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Unit 3Metabolism & Metabolic Disease
Carbohydrate Metabolism
PAUL ANDERSON 2008
Pathophysiology 101-823
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Learning Objectives1. Describe the metabolic functions of carbohydrates.2. Describe the following pathways of Cell Respiration: for each state
the type of reactions & their functions, compare aerobic vsanaerobic respiration, cellular locations.- Glycolysis- Krebs (TCA) Cycle- Oxidative Phosphorylation
3. Describe Gluconeogenesis and its hormonal controls.
4. Describe the following processes in liver and muscle.- Glycogenesis- Glycogenolysis
5. Define Glycogen Storage Diseases and predict the biochemicalconsequences of enzyme deficiencies in the pathways listed.
6. Define Mitochondrial Disease and explain the symptoms.References: Martini, Essentials of Anatomy & Physiology, Ch. 17Porth, Essentials of Pathophysiology, Ch. 4, p.67 (mitochondrial disease), Ch.
32 Glucose Metabolism
Or Porth, Pathophysiology (hard cover), Ch. 7, pp. 140-141 (mitochondrialdisease), Ch. 43 Glucose Metabolism
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Functions of Carbohydrates -2Functions of Carbohydrates -2
Carbohydrates provide STORED ENERGY as glycogen(mainly in liver, muscles) Hepatic glycogen acts as a reservoir for the blood sugar. Blood glucose levels are controlled by hormones whichaffect Gycogen storage.
glucose
insulin
glycogen
glucagonepinephrineHyperglycemichormones
Hypoglycemichormone
+
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Pathways of Carbohydrate MetabolismPathways of Carbohydrate Metabolism
Cell Respiration- Glycolysis- Krebs (TCA) Cycle- Oxidative Phosphorylation
Gluconeogenesis
Glycogenesis Glycogenolysis
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CELL RESPIRATION
CELL RESPIRATION is the process of generatingATP through the energy released fromOXIDATION of organic compounds.
CELL RESPIRATION in AEROBIC CELLS involvesthree metabolic pathways- GLYCOLYSIS
- the KREBS CYCLE (TCA or Citric Acid Cycle)- OXIDATIVE PHOSPHORYLATION. The KREBS CYCLE and OXIDATIVE
PHOSPHORYLATION require OXYGEN and occur
in the MITOCHONDRIA. GLYCOLYSIS occurs in the CYTOSOL and can
occur in the presence or absence of oxygen. Cell Respiration begins with glycolysis: the usual
starting point is glucose.
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CELL RESPIRATION
CELL RESPIRATION consists of two COUPLED REACTIONS ,the EXERGONIC OXIDATION of GLUCOSE and theENDERGONIC SYNTHESIS of ATP .
C6H12 O6 + 6O 2 6CO 2 + 6H 2O + ENERGY
38ATP + 38H 2O
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CELL RESPIRATION
Oxidation of glucose does not occur in one reaction but in aseries of smaller DEHYDROGENATION reactions, each of which releases a small amount of energy.
DEHYDROGENATIONS remove ELECTRONS from a
compound and so are also OXIDATIONS . OXIDATIONS always occur with REDUCTION of another
compound (which accepts HYDROGEN or ELECTRONS). The two half reactions make up one REDOX REACTION .
Whereas OXIDATION is EXERGONIC REDUCTION isENDERGONIC and so the two half reactions are COUPLED .
Note: Electrons lose energy as they flow from
XH 2 to an oxidising agent, Y.
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CELL RESPIRATION
When ELECTRONS are transferred to an
OXIDISING AGENT they are moving to alower energy state.
The energy difference appears as released
free energy which can be used to form ATP .
CELL RESPIRATION consists of a series of these REDOX REACTIONS which releaseenergy for ATP SYNTHESIS .
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ElectronFlow in CellRespiration
ReleasesEnergy for
ATPSynthesis
NADH
NAD ++++
E l e c t r o n t r a n s p o r t
c h a i n
2e
Controlledrelease of energy for synthesis
of ATP
ATP
H++++
2 H ++++2e
H2O
O 221
H 2 is transferred by acoenzyme (usually NAD )to carriers on an electrontransport chain. Redox reactions on thechain release energy forATP synthesis . Oxygen ,the final H 2acceptor and most
powerful oxidisingagent is reduced to H 2 O .
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Oxidative Phosphorylation & TheElectron Transport Chain
OXIDATIVE PHOSPHORYLATION is theindirect way of generating ATP from ADPand Pi using the energy released from REDOXREACTIONS on the ELECTRON TRANSPORT(RESPIRATORY) CHAIN .
The ELECTRON TRANSPORT CHAIN is aseries of compounds on the INNER MITOCHONDRIAL MEMBRANE which
transfers H 2 or electrons from onecompound to another in a series of REDOXREACTIONS.
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The Electron Transport Chain - 1
The ELECTRON TRANSPORT CHAIN is a series of increasingly more powerful OXIDISING AGENTSbeginning with REDUCED NAD (NADH) andending with OXYGEN .
As ELECTRONS pass along the chain they are
moving to lower and lower energy levels .
Each member of the chain is alternately REDUCED(when it receives ELECTRONS ) and then
OXIDISED (when it loses ELECTRONS ).
When reduced each compound acts as aREDUCING AGENT for the next member of thechain.
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The Electron Transport Chain - 2
The first member of the ELECTRON TRANSPORTCHAIN is NADH (reduced Nicotinamide AdenineDinucleotide ) which contains the vitamin NicotinicAcid (Niacin ).
NAD picks up hydrogens from compounds of
GLYCOLYSIS and the KREBS CYCLE and transfersthem to a Flavoprotein , the next member of thechain on the inner mitochondrial membrane .
Flavoprotein is a conjugated protein consisting of an enzyme complex ( NADH dehydrogenase )containing a non - protein FMN ( FlavinMononucleotide ) which receives and passes on H 2
NADH + H + + FMN --------> NAD + + FMNH 2
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The Electron Transport Chain - 3
A lipid ( COENZYME Q or UBIQUINON E) takes ELECTRONSfrom FMN and transfers them to CYTOCHROMES ( PROTEINpigments).
The last CYTOCHROME is CYTOCHROME OXIDASE whichtransfers ELECTRONS to OXYGEN reducing it to H 2 O .
The energy drop for electrons passed from NADH to H 2O isenough to generate a maximum of 3 ATP per NADHmolecule.
HYDROGENS are also delivered to the chain by FADH 2.
REDUCED FAD ( Flavin Adenine Dinucleotide ) enters thechain at a lower level than NADH so generates only 2 ATP perFADH 2 .
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The Electron Transport Chain - 4
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Glycolysis Overview
GLYCOLYSIS the first stage of CELL RESPIRATION Glucose is partially oxidised and split into 2 molecules of Pyruvic Acid (Pyruvate )
Glycolysis occurs in the cytosol outside the mitochondrion. Glycolysis produces 2 molecules of ATP per glucoseby substrate phosphorylation and 2 NADH.
Glucose
2 NAD ++++ 2 NADH 2 H ++++
2 ADP2 ATP2 P
2
2 Pyruvate
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Enzyme
PPP
ADP
P
ATP
P
Adenosine
Substrate Phosphorylation
A net yield of 2 ATPmoleculesaresynthesiseddirectly inGLYCOLYSIS
(withoutusing theelectrontransportchain)This is calledSUBSTRATEPHOSPHOR YLATION.
PhosphorylatedOrganic substrate
molecule(phosphate donor)
Phosphate
transferred to ADP
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Steps of Glycolysis
STEPS IN GLYCOLYSIS
When glucose first enters the
cell, it is phosphorylated by ATP
A second phosphorylationoccurs using a second ATP.
The hexose is split into twotrioses (glycerose), each of which continues in glycolysis
Another phosphorylation occurs(using Pi) and NAD is reduced toNADH (2 NADH per glucose)
Each 3 C molecule isconverted to pyruvic acidproducing 2 ATP (4 ATP perglucose)
GlucoseINTERSTITIAL
FLUID
CYTOSOL
Glucose-6-phosphate
From mitochondriaTo mitochondria
1,3-Bisphosphoglyceric acid
To mitochondria
Pyruvic
acid
ENERGY SUMMARY
NET GAIN:
Steps 1 & 2:Step 5:
+2 ATP
2 ATP+4 ATP
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Aerobic Glycolysis
Glucose
2 NAD ++++ 2 NADH2 H ++++
2 ADP2 ATP2 P
2 Pyruvate
2 NADH 2 molecules result from GLYCOLYSIS of oneGLUCOSE so a maximum of 6 ATP can be formed byOXIDATIVE PHOSPHORYLATION ( 3 from each NADH ).
Since 2 ATP are formed directly during GLYCOLYSIS bySUBSTRATE PHOSPHORYLATION a maximum of 8 ATP canresult from GLYCOLYSIS .
Electron transport chain 6 ATP
Substratephosphorylation
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Anaerobic Glycolysis:Lactic Acid Fermentation
During vigorous exercise O 2 is used up rapidly so anaerobicconditions occur in MUSCLE CELLS: pyruvate is reduced toLactic Acid ( lactate ) instead of entering the mitochondrion.This process is called Lactic Acid Fermentation. Aerobically pyruvate enters the mitochondrion and isconverted to acetyl coenzyme A which enters the KrebsCycle.
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GLYCOLYSIS
Glucose
2 2
2 2
NAD ++++ NADH
ATPP2ADP
++++ 2 Pyruvate
NADH NAD ++++2 2
2 Lactate
Anaerobically pyruvate is reduced to lactic acid ( lactate )by NADH in Lactic Acid Fermentation
Fermentation functions to regenerate NAD anaerobicallyso that glycolysis can continue (glycolysis needs NAD) .The net energy yield from anaerobic GLYCOLYSIS is 2ATP from substrate phosphorylation .
Anaerobic Glycolysis:Lactic Acid Fermentation
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Acetyl CoA(acetyl coenzyme A)
Coenzyme A
Pyruvate
CO 2
NAD ++++ NADH H++++
CoA
++++
Before entering the KREBS CYCLE PYRUVATE enters theMITOCHONDRION and is OXIDATIVELY DECARBOXYLATED ,losing H 2 and CO 2.*
H 2 is taken by NAD forming NADH 2 while the remaining ACETYL
GROUP is combined with COENZYME A to form acetyl coenzyme A. COENZYME A is formed from the B vitamin PANTOTHENIC ACIDand functions to deliver acetyl GROUPS to the KREBS CYCLE .
Formation of Acetyl Coenzyme A
Electron transport chain 6 ATP* Decarboxylations
involve a coenzyme(cocarboxylase)containing vit B1 ,thyamine)
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The Krebs (TCA or Citric Acid) Cycle
The Krebs CYCLE is thefinal pathway for theCATABOLISM of variousorganic molecules in cells.
The KREBS CYCLE takes 2CARBON acetyl GROUPSand OXIDISES them bydehydrogenation forming
CO2 as an end product.ACETYL GROUPS maycome from pyruvate, fattyacids or from some aminoacids.
H2 from acetyl groups arefed into the electrontransport chain by NAD orFAD forming ATP by
oxidative phosphorylation.
Fatty acids Glucose Amino acids
Smallcarbonchains
TCAcycle
Electrontransportsystem
Coenzymes
ATP
CO 2O2
H2OMITOCHONDRIA
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The Krebs Cycle: Decarboxylations
The KREBS CYCLE operatesonly under aerobic conditionsand occurs in the matrix of the
MITOCHONDRION .The substrates of the Krebscycle are various organic acids(referred to by their anion).
ACETYL COENZYME A transfersthe acetyl GROUP to the 4carbon oxaloacetate to form the6 carbon citrate (citric ortricarboxylic acid).
2 more DECARBOXYLATIONSoccur. From each originalGLUCOSE these reactions wouldform 4 CO 2 molecules giving atotal of 6 DECARBOXYLATIONSfrom each original GLUCOSE.
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The Krebs Cycle: Sources of ATP
With each turn of the KREBS CYCLE from CITRATE toOXALOACETATE 3 NADH 2 molecules are formed and atotal of 9 ATP molecules will result from OXIDATIVE
PHOSOPHORYLATION.These reactions generate 18 ATPs from each originalGLUCOSE which entered GLYCOLYSIS.
FAD acts as a H 2 carrier in one case and this reaction willgenerate 2 ATPs from oxidative PHOSPHORYLATION (or 4ATPs from each original GLUCOSE).
One SUBSTRATE PHOSPHORYLATION occurs. Thenucleotide GUANOSINE DIPHOSPHATE (GDP) isPHOSPHORYLATED to create a high energy molecule(GTP).
GTP then transfers its phosphate to ADP to generate oneATP (2 from each glucose).
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Copyright 2007 Pearson Education, Inc., publishing as Benjamin CummingsFigure 17-47 of 7
Pyruvic acid
Coenzyme A
NADHCO 2
Coenzyme AAcetyl-CoA
4-carbon
4-carbon
2H
2H
TCACYCLE
FADH 2NADH
2H
2H
5-carbon
CO 2
CO 2
Citric acid6-carbon
NADH
NADH
O 2
ATP
ATP
H2O
ELECTRONTRANSPORT
SYSTEM
Energy
Yield fromKrebsCycle
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Summary of Energy Yield from Krebs Cycle
3
3
3
2
3
OxidativeDecarboxylationof Pyruvate
KrebsCycle
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Summary of Cell Respiration
In cytoplasmIn cytoplasm
In cytoplasmIn cytoplasm
Inmitochondrion
Inmitochondrion
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Gluconeogenesis The liver has enzymes to reverse glycolysis, forming glucose from
pyruvate or from oxaloacetate of the Krebs Cycle. This process is called GLUCONEOGENESIS (2) and converts lactic
acid, glycerol & glucogenic amino acids to glucose
- during exercise it converts LACTIC ACID back to glucose. which issent back to the muscles to reenter glycolysis- when carbohydrates are unavailable as in starvation or diabetesmellitus gluconeogenesis maintains the blood glucose level(especially for brain cells).
GLUCONEOGENESISis stimulated byGlucocorticoids(mainly cortisol )released in times of stress via ACTH andby glucagon (bothhyperglycemic
hormones).
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Carbohydrates can be stored in the body in the form of gycogen mainly in liver and muscle tissues.
Glycogenesis is the metabolic pathway by whichglycogen is formed from glucose. Glycogenolysis is the metabolic pathway by which
glycogen is broken down to glucose or glucose - 6 - (P). The function of hepatic glycogenesis and
glycogenolysis is to control the blood glucose levelby storing glucose when blood sugar levels are high andreleasing glucose when blood sugar levels are low.
To release glucose to the blood cells must remove the
phosphate from glucose 6 phosphate with the enzymeglucose 6 phosphatase . Liver cells have this enzymebut muscle cells do not.
Muscle glycogen is primarily for use by muscle cellsand muscle cells do not respond to glucagon.
Functions of Glycogen
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Glycogenesis & Glycogenolysis
Glycogenesis Requires enzymes,glucokinase (or hexokinase)to phosphorylate glucose,glycogen synthetase (for 1-4bonds), branching enzyme(for 1-6 bonds)in liver and skeletal muscle
stimulated by insulin Glycogenolysis
enzymes phosphorylase (breaks 1-4 bonds), debranchingenzyme (breaks 1-6 bonds)to form glucose 1-phosphate enzyme glucose 6 phosphatase releases glucose for the blood:only in hepatocytes so muscle cant release glucose Hepatic phosphorylase activated by glucagon & epinephrine ,muscle glycogenolysis stimulated by epinephrine only.
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Glucose-6-phosphate may enter Glycolysis or (in liver) be dephosphorylated for release to
the blood.Liver Glucose-6-phosphatase catalyzes the following, essential to the liver's role inmaintaining blood glucose:
glucose-6-phosphate + H 2O glucose + P i
Most other tissues lack this enzyme.
Pathways in the Liver
Glycogen Glucose
Hexokinase or Glucokinase
Glucose-6-Pase Glucose-1-P Glucose-6-P Glucose + P i
Glycolysis Pathway
PyruvateGlucose metabolism in liver.
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Glycogen StorageDiseases are Inborn Errorsof Metabolism (enzymedeficiencies) associated withabnormal glycogenaccumulation within liver ormuscle cells.
Some enzymes whosedeficiency leads to glycogenaccumulation are part of theinter-connected pathwaysshown here.
Glycogen Storage Diseases
glycogen
glucose-1-PGlucose-6-Phosphatase
glucose-6-P glucose + P i
fructose-6-PPhosphofructokinase
fructose-1,6-bisP
Glycolysis continued
ff f Gl S i
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When an enzyme defect affects mainly glycogenstorage in liver , a common symptom ishypoglycemia , relating to impaired mobilizationof glucose for release to the blood during fasting.
When the defect is in muscle tissue, weakness &
difficulty with exercise result from inability toincrease glucose entry into Glycolysis duringexercise.
Additional symptoms depend on the particularenzyme that is deficient.
Effects of Glycogen Storage Diseases
E l f Gl S Di
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Examples of Glycogen Storage Diseases
Note: these glycogen storage diseases are autosomal recessive
Glycogen Storage Disease Symptoms , in addition toglycogen accumulation
Type I , liver deficiency of
Glucose-6-phosphatase (vonGierke's disease)
hypoglycemia (low blood
glucose) when fasting, liver enlargement.
Type IV , deficiency of branching enzyme in variousorgans, including liver (Andersen's disease)
liver dysfunction and earlydeath.
Type V , muscle deficiency of Glycogen Phosphorylase (McArdle's disease)
muscle cramps with exercise.
Type VII , muscle deficiency of Phosphofructokinase .
inability to exercise .
Mit h d i l Di
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Mitochondrial Disease
Mitochondrial disease is usually caused by aninherited defect in mitochondrial DNA.
Mitochondria are inherited from the ova so aretransmitted from mother to all offspring andfrom daughters to all their offspring.Mitochondrial disorders result in a lack of ATP
in all cells causing:
Lactic acidosis Fatigue Multiple organ damage, (e.g. brain, visual,auditory pathways).