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8/7/2019 Caudales Amino Acid Metabolism
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Amino Acid Metabolism
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Dy namics of ProteinAnd Amino Acid Metabolism
Dietar y Proteins Digestion to Amino Acids
Transport in Blood to Cells
Protein S y nthesis Functional Proteins
Protein Degradation In
Proteasomes FollowingTagging With Ubiquitin
Amino Acids
Metabolites
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Digestion of ProteinsStomach: Pepsinogen Pepsin (max. act. pH 2)
Small Intestine: Tr y psinogen Tr y psin
Tr y psin cleaves:
Chy motr y psinogen to chy motr y psin
Proelastase to elastaseProcarbox y peptidase to carbox y peptidase
Aminopeptidases (from intestinal epithelia)
Enteropeptidase
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Lumen
Amino Acids Oligopeptides
Intestinal Absorption
Oligopeptides
Amino Acids
Peptidases
Blood
Transport Protein
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Incorporation of NH 4+
Into Organic
Compounds1) NH 4
++ HCO3
-+ 2 ATP NH 2 CO2 PO3
-2 + 2 ADP +
Carbamoy l Phosphate P i + 2 H +
2) NH 4+
+
Carbamoy l
Phosphate
S y nthase I
(CPS-I)
Glutamate
dehy drogenaseO
- O 2 CCH 2 CH 2 CCO 2 -
E-K etoglutarate Glutamate
3+
-2 2 2 2
-
T A y cle
NADP+NADPH +
H+
mitochondria
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Incorporation of NH 4+
Into Organic
Compounds (Cont.)
NH
+
¡ O¢
CCH ¢
CH ¢
CHCO¢
¡ + NH 4++
2 ATP
£
¤
2 2 2 2 ¥
Glutamine
Glutamate Glutamine
S y nthaseMg
¦ ¦
of glutamine donated to other compounds
in sy nthesis of purines, py rimidines,
and other amino acids
)
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Biosy nthesis of Amino Acids:
Transaminations
Amino Acid 1 +E-K eto Acid 2 Amino Acid 2 +E-K eto Acid 1
§
+
-2 2 2 2
-
Glutamate
R- 2 -+
O
-O 2 CCH 2 CH 2 CCO 2
-
E-K etoglutarate
̈
̈
©
+
P y ridoxal phosphate (P LP)Dependent Aminotransferase
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Transaminations: ole of P LP
2 P 3-2
3
2 2 2 -
3+
2 -
2 P 3-2
3
2
2 P 3-2
3
2 2 2 -
2 -
2 2
2 P 3-2
3
2
- 2 2 2 2 -
+ +
++
- 2 2 2 2
-
2
Tautomerization
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TransaminationsGlutamate E-K etoglutarate
+ +
P y ruvate Alanine
Glutamate E-K etoglutarate
+ +
Oxaloacetate Aspartate
Glutamate-P y ruvate
Aminotransferase
(Alanine Transferase ALT)
Glutamate-Oxaloacetate
Aminotransferase
(Aspartate Transferase AST)
Blood levels of these aminotransferases, also called transaminases,are important indicators of liver disease
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Metabolic Classification of the AminoAcids
� Essential and Non-essential
� Glucogenic and K etogenic
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Non-Essential Amino Acids in Humans
� Not required in diet
� Can be formed from E-keto acids by
transamination and subsequent reactions
� Alanine
� Asparagine
� Aspartate
� Glutamate� Glutamine
� Gl y cine
� Proline
� Serine
� C y steine (from Met*)� T y rosine (from Phe*)
* Essential amino acids
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Essential Amino Acids in Humans
� Required in diet
� Humans incapable of forming requisite
carbon skeleton
� Arginine*
� Histidine*
� Isoleucine
� Leucine� Valine
� Ly sine
� Methionine
� Threonine
� Pheny lalanine� Tr y ptophan
* Essential in children, not in adults
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Glucogenic Amino Acids� Metabolized to E-ketoglutarate, py ruvate, oxaloacetate,
fumarate, or succiny l CoAPhosphoenolpy ruvate Glucose
� Aspartate
� Asparagine
� Arginine
� Pheny lalanine
� T y rosine� Isoleucine
� Methionine
� Valine
� Glutamine
� Glutamate
� Proline
� Histidine
� Alanine
� Serine
� C y steine
� Gl y cine
� Threonine
� Tr y ptophan
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K etogenic Amino Acids� Metabolized to acet y l CoA or acetoacet y l CoA
Animals cannot convert acet y l CoA or acetoacet y l CoA to py ruvate
� Isoleucine
� Leucine *
� Ly sine *
� Threonine
� Tr y ptophan
� Pheny lalanine� T y rosine
* Leucine and l y sine are onl y ketogenic
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Amino Acids Formed From E-K etoglutarate
-
-
-
-
-
Transamination or
Glutamatedehy drogenase
E-K eto-
glutarate
Glutamate
Glutamine
Glutamine
sy nthase
! !
" # 2 -
$
4 Steps
Proline
%
&
% 2 2 2 2 - rnithine
5 Steps
Arginine
Urea y cle
'
(
2
2 N= - N 2 2 2 2 -
Guanidino group
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GABA Formation
H 3+
-O 2 CCH 2 CH 2 CHCO 2
-
H 3+
-O 2 CCH 2 CH 2 CH 2
Glutamate Gamma-aminobut y rate
(GABA)
GABA is an important inhibitor y neurotransmitter in the brain
Drugs (e.g., benzodiazepines) that enhance the effectsof GABA are useful in treating epilepsy
Glutamatedecarbox y lase
CO2
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Arginine S y nthesis: The Urea C y cle
H 3+
-O 2 CC H 2 C H 2 C H C O 2
-
H C OC H 3
-O 2 CC H 2 C H 2 C H C O 2
-
H 3+
H 3 C H 2 C H 2 C H 2 C H C O 2
-+
H 4
+ +
H
C O
3
-H
2 C O
2 P O
3
-2
Glutamate -Acet y lglutamate
Ornithine
H 3+
H 2 C O H C H 2 C H 2 C H 2 C H C O 2
-
)
-Acet y lglutamatesy nthase
CoASAc
4 Steps
CPS -I
Ornithine
Transcarbamoy lase ( OTC)
(mitochondria)
Citrulline
Ureido group
Carbamoy l phosphate
Activates
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Urea Formation
� Occurs primaril y in liver; excreted by kidney
� Principal method for removing ammonia
� H y perammonemia:
� Defects in urea c y cle enz y mes (CPS, OTC, etc.)
� Severe neurological defects in neonates
� Treatment:
» Stop protein intake
» Dial y sis
» Increase ammonia excretion: Na benzoate, Na pheny lbut y rate, L-
arginine, L-citrulline
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Blood Urea Nitrogen
� Normal range: 7-18 mg./d L
� Elevated in amino acid catabolism
� Glutamate N-acet y lglutamateCPS-1 activation
� Elevated in renal insufficienc y
� Decreased in hepatic failure
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S y nthesis of Nitric Oxide
NH 3+NH 2
H 2 N =C-HN CH 2 CH 2 CH 2 CHCO 2 -
+
NH 3+
NH 2 CONH CH 2 CH 2 CH 2 CHCO 2 - + NO
Nitric oxide sy nthase (NOS)
Arginine
Citrulline
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Nitric Oxide
� Cell messenger
� Implicated in a wide range of phy siological
and pathophy siological events:
� Vasodilation:
� Activates guany l y l c y clase cGMP � Nitrogl y cerin Gl y cerin + NO
� Sildenafil (Viagra): in vascular smooth muscle:
NO cGMP GMP
Phospho-
diesterase-5
Blocks
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Formation of Serine
G H H
I H
P
G Q G
R
S
P
I
I G
P
S
I H
P
G Q G
R
S
P
I G
P
S
I = G
T U
V
+U
W U
X
Y ` Y
V
a X
W
W Y
X
a
T U
V
+U
W U
X
Y U
W Y
X
a
W
Glucose Gl y col y sis
hospho
gl y ceratehospho
hy drox y py ruvate
hosphoserineSerine (Ser)
y ruvate
Dehy drogenase
b AD+b ADH +
H +
Glutamate
E-K etoglutarate
Transaminase
Phosphatase
3 Steps
Inhibits
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Conversion of Serine to Gl y cine
N
N
N
NH2N
OH
CH2NHR
H
H
N
H
NCH2
N
H2C
Folate
Tetrahy drofolate(FH 4)
Dihy drofolatereductase
N 5 , N 10 -Methy lene FH 4
NH 3+H
C H 2 OH
CO 2 -
C Serine
NH 3+H
H
CO 2 -
C
Gl y cine
Serine hy drox y methy l transferase (P LP-dep.)
K ey intermediate
in biosy nthesis of
purines and
formation of
thy mine Important in
biosy nthesis of heme,porphy rins, and purines
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Sulfur-Containing Amino Acids
c
d
C S C C C C -
e
f
S C g
C g
C C g
-
h
i
C p C C p
-
h
i
S C q
C q
C C q
-r
s
S C t
C C t
-C
u
C C v
C v
-
Methionine(Essential)
L- omoc y steine
Methionine
S y nthase
(Vit. B1 -dep.)F 4
5-Methy l
F 4
w x
y
�
x
C x �
� x
C �
�
-
C Serine
C y stathionine
C y stathionine
F-sy nthase
(P LP-dep.)
C y stathioninel y ase
C y steine(Non-essential)
+
F-H y drox y -but y rate
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Homoc y steine
Homoc y steinuria
� Rare; deficienc y of c y stathionine F-sy nthase
� Dislocated optical lenses
� Mental retardation
� Osteoporosis� Cardiovascular disease death
High blood levels of homoc y steine associated with
cardiovascular disease
� May be related to dietar y folate deficienc y
� Folate enhances conversion of
homoc y steine to methionine
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Methionine Metabolism: Methy l Donation
�
�
�
�
�
�
�
�
�
-� 2 � �
�
�
�
2 �
�
2 - � -�
2 �
�
�
2
�
�
3 +�
�
3
+3
+
3 2 2 2 -
�
�
�
�
�
�
�
�
�
-� 2 � �
�
�
�
2 �
�
2 - � -�
2 �
�
�
2
�
�
3+
�
�
�
�
�
� � � �
� 3 � � � 2 � � 2 � � 2 - � - � 2 �
� � 2
� � 3
+
-Adenosy l methioninesy nthase
ATP
-Adenosy l
Methionine
( AM)
-Adenosy l
homoc y steine
Methy l-transferases
Decarbox y lated AM
AM
Decarbox y lase
2
Methionine
R-
R- 3
+
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Pol y amine Biosy nthesis
3+
3 2 2 2 2 -
+
3
3
++++
3
3
++
rnithine(from urea c y cle)
Putrescine
2
� rnithine
decarbox y lase
( � DC )
(P LP-dep.)
Decarbox y lated SAM
Spermidinesy nthase
5¶-Methy lthio-
adenosine
� 3 �
�
�
� � 3
�
+++
Spermidine
Spermine
Decarbox y lated
SAM
Spermine
sy nthase
5¶-Methy lthio-
adenosine
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Pol y amines
� Spermidine and spermine found in virtuall y
all procar y otic and eucar y otic cells
� Precise role undefined � Bind to nucleic acids
� Inhibition of biosy nthetic pathway :
H 2 N NH 2
O 2 H
HF 2
E-Difluoromethy l-
ornithine ( DFMO)
(Eflornithine) - inhibits ODC;
used to treat Pneumoc y stis carinii infectons
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Creatine and Creatinine
H 3+H 2
+H 2 =C-H C H 2 C H 2 C H 2 C H C O 2
-
ArginineGl y cine Ornithine
Arginine-gl y cine
transamidinase
( K idney )H 2
H 2 =C-H C H 2 C O 2 -
+
Guanidoacetate
HPO3
-2
C H 3
+H 2 =C- C H 2 C O 2
-
Guanidoacetate
Methy ltransferase
( Liver)
SAM + AT P
S-Adenosy l-
homoc y steine
+ ADP
P hosphocreatine
H
C H 3
H
O
Creatinine(Urine)
�
on-enz y matic (Muscle)
H 2
C H 3
H 2 =C- C H 2 C O 2 -
+
Creatine kinase(Muscle)
AT P
Creatine ADP
+ P i
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Creatine and Creatinine
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Creatine:
� Dietar y supplement
� Used to improve athletic performance
Creatinine:� Urinar y excretion generall y constant;
proportional to muscle mass
Creatinine Clearance Test:
� Compares the level of creatinine in urine (24 hrs.)
with the creatinine level in the blood � Used to assess kidney function
� Important determinant in dosing of several drugs
in patients with impaired renal function
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Histidine Metabolism:Histamine Formation
N
N H
H �
H �
�
N H �
N
N H
H �
H �
N H �
Histidine Histamine
Histidine
decarbox y lase
�
Histamine:
� S y nthesized in and released by mast cells
� Mediator of allergic response: vasodilation, bronchoconstriction
(H 1 receptors)
� H 1 blockers: Diphenhy dramine (Benadr y l)
Loratidine ( laritin)
� Stimulates secretion of gastric acid (H
receptors) H
blockers: imetidine (Tagamet); ranitidine (Zantac)
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Pheny lalanine and T y rosine
C 2 C C 2-
3+
C 2 C C 2-
3+
2
C C C 3
2
C C C 3
Pheny lalanine(Essential)
T y rosine
( on-essential)
Pheny lalanine-4-
Monoox y genase
(Pheny lalanine
hy drox y lase)
2
2
+
+
ADP + +
ADP +
Tetrahy drobiopterin
(B 4)
Dihy drobiopterin
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Normal Utilization of Pheny lalanine
Pheny lalanine
Protein (~25%)
T y rosine (~75%)
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Sapropterin ( K uvan)
Indicated for reduction of pheny lalanine blood levels in patients with BH 4-responsive P K U
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Catecholamine Biosy nthesis
C 2 C C 2-
3+
C 2 C C 2-
3+
C 2 C 2 2
C C 2 2
C C 2 C 3
T y r hy drox y lase
2
T y rosine Dihy drox y pheny lalanine
( D PA)
Dopamine
D PA
decarbox y lase C 2
Dopamine
hy drox y lase
orepinephrine
Catechol
Epinephrine
(Adrenaline)
SAM
S -Adenosy l -
homoc y steine
Methy l
transferase
D PA, dopamine, norepinephrine,
and epinephrine are all neurotransmitters
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L-DOPA in Parkinsonism
Blood Brain
Blood Brain Barrier
L-DOPA L-DOPA Dopamine
Dopamine
H O
H OCH 2 -C -C O 2 H
CH 3
H H 2 C arbidopa
Blocks
Parkinsonism associated with
dopamine in brain through loss of
neurons in basal ganglia.C arbidopa + L-DOPA
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Monoamine Oxidase (MAO)
MAO
(in mitochondria)
R R¶
OH H Norepi
OH CH 3 Epi H H Dopamine
CHCH 2 NH R'
HO
HO
R
CHCHO
HO
HO
R
CHCO 2 H
HO
HO
RUrinar y metabolite
MAO inhibitors (e.g., trany lc y promine) are useful
in the treatment of depression
Brain levels of dopamine and norepi.; alsoserotonin
Aldehy de
dehy drogenase
R=OH Vanill y lmandelic acid (VMA)R=H Homovanillic acid (HVA)
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T y ramineOH
CH 2 CH 2 H 2
T y ramine
OH
CH 2 CHO
MAO
� T y ramine found naturall y in several t y pes of cheese;also beer and red wine.
� T y ramine intake can cause hy pertensive crisis inpersons taking a MAO inhibitor ( norepi release)
( blood pressure)
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Catechol-O-Methy l Transferase (COMT)
C C 2 R'
H O
H O
R
C H C H 2 H R'
H O
C H 3 O
R
COMT
Inactivemetabolite
SAM S-Adenosy l-
homoc y steine
� COMT found in c y toplasm� Terminates activit y of catecholamines
� Catecholamine excretion products result from
combined actions of MAO and COMT
� Inhibitors of COMT (e.g., tolcapone) useful in Parkinson¶s disease
Activecatecholamine
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Homogentisic Acid Formation
C H 2 C H C 2-
H 3+
H
H
H
C H 2 C 2-
Transamination
T y rosinep-H y drox y pheny l -
py ruvate
Homogentisate
p-H y drox y pheny l -
py ruvate
diox y genase(ascorbate-dep.)
2
C 2
C H 2 CC 2-
H
Homogentisate
diox y genase
2
C leavage of aromatic ring
Fumarate + acetoacetate
Deficient inalkaptonuria
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Alkaptonuria
� Deficienc y of homogentisate diox y genase
� Urine turns dark on standing� Oxidation of homogentisic acid
� Asy mptomatic in childhood
� Tendenc y toward arthritis in adulthood
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Melanin Formation
C H 2 C H C 2 -
H 3+
C H 2 C H C 2 -
H 3+
HO
HO
H ighl y colored
pol y meric intermediates
Melanin
(Black pol y mer)
T y r hy drox y lase
DOPA
Dopaquinone
C H 2 C H C O 2 -
H 3+
HO
T y rosine
T y rosinase
Melanin formed in skin (melanoc y tes), ey es, and hair
In skin, protects against sunlight
Albinism: genetic deficienc y of t y rosinase
O2
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Tr y ptophan Metabolism: Serotonin Formation
H
C H 2 C H C O 2 -
H 3
+
H
C H 2 C H C O 2 -
H 3
HO
+
H
C H 2 C H 2 H 2
HO
Tr y ptophan(Trp)
Indole ring
Trp
hy drox y lase
O2
5-H y drox y -
tr y ptophan
Decarbox y lase
C O2 5-H y drox y -
tr y ptamine (5-H T);
Serotonin
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Serotonin
� Serotonin formed in:� Brain (neurotransmitter; regulation of sleep, mood, appetite)
� Platelets (platelet aggregation, vasoconstriction)
� Smooth muscle (contraction)
� Gastrointestinal tract (enterochromaffin cells - major storage site)
� Drugs affecting serotonin actions used to treat:� Depression
�Serotonin-selective reuptake inhibitors (SS RI)
� Migraine
� Schizophrenia� Obsessive-compulsive disorders
� Chemotherapy -induced emesis
Some hallucinogens (e.g., LS D) act as serotonin agonists
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� Food supplement promoted for serotonin effects� L-Tr y ptophan disaster (1989):
� Eosinophilia-my algia sy ndrome (EMS)
(http://emedicine.medscape.com/article/1066811-overview)
� Severe muscle and joint pain
� Weakness
� Swelling of the arms and legs
� Fever
� Skin rash
� Eosinophilia� Many hundreds of cases; several deaths
� Traced to impurities
L-Tr y ptophan
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Serotonin Metabolism: 5-HIAA
H
C H 2 C H 2 H 2
H O
H
C H 2 C H O
H O
H
C H 2 CO 2 H
H O
Serotonin
MAO
Dehy drogenase
5-H y drox y indole acetic
acid (5-HIAA) (Urine)
C arcinoid tumors:
� Malignant GI tumor t y pe� Excretion of large amounts of 5-HIAA
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Serotonin Metabolism: Melatonin
N H
CH 2 CH 2 NHCOCH 3
H 3 CO
N H
CH 2 CH 2 NH 2
HO2 Steps
Serotonin Melatonin
Melatonin:
� Formed principall y in pineal gland � S y nthesis controlled by light, among other factors
� Induces skin lightening
� Suppresses ovarian function
� Possible use in sleep disorders
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Tr y ptophan Metabolism:Biosy nthesis of Nicotinic Acid
N
-
N j
Tr y ptophan
N
Nicotinic acid (Niacin)
Several steps
Nicotinamide adenine
dinucleotide (NAD)