne from diacylglycerol and CDP-choline.D. Phosphatidylcholimne from diacylglycerol and CDP-choline.

Answer:Answer: C.C. The only pyrimidine that requires folate for its The only pyrimidine that requires folate for its synthesis is thymine (dUMP → dTMP). Folate is required for synthesis is thymine (dUMP → dTMP). Folate is required for incorporation of carbons 2 and 8 into all purine molecules. Theincorporation of carbons 2 and 8 into all purine molecules. TheSynthesis of creatine phosphate and of phosphatidylcholine do notSynthesis of creatine phosphate and of phosphatidylcholine do notRequire folate. Folate deficiencies during pregnancy can lead toRequire folate. Folate deficiencies during pregnancy can lead toNeural tube defects (e.g., spina bifida) in the fetus. Neural tube defects (e.g., spina bifida) in the fetus.

Excessive degradation of AMP and GMP would result in Excessive degradation of AMP and GMP would result in Increased urinary excretion of,Increased urinary excretion of,

A. CreatineA. CreatineB. UreaB. UreaC. Uric AcidC. Uric AcidD. ThiamineD. ThiamineE. ThymineE. Thymine

Answer:Answer: C.C. The purine bases, adenine (A) and guaninie (G), are The purine bases, adenine (A) and guaninie (G), are oxidized to uric acid, which is excreted in the urine. Excessive oxidized to uric acid, which is excreted in the urine. Excessive Production of uric acid can result in the condition known as gout.Production of uric acid can result in the condition known as gout.

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The component that would be elevated to the greatest extentThe component that would be elevated to the greatest extentin the blood of a person suffering from in the blood of a person suffering from GoutGout is_______. is_______.

A. bilirubin.A. bilirubin.B. uric acid.B. uric acid. C. creatine kinase.C. creatine kinase.D. blood urea nitrogen.D. blood urea nitrogen.

Answer:Answer: B. B.

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The genetic defect in the hypoxanthine guanine The genetic defect in the hypoxanthine guanine phosphoribosyl transferse (HGPRT) will leads to,phosphoribosyl transferse (HGPRT) will leads to,

A.A. Parkinson’s disease.Parkinson’s disease.B.B. Cystinuria.Cystinuria.C.C. Pellagra.Pellagra.D.D. Lesch-Nyhan syndrome.Lesch-Nyhan syndrome.E.E. Hartnup’s disease.Hartnup’s disease.

Answer: D.Answer: D. The defect in the purine salvage enzyme HGPRT The defect in the purine salvage enzyme HGPRTcauses Lesch-Nyhan syndrome.causes Lesch-Nyhan syndrome.

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De novo pyrimidine synthesis requires,De novo pyrimidine synthesis requires,

A. Phosphorobosyl pyrophosphate (PRPP) for the initial step.A. Phosphorobosyl pyrophosphate (PRPP) for the initial step.B. Tetrahydrofolate for the incorporation of carbon 2 and 8.B. Tetrahydrofolate for the incorporation of carbon 2 and 8.C. C. Both carbon and nitrogen of aspartate to form the ring.Both carbon and nitrogen of aspartate to form the ring.D. NHD. NH44

++ as a substrate for carbamoyl phosphate synthetase II. as a substrate for carbamoyl phosphate synthetase II.

E. Glycine as the source of two nitrogens in the ring. E. Glycine as the source of two nitrogens in the ring.

Answer:Answer: C.C. Options A and B are true for purine synthesis. During Options A and B are true for purine synthesis. During pyrimidine synthesis, the entire aspartate molecule is incorporatedpyrimidine synthesis, the entire aspartate molecule is incorporatedInto the ring. Glutamine is the substrate for carbamoyl phosphate Into the ring. Glutamine is the substrate for carbamoyl phosphate synthase II, the enzyme involved in pyrimidine biosynthesis. (NHsynthase II, the enzyme involved in pyrimidine biosynthesis. (NH44

++

Ions is the substrate for the synthase I in the urea synthesis).Ions is the substrate for the synthase I in the urea synthesis).Glycine supplies one nitrogen for purine synthesis.Glycine supplies one nitrogen for purine synthesis.

5-Fluorouracil (5-FU) is an effective chemotherapeutic agent 5-Fluorouracil (5-FU) is an effective chemotherapeutic agent Because interferes with DNA synthesis by directly inhibitingBecause interferes with DNA synthesis by directly inhibitingthe reaction in which,the reaction in which,

A. FHA. FH22 → FH → FH44..

B. dUMP → TMP.B. dUMP → TMP.C. Glutamine+ PRPP → Phosphoribosylamine.C. Glutamine+ PRPP → Phosphoribosylamine.D. Methyl BD. Methyl B1212 → B → B1212..

Answer: B.Answer: B. Methotrexate inhibits reaction A. 5-FU inhibits Methotrexate inhibits reaction A. 5-FU inhibitsreaction B. The remaining reactions are not directly affected byreaction B. The remaining reactions are not directly affected by5-FU. Reaction C is the first step in purine biosynthesis, and 5-FU. Reaction C is the first step in purine biosynthesis, and reaction D provides the methyl group for the biosynthesis of reaction D provides the methyl group for the biosynthesis of methionine from homocysteine.methionine from homocysteine.

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7. 5-Fluorouracil (5-FU) is an effective chemotherapeutic agent 7. 5-Fluorouracil (5-FU) is an effective chemotherapeutic agent because it interferes with DNA synthesis by directly inhibiting because it interferes with DNA synthesis by directly inhibiting which of the following reactions?.which of the following reactions?.

(A)(A). Dihydrofolate (FH. Dihydrofolate (FH22) →) → tetrahydrofolate (FHtetrahydrofolate (FH44).).

(B)(B). Deoxyuridine monophosphate (dUMP) → . Deoxyuridine monophosphate (dUMP) → thymidinemonophosphate (dTMP).thymidinemonophosphate (dTMP).

(C). Glutamine + phosphoribosyl 1-pyrophosphate (PRPP) →(C). Glutamine + phosphoribosyl 1-pyrophosphate (PRPP) → phosphoribosylamine.phosphoribosylamine.

(D). Methyl B(D). Methyl B1212→ vitamin B→ vitamin B1212. .

(E). Vitamin B(E). Vitamin B1212→ methyl B→ methyl B1212..

Ans: Ans: B.B. Methotrexate inhibits the reaction of dihydrofolate (FHMethotrexate inhibits the reaction of dihydrofolate (FH22) →) →

tetrahydrofolate (FHtetrahydrofolate (FH44), which is mediated by dihydrofolate reductase. 5-FU ), which is mediated by dihydrofolate reductase. 5-FU

inhibits the reaction of deoxyuridine monophosphate (dUMP)→ thymidine inhibits the reaction of deoxyuridine monophosphate (dUMP)→ thymidine monophosphate (dTMP). The remaining reactions are not directly affected by monophosphate (dTMP). The remaining reactions are not directly affected by 5-FU. Glutamine to create phosphoribosylamine is the first step in purine 5-FU. Glutamine to create phosphoribosylamine is the first step in purine biosynthesis. Methyl Bbiosynthesis. Methyl B1212→ vitamin B→ vitamin B1212 provides the methyl group for the provides the methyl group for the

biosynthesis of methionine from homocysteine; and the reverse reaction does biosynthesis of methionine from homocysteine; and the reverse reaction does not occur in the cell because there is no demethylation for .the reaction.not occur in the cell because there is no demethylation for .the reaction.

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23. A 57-year-old sales representative for a biotechnology firm has a history of alcohol 23. A 57-year-old sales representative for a biotechnology firm has a history of alcohol abuse and hyperuricemia, He attends an out-of-town conference and gorges himself on abuse and hyperuricemia, He attends an out-of-town conference and gorges himself on appetizers, including liver pate, caviar, aid sweetbreads before dinner. Early the appetizers, including liver pate, caviar, aid sweetbreads before dinner. Early the following morning he develops a painful swelling in his big toe. In addition to the alcohol following morning he develops a painful swelling in his big toe. In addition to the alcohol consumed with his meals, which of the component may have contributed to this consumed with his meals, which of the component may have contributed to this episode?.episode?.

A). CarbohydrateA). CarbohydrateB). CholesterolB). CholesterolC). C). Nucleic acidNucleic acidD). Protein D). Protein E). Triglyceride.E). Triglyceride.

Answer is C.Answer is C. Purines from ingested nucleic acids are converted to uric acid by Purines from ingested nucleic acids are converted to uric acid by intestinal epithelial cells and released into the blood for potential excretion by the intestinal epithelial cells and released into the blood for potential excretion by the kidney. Foods rich in DNA (caviar) or RNA (liver pate and sweetbreads [pancreas], kidney. Foods rich in DNA (caviar) or RNA (liver pate and sweetbreads [pancreas], derived from organs with active protein synthesis) are particularly rich sources of derived from organs with active protein synthesis) are particularly rich sources of purines, and their ingestion coupled with excess alcohol consumption presumably purines, and their ingestion coupled with excess alcohol consumption presumably increased his plasma urate levels to the point at which uric acid crystallized in a increased his plasma urate levels to the point at which uric acid crystallized in a susceptible joint. The resultant painful swelling is gout. The pain is caused by susceptible joint. The resultant painful swelling is gout. The pain is caused by precipitation of uric acid crystals in the joints with attendant inflammation.precipitation of uric acid crystals in the joints with attendant inflammation.

CarbohydrateCarbohydrate (choice (choice A), cholesterol A), cholesterol (choice (choice B), protein B), protein (choice D),(choice D), and TGs and TGs (choice (choice E) by themselves do not contain purines, and their metabolism does not contribute to E) by themselves do not contain purines, and their metabolism does not contribute to the uric acid pool. To the extent that protein-rich foods are cellular, they will, however, the uric acid pool. To the extent that protein-rich foods are cellular, they will, however, contain nucleic acids that will be catabolized to uric acid.contain nucleic acids that will be catabolized to uric acid.

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18. Pregnant women frequently suffer from folate 18. Pregnant women frequently suffer from folate deficiencies. A deficiency of folate would decrease the deficiencies. A deficiency of folate would decrease the production ofproduction of

A. creatine phosphate from creatine.A. creatine phosphate from creatine.B. all of the pyrimidines required for RNA synthesis.B. all of the pyrimidines required for RNA synthesis.C. C. the thymine nucleotide required for DNA synthesis.the thymine nucleotide required for DNA synthesis.D. phosphatidylcholine from diacylglycerol and CDP-choline.D. phosphatidylcholine from diacylglycerol and CDP-choline.

18-C.18-C. The only pyrimidine that requires folate for its synthesis is The only pyrimidine that requires folate for its synthesis is thymine (dUMP → dTMP). Folate is required for incorporation of thymine (dUMP → dTMP). Folate is required for incorporation of carbons 2 and 8 into all purine molecules. The synthesis of carbons 2 and 8 into all purine molecules. The synthesis of creatine phosphate and of phosphatidylcholine do not require creatine phosphate and of phosphatidylcholine do not require folate. Folate deficiencies during pregnancy can lead to neural folate. Folate deficiencies during pregnancy can lead to neural tube defects (e.g., spina bifida) in the fetus.tube defects (e.g., spina bifida) in the fetus.

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25. Excessive degradation of AMP and GMP would result in25. Excessive degradation of AMP and GMP would result inIncreased urinary excretion of Increased urinary excretion of

A. Creatinine.A. Creatinine.B. Urea.B. Urea.C. Uric acid.C. Uric acid.D. Thiamine.D. Thiamine.E Thymine.E Thymine.

25-C.25-C. The purine bases, adenine (A) and guanine (G), are The purine bases, adenine (A) and guanine (G), are oxidized to uric acid, which is excreted in the urine. Excessive oxidized to uric acid, which is excreted in the urine. Excessive production of production of uric aciduric acid can result in the condition known as can result in the condition known as goutgout..

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26. 26. DeDe novonovo pyrimidine synthesis requires pyrimidine synthesis requires

A.A. phosphoribosyl pyrophosphate (PRPP) for the initial step.phosphoribosyl pyrophosphate (PRPP) for the initial step.B.B. tetrahydrofolate for the incorporation of carbons 2 and 8.tetrahydrofolate for the incorporation of carbons 2 and 8. C.C. both carbon and nitrogen of aspartate to form the ring. both carbon and nitrogen of aspartate to form the ring. D.D. NHNH44

++ as a substrate for carbamoyl phosphatesynthetase II. as a substrate for carbamoyl phosphatesynthetase II.

E.E. glycine as the source of two nitrogens in the ring.glycine as the source of two nitrogens in the ring.

26-C.26-C. Options A and B are true for purine but not pyrimidine Options A and B are true for purine but not pyrimidine biosynthesis. During pyrimidine synthesis, the entire aspartate biosynthesis. During pyrimidine synthesis, the entire aspartate molecule is incorporated into the ring. Glutamine is the substrate molecule is incorporated into the ring. Glutamine is the substrate for carbamoyl phosphate synthetase II, the enzyme involved in for carbamoyl phosphate synthetase II, the enzyme involved in pyrimidine biosynthesis. (NHpyrimidine biosynthesis. (NH44

++ is the substrate for synthetase I is the substrate for synthetase I

used in urea synthesis.) Glycine supplies one nitrogen for purineused in urea synthesis.) Glycine supplies one nitrogen for purine synthesis.synthesis.

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27. 5-Fluorouracil (5-FU) is an effective chemo-therapeutic 27. 5-Fluorouracil (5-FU) is an effective chemo-therapeutic agent because it interferes with DNA synthesis by directlyagent because it interferes with DNA synthesis by directlyinhibiting the reaction in whichinhibiting the reaction in which

A.A. FHFH22 → FH → FH44..

B.B. dUMP dUMP →→ dTMP dTMPC.C. glutamine + PRPP → phosphoribosylamineglutamine + PRPP → phosphoribosylamineD.D. methyl Bmethyl B1212→ B→ B1212..

27-B.27-B. Methotrexate inhibits reaction A. 5-FU inhibits reaction B. Methotrexate inhibits reaction A. 5-FU inhibits reaction B. The remaining reactions are not directly affected by 5-FU. The remaining reactions are not directly affected by 5-FU. Reaction C is the first step in purine biosynthesis, and reaction DReaction C is the first step in purine biosynthesis, and reaction Dprovides the methyl group for the biosynthesis of methionineprovides the methyl group for the biosynthesis of methioninefrom homocysteine.from homocysteine.

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59. Match each condition below with the component that would be59. Match each condition below with the component that would beelevated to the greatest extent in the blood.elevated to the greatest extent in the blood.

DiseaseDisease AnswerAnswer ComponentComponent

A. GoutA. Gout 1. Bilirubin1. Bilirubin

B. Myocardial infarctionB. Myocardial infarction 2. Uric acid2. Uric acid

C. HepatitisC. Hepatitis 3. Creatine kinase3. Creatine kinase

D. Kidney disease.D. Kidney disease. 4. Blood urea nitrogen 4. Blood urea nitrogen (BUN)(BUN)

In gout, uric acid crystals precipitate in joints, causing severe pain.In gout, uric acid crystals precipitate in joints, causing severe pain.

A-2 Uric acidA-2 Uric acidB-3 Creatine kinaseB-3 Creatine kinaseC-1 BilirubinC-1 BilirubinD-4 BUN. D-4 BUN.

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Match each Disorder below with the Enzyme Match each Disorder below with the Enzyme DeficiencyDeficiency

DisorderDisorder AnswerAnswer Enzyme DeficiencyEnzyme Deficiency

1.Congenital Erythropoietic 1.Congenital Erythropoietic PorphyriaPorphyria

Uroporphyrinogen Uroporphyrinogen Decarboxylase.Decarboxylase.

2. Porphyria Cutanea 2. Porphyria Cutanea Tarda (PCT)Tarda (PCT)

B. Uroporphyrinogen III B. Uroporphyrinogen III Synthase.Synthase.

3. Erythropoietic 3. Erythropoietic ProptoporphyriaProptoporphyria

Ferrochelatase.Ferrochelatase.

Ans: 1-B, 2-A, 3-C.Ans: 1-B, 2-A, 3-C.

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11. A11. A 56-year-old diabetic with end-stage renal disease receives a 56-year-old diabetic with end-stage renal disease receives akidney transplant from his son. His nephrologist is concerned forkidney transplant from his son. His nephrologist is concerned forthe possibility of transplant rejection and puts the patient on the possibility of transplant rejection and puts the patient on mycophenolic acidmycophenolic acid, which , which inhibits which important enzyme in theinhibits which important enzyme in thesynthesis of nucleotidessynthesis of nucleotides?.?.

A.A. PRPP. PRPP. B.B. IMP dehydrogenaseIMP dehydrogenaseC.C. Adenylosuccinate synthase.Adenylosuccinate synthase.D.D. Ribonucleotide reductase.Ribonucleotide reductase.E.E. Adenylosuccinase.Adenylosuccinase.

Answer-B.Answer-B. Mycophenolic acid, a potent Mycophenolic acid, a potent immunosuppressantimmunosuppressant, is an , is an inhibitor of inhibitor of IMP dehydrogenaseIMP dehydrogenase, which normally converts IMP to , which normally converts IMP to xanthosine monophosphate. PRPP synthase catalyses the initial step inxanthosine monophosphate. PRPP synthase catalyses the initial step innucleotide metabolism, forming PRPP from ATP and ribose. nucleotide metabolism, forming PRPP from ATP and ribose. Adenylosuccinate synthase and adenylosuccinase are sequential Adenylosuccinate synthase and adenylosuccinase are sequential enzymes in the synthesis of AMP.enzymes in the synthesis of AMP.

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15. A child is noted to have recurrent respiratory infections that necessitate 15. A child is noted to have recurrent respiratory infections that necessitate hospitalization. His lab tests demonstrate a decrease in T cells, B cells, andhospitalization. His lab tests demonstrate a decrease in T cells, B cells, andnatural killer cells and decreased antibodies. He is found to have natural killer cells and decreased antibodies. He is found to have severe severe combined immuno deficiency (SCID).combined immuno deficiency (SCID). The enzyme that is defective in this The enzyme that is defective in this

disorder is important in which of the following processes?.disorder is important in which of the following processes?.

A.A. Conversion of ribonucleotides to deoxyribonucleotides. Conversion of ribonucleotides to deoxyribonucleotides. B.B. Formation of AMP.Formation of AMP.C.C. Degradation of deoxyadenosine triphosphate (dATP)Degradation of deoxyadenosine triphosphate (dATP)D.D. Synthesis of UMP. Synthesis of UMP. E.E. Conversion of deoxyuridine mono-phosphate (dUMP) to Conversion of deoxyuridine mono-phosphate (dUMP) to

thymidinemonophosphate (dTMP).thymidinemonophosphate (dTMP).

Answer-C.Answer-C. The enzyme deficiency in severe combined immunodeficiency The enzyme deficiency in severe combined immunodeficiency(SCID) is likely (SCID) is likely adenosine deaminaseadenosine deaminase, which normally degrades adenosine to , which normally degrades adenosine to inosine. The conversion of ribonucleotides to deoxyribonucleotides is inosine. The conversion of ribonucleotides to deoxyribonucleotides is performed by ribonucleotide reductase. AMP is formed from IMP through the performed by ribonucleotide reductase. AMP is formed from IMP through the action of adenylosuccinate synthetase, followed by the action of action of adenylosuccinate synthetase, followed by the action of adenylosuccinate. UMP synthase is an important enzyme in the formation of adenylosuccinate. UMP synthase is an important enzyme in the formation of UMP and, subsequently, cytidine triphosphate (CTP) and thymidine UMP and, subsequently, cytidine triphosphate (CTP) and thymidine triphosphate (TTP). The conversion of deoxyuridine monophosphate triphosphate (TTP). The conversion of deoxyuridine monophosphate (dUMP) to thymidine mono-phosphate (dTMP) is mediated by thymidylate(dUMP) to thymidine mono-phosphate (dTMP) is mediated by thymidylatesynthase.synthase.

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17.17. A 58-year-old man is awoken by a throbbing ache in his A 58-year-old man is awoken by a throbbing ache in his great toegreat toe. He has suffered these symptoms before, usually after . He has suffered these symptoms before, usually after indulging in a indulging in a rich mealrich meal. On exam, he is noted to have an angry . On exam, he is noted to have an angry inflamed great toe; also of note are several small nodules on the inflamed great toe; also of note are several small nodules on the antihelix of his ear. Inhibition of which of the following enzymes antihelix of his ear. Inhibition of which of the following enzymes might prevent further occurrences of this man's ailments?.might prevent further occurrences of this man's ailments?.

A. Carbamoyl phosphate synthetase-II.A. Carbamoyl phosphate synthetase-II.B. Hypoxanthine-guanine phosphoribosyl transferase (HGPRT).B. Hypoxanthine-guanine phosphoribosyl transferase (HGPRT).C. PRPP synthetase. C. PRPP synthetase. D. Xanthine oxidase. D. Xanthine oxidase. E. Orotate phosphoribosyl transferase.E. Orotate phosphoribosyl transferase.

Answer-D.Answer-D. Gout is caused by either the increased production or reduced Gout is caused by either the increased production or reduced excretion of uric acid, leading to the deposition of urate crystals. Allopurinol, a excretion of uric acid, leading to the deposition of urate crystals. Allopurinol, a xanthine oxidase inhibitor, decreases the production of urate from xanthine oxidase inhibitor, decreases the production of urate from hypoxanthine and xanthine. Carbamoyl phosphate synthase-II is an enzyme in hypoxanthine and xanthine. Carbamoyl phosphate synthase-II is an enzyme in pyrimidine biosynthesis. HGPRT is an enzyme in the pathway for purine pyrimidine biosynthesis. HGPRT is an enzyme in the pathway for purine salvage. Orotate phosphoribosyi transferase is important in the synthesis of salvage. Orotate phosphoribosyi transferase is important in the synthesis of pyrimidines. PRPP synthetase is an important enzyme in the biosynthesis of pyrimidines. PRPP synthetase is an important enzyme in the biosynthesis of purines; overactivity can cause gout.purines; overactivity can cause gout.

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6. A 36-year-old Greek man with viral pneumonia has a self-6. A 36-year-old Greek man with viral pneumonia has a self-limiting episode of hemolysis. Over the next week, he has anlimiting episode of hemolysis. Over the next week, he has anincreased rate of reticulocytosis. Which of the following increased rate of reticulocytosis. Which of the following compounds serves as a precursor to heme in the reticulocytes?.compounds serves as a precursor to heme in the reticulocytes?.

A.A. αα-Ketoglutarate-KetoglutarateB.B. FumarateFumarateC.C. IsocitrateIsocitrateD.D. Oxaloacetate Oxaloacetate E.E. Succinyl-CoASuccinyl-CoA

Ans: E.Ans: E.

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8. A 23-year-old, single, unemployed woman in her eighth month 8. A 23-year-old, single, unemployed woman in her eighth month of pregnancy is seen in a volunteer-staffed obstetrics clinic. Her of pregnancy is seen in a volunteer-staffed obstetrics clinic. Her first child, born at home and exclusively breast-fed, had first child, born at home and exclusively breast-fed, had prolonged diarrhea and died from an intracranial hemorrhage at 1 prolonged diarrhea and died from an intracranial hemorrhage at 1 month of age. To help prevent a similar problem in this month of age. To help prevent a similar problem in this pregnancy, the resident gives her a free prescription for a vitamin pregnancy, the resident gives her a free prescription for a vitamin and advises her to take one 20-mg tablet each day. He also and advises her to take one 20-mg tablet each day. He also informs her that the infant should receive an injection of this informs her that the infant should receive an injection of this vitamin soon after birth. The vitamin prescribed is required as a vitamin soon after birth. The vitamin prescribed is required as a coenzyme by which of the following enzymes?.coenzyme by which of the following enzymes?.

(A). (A). δδ-Aminolevulinate synthase-Aminolevulinate synthase(B). (B). الال-GlutamyI carboxylase-GlutamyI carboxylase(C). Homocysteine methyltransferase(C). Homocysteine methyltransferase(D). Prolyl hydroxylase (D). Prolyl hydroxylase (E). Thrombin.(E). Thrombin.

Ans: A.Ans: A. ?

13. A 9-year-old girl with mild mental retardation was healthy at 13. A 9-year-old girl with mild mental retardation was healthy at birth but presented during the first week of life with vomiting, birth but presented during the first week of life with vomiting, lethargy, seizures, and hypertonia. An amino acid screen lethargy, seizures, and hypertonia. An amino acid screen revealed elevated levels of leucine, isoleucine, and valine, sorevealed elevated levels of leucine, isoleucine, and valine, sothe child was put on a special diet restricted in these aminothe child was put on a special diet restricted in these aminoacids. She has had no medical problems related to her disease acids. She has had no medical problems related to her disease since that time. Which of the following enzymes is most likely since that time. Which of the following enzymes is most likely deficient in this child?.deficient in this child?.

A.A. Branched chain ketoacid dehydrogenaseBranched chain ketoacid dehydrogenaseB.B. Cystathionine synthaseCystathionine synthaseC.C. Methylmalonyl CoA mutaseMethylmalonyl CoA mutaseD.D. Ornithine transcarbamoylase Ornithine transcarbamoylase E.E. Propionyl CoA carboxylase.Propionyl CoA carboxylase.

Ans: A.Ans: A.

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The Reactions of the Urea The Reactions of the Urea CycleCycle

NAGNAG

DeDe novonovo Pyrimidine Synthesis Pyrimidine Synthesis

AlkaptonuriaAlkaptonuria Deficiency of Deficiency of homogentisate homogentisate dioxygenase.dioxygenase.

Urine turns dark on Urine turns dark on standing.standing.

Oxidation of Oxidation of homogentisic acid.homogentisic acid.

Asymptomatic in Asymptomatic in childhood.childhood.

Tendency toward Tendency toward arthritis in adulthood.arthritis in adulthood.

PKU, Tyrosemia & Alkaptonuria

Pathway of Porphyrin Synthesis:Pathway of Porphyrin Synthesis:Formation of PorphobilinogenFormation of Porphobilinogen

PLP

PLP = Pyridoxal phosphate

7. A 48-year-old man developed abdominal colic, muscle pain, 7. A 48-year-old man developed abdominal colic, muscle pain, and fatigue. Following a 3-week hospitalization, acute intermittent and fatigue. Following a 3-week hospitalization, acute intermittent porphyria was initially diagnosed based on a high level of urinaryporphyria was initially diagnosed based on a high level of urinaryδ-aminolevulinic acid. Subsequent analysis of the patient’s δ-aminolevulinic acid. Subsequent analysis of the patient’s circulating RBCs revealed that 70% contained elevated levels of circulating RBCs revealed that 70% contained elevated levels of zinc protoporphyrin, and the diagnosis was corrected. The correctzinc protoporphyrin, and the diagnosis was corrected. The correctDiagnosis is most likely to be, .Diagnosis is most likely to be, .

A.A. Protoporphyria.Protoporphyria.B.B. Congenital erythropoietic porphyria.Congenital erythropoietic porphyria.C.C. Lead poisoning.Lead poisoning.D.D. Barbiturate addiction .Barbiturate addiction .E.E. Iron deficiency.Iron deficiency.

Answer: C.Answer: C. Lead inhibits both ferrocheatase (increasing the zinc Lead inhibits both ferrocheatase (increasing the zincProtoporphyrin) and ALA dehydrase (increasing Protoporphyrin) and ALA dehydrase (increasing δδ -ALA)ALA)

PLPPLP

De novo Pyrimidine SynthesisDe novo Pyrimidine Synthesis

Synthesis of Purine Nucleotides, Showing the Synthesis of Purine Nucleotides, Showing the Inhibitory Effect of Some Structural AnalogsInhibitory Effect of Some Structural Analogs

PRPP is an allosteric PRPP is an allosteric Positive modulator inPositive modulator inthe step 1. the step 1.

AMP, CMP & IMP areAMP, CMP & IMP areInhibitors in step 1.Inhibitors in step 1.

The Reactions of the Urea The Reactions of the Urea CycleCycle

NAGNAG

Intermediary Metabolism Related to Intermediary Metabolism Related to Nitrogen Metabolism & The Urea Nitrogen Metabolism & The Urea

CycleCycle

CytosolCytosol

MitochondrionMitochondrionCO2

-

CO2-

+H3N-C-H

CH2

CH2

GluGlu

TCA CycleTCA Cycle

Urea Urea CycleCycle



NAG:N-acetyl glutamate; (in the formation of urea, one amino group is derived from free NH4+ ion, while the other is from aspartate. Carbon is obtained from CO2.(*) mitochondrial enzymes, the rest of the enzymes are cytosolic).

NAG*

*Cytosol

Mitochondria

**

The Ornithine Aminotransferase Reaction

This is a reversible reaction dependent on PLP, which normally favors ornithine degradation.

Ornithine aminotransferase

The reactions are independent and irreversible

Synthesis of Glutamine & its Conversion to Glutamate

**



NAG:N-acetyl NAG:N-acetyl glutamate; (in the glutamate; (in the formation of urea, formation of urea, one amino group one amino group is derived from is derived from free NHfree NH44+ ion, + ion, while the other is while the other is from aspartate. from aspartate. Carbon is obtained Carbon is obtained from COfrom CO22.(*) .(*) mitochondrial mitochondrial enzymes, the rest enzymes, the rest of the enzymes of the enzymes are cytosolic).are cytosolic).

NAGNAG*

*Cytosol

Mitochondria

**

**

Biosynthesis of CatecholaminesBiosynthesis of Catecholamines

Catecholamins:Catecholamins: include include adrenaline, noradrenalineadrenaline, noradrenaline and and dopamine (DOPA),dopamine (DOPA), with roles as hormones and with roles as hormones and neurotransmitters. neurotransmitters. CatecholaminesCatecholamines (epinephrine and (epinephrine and norepinephrine) are produced naturally in the body and function norepinephrine) are produced naturally in the body and function as key neurologic chemicals.as key neurologic chemicals.

PLP

Synthesis of dTMP from dUMP, IlustratingSynthesis of dTMP from dUMP, Ilustrating Sites of Action of Sites of Action of Antineoplastic DrugsAntineoplastic Drugs

Methotrexate:Methotrexate: An anticancer drug that acts as a An anticancer drug that acts as a folic acid antagonistfolic acid antagonist to interfere with cellular to interfere with cellular reproduction and is used in the treatment of reproduction and is used in the treatment of psoriasis, certain cancers, and certain inflammatory psoriasis, certain cancers, and certain inflammatory diseases, such as rheumatoid arthritis. diseases, such as rheumatoid arthritis.

5-Fluorouracil:5-Fluorouracil: An antineoplastic agent, used An antineoplastic agent, used especially in the treatment of cancers of the skin, especially in the treatment of cancers of the skin, breast, and digestive system.breast, and digestive system.

Salvage Pathways of PurineSalvage Pathways of Purine Nucleotide SynthesisNucleotide Synthesis

Lesch-Nyhan SyndromeLesch-Nyhan Syndrome is characterized is characterized by the by the deficiency of hypoxanthine-guanine deficiency of hypoxanthine-guanine phosphoribosyl transferase (HGPRTphosphoribosyl transferase (HGPRT), leads ), leads to accumulation of PRPP and uric acid, the to accumulation of PRPP and uric acid, the condition is know as “condition is know as “Hyperuricemia”.Hyperuricemia”.

HyperuricemiaHyperuricemia is the presence of high levels of uric is the presence of high levels of uric acid / sodium urate crystals in the blood. The upper acid / sodium urate crystals in the blood. The upper end of the normal range is 360 µmol/L (6 mg/dL) for end of the normal range is 360 µmol/L (6 mg/dL) for women and 400 µmol/L (6.8 mg/dL) for men. women and 400 µmol/L (6.8 mg/dL) for men.

PRPP=Phosphoribosyl pyrophospate.PRPP=Phosphoribosyl pyrophospate.

Phenylketoneuria (PKU)Phenylketoneuria (PKU)

DeficiencyDeficiency

HomocystinuriaHomocystinuria

CystathionuriaCystathionuria

Trans-Sulfuration PathwayTrans-Sulfuration Pathway

Enzyme Deficiency in HomocystinuriaEnzyme Deficiency in Homocystinuria

CystathinaseCystathinase

NHNH33PLPPLP

Trans-Sulfuration pathway is Trans-Sulfuration pathway is analagous to transamination for AAs.analagous to transamination for AAs.

Two RXNs, both use pyridoxal Two RXNs, both use pyridoxal phosphate (Vit Bphosphate (Vit B66) as a cofactor (as ) as a cofactor (as

with transamination).with transamination).

☻

BB66

Summary of the Summary of the Metabolism of Metabolism of Amino Acids Amino Acids

Biosynthesis of CatecholaminesBiosynthesis of Catecholamines

Catecholamins:Catecholamins: include include adrenaline, noradrenalineadrenaline, noradrenaline & & dopamine dopamine (DOPA),(DOPA), with roles as hormones and neurotransmitters. with roles as hormones and neurotransmitters.

CatecholaminesCatecholamines (epinephrine & norepinephrine) are produced (epinephrine & norepinephrine) are produced naturally in the body and function as key neurologic chemicals.naturally in the body and function as key neurologic chemicals.

** **PLPPLP **

Ubiquitin-Proteosome Degradation Ubiquitin-Proteosome Degradation Pathway of Proteins Pathway of Proteins

Key Concept Map For Heme MetabolismKey Concept Map For Heme Metabolism

**

Synthesis of dTMP from dUMP, IlustratingSynthesis of dTMP from dUMP, Ilustrating Sites of Action of Sites of Action of Antineoplastic Drugs

Methotrexate:Methotrexate: An anticancer drug that acts as a An anticancer drug that acts as a folic acid antagonistfolic acid antagonist to interfere with cellular to interfere with cellular reproduction and is used in the treatment of reproduction and is used in the treatment of psoriasis, certain cancers, and certain inflammatory psoriasis, certain cancers, and certain inflammatory diseases, such as rheumatoid arthritis. diseases, such as rheumatoid arthritis.

5-Fluorouracil:5-Fluorouracil: An antineoplastic agent, used An antineoplastic agent, used especially in the treatment of cancers of the skin, especially in the treatment of cancers of the skin, breast, and digestive system.breast, and digestive system.

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Half-Life of the Amino AcidsHalf-Life of the Amino Acids

What determines whether a What determines whether a protein will become ubiquinated?protein will become ubiquinated?

NHNH44++ * *

Ammonium ion

Uric acidH2N-C-NH2

Urea

O

NH4+

O

O

HN

NH

NH

NH

O

Most terrestrial vertebrates Birds & reptilesFish & other

aquatic vertebrates

Some animals excrete NH4

+ or uric acid.

Amino Amino acidsacids

The carbon chains are broken down to molecules that feed into the TCA cycle.

Most mammals convert amino-acid nitrogen to urea for excretion

Excretion of Nitogenous Waste ProductsExcretion of Nitogenous Waste Products

Degradation of Degradation of Purine Purine

Nucleotides to Nucleotides to Uric AcidUric Acid

*

HomocystinuriaHomocystinuria

CystathionuriaCystathionuria

Trans-Sulfuration PathwayTrans-Sulfuration Pathway

Enzyme Deficiency in HomocystinuriaEnzyme Deficiency in Homocystinuria

CystathinaseCystathinase

NHNH33PLPPLP

Trans-Sulfuration pathway is Trans-Sulfuration pathway is analagous to transamination for AAs.analagous to transamination for AAs.

Two RXNs, both use pyridoxal Two RXNs, both use pyridoxal phosphate (Vit Bphosphate (Vit B66) as a cofactor (as ) as a cofactor (as

with transamination).with transamination).

☻

BB66

Alb

inis

mA

lbin

ism

Patient with oculocutaneous Patient with oculocutaneous albinism, showing blond hair &albinism, showing blond hair &white eyebrows and lashes.white eyebrows and lashes.

**

Transport of Ammonia from Transport of Ammonia from Peripheral Tissues to the LiverPeripheral Tissues to the Liver

Genetic Deficiencies in Some of the Urea CycleGenetic Deficiencies in Some of the Urea Cycle Enzymes can be Treated Pharmacologically Enzymes can be Treated Pharmacologically

Benzoate

Benzoyl-CoA

Hippurate (benzoylglycine)

CO2-

ATP + CoA-SH

AMP + PPi

Glycine

CoA-SH

Phenylacetate

Phenylacetyl-CoA

O

S-CoA

Phenylacetyl-glutamine

ATP + CoA-SH

AMP + PPi

Glutamine

CoA-SH

The amide products of these reactions (hippurate and phenylacetylglutamine) are excreted in the urine. Synthesizing the Gly or Gln removes ammonia.

CO2-

O

S-CoA

O

NH

CO2-

O

N

NH2

O

HCO2

-

Lesions of the Lips of Lesch-Nyhan Patient Lesions of the Lips of Lesch-Nyhan Patient Caused by Self-mutilationCaused by Self-mutilation

DeDe novonovo Synthesis Precursors Synthesis Precursors

Ribonucleotides!

Formation of Bilirubin From HemeFormation of Bilirubin From Heme

Dubin-Johnson syndromeDubin-Johnson syndrome is an autosomal is an autosomal recessive disorder which causes an increase recessive disorder which causes an increase of conjugated bilirubin without elevation of liver of conjugated bilirubin without elevation of liver ALT & AST. ALT & AST.

Defect in the ability of hepatocytes to secrete Defect in the ability of hepatocytes to secrete conjugated bilirubin into the bile. It is usually conjugated bilirubin into the bile. It is usually asymptomatic but may be diagnosed in early asymptomatic but may be diagnosed in early infancy based on laboratory tests.infancy based on laboratory tests.

Enterohepatic circulationEnterohepatic circulation refers to the circulation of bile refers to the circulation of bile from the liver, where it is produced, to the small intestine, from the liver, where it is produced, to the small intestine, where it aids in digestion of fats and other substances, where it aids in digestion of fats and other substances, back to the liver. Endogenous bacteria play an important back to the liver. Endogenous bacteria play an important role in enterohepatic circulation.role in enterohepatic circulation.

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ENDOCYTOSIS

Exocytosis:Macromolecules and particles enter the cell by endocytosis.

Phagocytosis- part of the plasma membrane engulf large particlesa. Phagosome + lysome = Phagolysosome.

Cytoplasm

Exocytosis

ENDOCYTOSIS

Endocytosis:Macromolecules and particles enter the cell by endocytosis.

Phagocytosis- part of the plasma membrane engulf large particlesa. Phagosome + lysome = Phagolysosome.

Phagocytosis (Cellular Eating).

LiveLiverr

AlaninAlaninee

CarboCarbonn

NitrogeNitrogenn

UreUreaa

UrinUrinee

GlucosGlucosee

The Glucose-Alanine The Glucose-Alanine CycleCycle

MusclMusclee

AminAmino o acid acid 11

AlaninAlaninee

PyruvatPyruvatee

GlutamaGlutamatete

αα-KG-KG

GlycolyGlycolysissisGlucosGlucos

ee

αα--KetoKetoacid1acid1

When muscles produce lactate during times of decreased O2, they also produce alanine. This alanine is shuttled to the liver where it is used to make glucose.

Reactions Catalyzed During AA Reactions Catalyzed During AA CatabolismCatabolism

A.A. Alanine AminoransferaseAlanine AminoransferaseB.B. Aspartate Aspartate

AminotransfereaseAminotransferease

Alanine Aminotransferase & Alanine Aminotransferase & Aspartate Aspartate

AminotransferaseAminotransferaseestimations are widely used estimations are widely used

to to assess liver function.assess liver function.

A patient presents with Hemolytic Anemia. Which of the followingA patient presents with Hemolytic Anemia. Which of the followingshould be elevated in the BLOOD?.should be elevated in the BLOOD?. A.A. Bilirubin Bilirubin B.B. Ammonia Ammonia C.C. UreaUreaD.D. MitochondriaMitochondriaE.E. RiboseRibose

Ans: A.Ans: A.

Your patient is a 60-year-old male who has a long history ofYour patient is a 60-year-old male who has a long history ofalcohol abuse. He is confused, has an enlarged liver, and a alcohol abuse. He is confused, has an enlarged liver, and a flapping tremor at the wrist (asterixis). Your diagnosis is hepatic flapping tremor at the wrist (asterixis). Your diagnosis is hepatic encephalopathy. A treatment is a diet of branched-chain amino encephalopathy. A treatment is a diet of branched-chain amino acids. Which one of the following sets of amino acids is acids. Which one of the following sets of amino acids is composed of branched-chain amino acids?.composed of branched-chain amino acids?.

A. Methionine, proline, and cysteine.A. Methionine, proline, and cysteine.B. Glycine, alanine, and serine.B. Glycine, alanine, and serine.C. Valine, leucine, isoleucine.C. Valine, leucine, isoleucine.D. D. Aspartate, glutamate, and asparagine.Aspartate, glutamate, and asparagine.E.E. Tryptophan, phenylalanine, and tyrosine.Tryptophan, phenylalanine, and tyrosine.

Ans: C. Ans: C. Only valine, leucine, and isoleucine compose the only Only valine, leucine, and isoleucine compose the only set of branched-chain amino acids.set of branched-chain amino acids.

LiveLiverr

AlaninAlaninee

CarboCarbonn

NitrogeNitrogenn

UreUreaa

UrinUrinee

GlucosGlucosee

The Glucose-Alanine The Glucose-Alanine CycleCycle

MusclMusclee

AminAmino o acid acid 11

AlaninAlaninee

PyruvatPyruvatee

GlutamaGlutamatete

αα-KG-KG

GlycolyGlycolysissisGlucosGlucos

ee

αα--KetoKetoacid1acid1

When muscles produce lactate during times of decreased O2, they also produce alanine. This alanine is shuttled to the liver where it is used to make glucose.

1.Which biomolecule acts as a positive modulator for the first step of the urea cycle which is catalyzed by carbamoyl phosphate synthetase-I (CPS-I).

A. Gultamate.B. Glutamine. C. N-Acetyl Glutamate (NAG).D. Aspartate.E. Ammonium ions (NH4+).

Ans: C.

7. Which of the following is a common compound shared by The TCA cycle and the urea cycle?

A. α-ketoglutarate.B. Succcinyl Coenzyme A (CoA).C. Oxaloacetate.D. Fumarate.*E. Arginine.

Ans: D.

8. Which of the following enzymes requires adenosine triphosphate (ATP) to mediate its reactions?

A. Argininosuccinate lyase.B. Argininosuccinate synthetase.C. Arginase.D. Glutaminase.E. Ornitine transcarbamoylase.

Ans: B.

10. Two days after a full-term normal delivery, a neonate begins to hyperventilate, develops hypothermia and cerebral edema, and becomes comatose. Urinalysis reveals high levels of glutamine and orotic acid. The BUN is below normal. Which enzyme is most likely to be deficient in this child?

A. Cytoplasmic glutaminase.B. Cytoplasmic carbamoyl phosphate synthetase.C. Cytoplasmic orotidylate decarboxylase.D. Mitochondrial carbamoyl phosphate synthetase.E. Mitochondrial ornitihine transcarbamoylase.

Ans: E.

11. Transamination reactions are essential for ammonia assimilation. What cofactor is required to catalyze transamination reactions?

A. pyridoxal phosphate (PLP).B. thiamin pyrophosphate.C. biotin.D. NAD+.E. NADPH.

Ans: A.

12. Which of the following enzymes function in the biologicalassimilation of ammonia?

A. Glutamate dehydrogenase.B. Glutamine synthetase.C. Glutamate synthase.D. All of the above.***E. None of the above.

Ans: D.

A 55-year-old man suffers from cirrhosis of the liver. Toxins suchas ammonia are not properly metabolized by the liver and can now damage structures such as the brain. Which of the followingamino acids covalently binds ammonia and transports and storesit in a nontoxic form? A. Aspartate.B. Glutamate.C. Serine.D. Cysteine.E. Histidine.

Ans: B.

14. Which amino acid participates as a pathway intermediate in the urea cycle?

A. Lysine.B. Arginine.***C. Glutamine.D. Histidine.E. Tyrosine.

Ans: B

Urea Cycle Must Know Key PointsUrea Cycle Must Know Key Points1.1. Urea cycle occurs partly in ……….. and partly in the ……….Urea cycle occurs partly in ……….. and partly in the ……….

Ans:Ans: Mitochondria, Cytosol / Cytoplasm. Mitochondria, Cytosol / Cytoplasm.

2. The rate-limiting step (committed step) in the urea cycle is 2. The rate-limiting step (committed step) in the urea cycle is catalyzed by the enzyme …………catalyzed by the enzyme …………

Ans:Ans: Carbamoyl phosphate synthetase-I (CPS-I). Carbamoyl phosphate synthetase-I (CPS-I).

3. The biomolecule acts as a positive modulator in the first step of 3. The biomolecule acts as a positive modulator in the first step of the urea cycle is……………the urea cycle is……………Ans:Ans: N-Acetyl glutamate (NAG). N-Acetyl glutamate (NAG).

4. ………….can be converted to arginine by a series of reactions,4. ………….can be converted to arginine by a series of reactions, some of which requires urea cycle enzymes.some of which requires urea cycle enzymes.Ans:Ans: Glutamate. Glutamate.

5. The enzymes are responsible for producing the direct donors of nitrogen into the 5. The enzymes are responsible for producing the direct donors of nitrogen into the pathway producing urea, include ………. And ………..pathway producing urea, include ………. And ………..

Ans:Ans: Aspartate aminotransferase and carbmoyl phosphate sythetase.Aspartate aminotransferase and carbmoyl phosphate sythetase.

6. The accumulation of glutamine and orotic acid in the bood and an ultimate ammonia 6. The accumulation of glutamine and orotic acid in the bood and an ultimate ammonia toxicity in the newborn is due to the deficiency of the urea cycle enzyme……….toxicity in the newborn is due to the deficiency of the urea cycle enzyme……….

Ans: Ans: Mitochondrial ornitihine transcarbamoylase (OTC).Mitochondrial ornitihine transcarbamoylase (OTC).

7. The common nitrogen acceptor for all reactions involving transaminase is ……………7. The common nitrogen acceptor for all reactions involving transaminase is ……………

Ans: α-ketoglutarate.Ans: α-ketoglutarate.

8. The common nitrogen donor for all reactions involving transaminase is ……………8. The common nitrogen donor for all reactions involving transaminase is …………… Ans:Ans: Oxaloacetate (OAA). Oxaloacetate (OAA).

9. The common compound shared by the TCA cycle and the urea cycle is ……………… 9. The common compound shared by the TCA cycle and the urea cycle is ……………… Ans:Ans: Fumarate. Fumarate.

10. Hyperammonemia caused by a congenital defect of the urea cycle 10. Hyperammonemia caused by a congenital defect of the urea cycle enzyme………..which is characterized by accumulation of excess amount of arginine enzyme………..which is characterized by accumulation of excess amount of arginine in the blood.in the blood.

Ans: Ans: Arginase.Arginase.

11. The urea cycle enzyme which requires adenosine triphosphate (ATP) to mediate its 11. The urea cycle enzyme which requires adenosine triphosphate (ATP) to mediate its reactions is ?. reactions is ?.

Ans: Ans: Argininosuccinate synthetase.Argininosuccinate synthetase.

12. The reaction catalyzed by an urea cycle enzyme 12. The reaction catalyzed by an urea cycle enzyme ornithine aminotransferaseornithine aminotransferase which which requires --------- as a coenzyme, which converts ornithine and requires --------- as a coenzyme, which converts ornithine and αα-ketoglutarate into -ketoglutarate into glutamate. glutamate.

Ans:Ans: Pyridoxal phosphate (PLP). Pyridoxal phosphate (PLP).

NoNo DisorderDisorder Answer Answer Enzyme DefectEnzyme Defect

11 Hyperammonemia type IHyperammonemia type I A. Argininosuccinate synthaseA. Argininosuccinate synthase

22 Hyperammonemia type IIHyperammonemia type II B. Ornithine transcarbomylase (OTC)B. Ornithine transcarbomylase (OTC)

33 CitrullinemiaCitrullinemia C. Argininosuccinate lyaseC. Argininosuccinate lyase

44 Argininosuccinic AciduriaArgininosuccinic Aciduria D. ArginaseD. Arginase

55 HyperargininemiaHyperargininemia E. Carbamoyl-P synthase-I (CPS)E. Carbamoyl-P synthase-I (CPS)

Answer:Answer: 1E; 2-B; 3-A; 4-C; 5-D1E; 2-B; 3-A; 4-C; 5-D

Match the Urea Cycle Disorders With Match the Urea Cycle Disorders With the Enzyme Defectthe Enzyme Defect

Genetic Deficiencies in Some of the Urea Cycle Enzymes can be Treated Genetic Deficiencies in Some of the Urea Cycle Enzymes can be Treated Pharmacologically by eliminating the amino acids such as glycine and glutamine by Pharmacologically by eliminating the amino acids such as glycine and glutamine by administering, administering,

A. Aspartic acid.A. Aspartic acid.B. B. Benzoic acid and phenylacetate.Benzoic acid and phenylacetate.C. GABA.C. GABA.D. Pyridoxal phosphate.D. Pyridoxal phosphate.E. Methionine.E. Methionine.

Ans: B. Ans: B. The amide products of these reactions (hippurate and The amide products of these reactions (hippurate and phenylacetylglutamine) are excreted in the urine. Synthesizing the Gly or Gln phenylacetylglutamine) are excreted in the urine. Synthesizing the Gly or Gln removes ammonia.removes ammonia.

The Reaction Catalyzed by Glutamate Dehydrogenase which reversibly converts The Reaction Catalyzed by Glutamate Dehydrogenase which reversibly converts glutamate to glutamate to αα-ketoglutarate require the cofactor,-ketoglutarate require the cofactor,

A.A. ATPATPB.B. NADNADC.C. NAD(P)NAD(P)++ /NAD(P)H. /NAD(P)H. D.D. BiotinBiotinE.E. Pyridoxal phosphate.Pyridoxal phosphate.

Ans: C. Ans: C. The cofactors require by the glutamate dehydrogenase isThe cofactors require by the glutamate dehydrogenase isNAD(P)+ /NAD(P)H. NAD(P)+ /NAD(P)H.

Hyper ammonemia II is characterized by mitochondrial ornithine transcarbamoylase deficiency, with the common signs and symptoms include hyperventilation, develops hypothermia and cerebral edema, and becomes comatose. Patients urine will show increased excretion of glutamine and orotic acid, but BUN will be below normal.

Glutamate: The amino acids glutamate covalently binds ammonia and transports and stores it in a nontoxic form.

Arginase: The urea cycle enzyme arginase deficiency will lead to the accumulation of NH4+ ions in blood, characterized by vomiting and tremors.

Aspartate: Via the enzymes of urea cycle, aspartate provides nitrogen for synthesis of arginine, it provides NH2 group.

Ammonium ions (NH4+) and CO2 will accumulate in blood in the absence of a CPS-I, Hyperammonemia due to CPS-I deficiency.

Via the enzymes of urea cycle, aspartate provides nitrogen forsynthesis of arginine, the guanidine group of arginine will be releases as urea and the byproduct ornithine, ornithine will be transferred to mitochondria.

LFTs: Estimation of serum ALT, AST, gamma glutamyl trasferase, alkaline phosphatase, total protein, albumin/globulin ratio, bilirubin estimation will be helpful to evaluate liver function, and hence referred as liver function tests (LFTs).

Urea synthesis will increase on high protein diet, prolonged starvation and muscle wasting diseases.

The urea cycle enzyme The urea cycle enzyme Arininosuccinate synthetaseArininosuccinate synthetase requires adenosine requires adenosine Triphosphate Triphosphate (ATP)(ATP) to mediate its reaction to mediate its reaction

Fumarate is the common compound shared by Urea Cycle and TCA cycle.Fumarate is the common compound shared by Urea Cycle and TCA cycle.

The amino acid ornitine will be recycled between mitochondria and cytoplasm in The amino acid ornitine will be recycled between mitochondria and cytoplasm in urea cycle.urea cycle.

The rate-limiting step in Urea cycle is catalyzed by CPS-I, The rate-limiting step in Urea cycle is catalyzed by CPS-I,

Presence of excess amount of CO2 and NH4+ ions and aspartate and Presence of excess amount of CO2 and NH4+ ions and aspartate and availability of NAG stimulates the Urea cycle, and hence ammonia toxicity will be availability of NAG stimulates the Urea cycle, and hence ammonia toxicity will be cleared as urea production and excretion in urine. Sodium benazoate cleared as urea production and excretion in urine. Sodium benazoate administration will reduce ammonia toxicity by utilizing glycine and increasing the administration will reduce ammonia toxicity by utilizing glycine and increasing the excretion of glycine as Hippuric acid.excretion of glycine as Hippuric acid.

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