Glycolysis & the Oxidation of Pyruvate

Home , Aldolase A deficiency, Pyruvate dehydrogenase

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Glycolysis & the Oxidation of Pyruvate 17

Peter A. Mayes, PhD, DSc, & David A. Bender, PhD

BIOMEDICAL IMPORTANCE GLYCOLYSIS CAN FUNCTION UNDER Most tissues have at least some requirement for glucose. ANAEROBIC CONDITIONS In brain, the requirement is substantial. Glycolysis, the When a muscle contracts in an anaerobic medium, ie, major pathway for glucose metabolism, occurs in the one from which oxygen is excluded, glycogen disap- cytosol of all cells. It is unique in that it can function ei- pears and lactate appears as the principal end product. ther aerobically or anaerobically. Erythrocytes, which When oxygen is admitted, aerobic recovery takes place lack mitochondria, are completely reliant on glucose as and lactate disappears. However, if contraction occurs their metabolic fuel and metabolize it by anaerobic gly- under aerobic conditions, lactate does not accumulate colysis. However, to oxidize glucose beyond pyruvate and pyruvate is the major end product of glycolysis. (the end product of glycolysis) requires both oxygen Pyruvate is oxidized further to CO2 and water (Figure and mitochondrial enzyme systems such as the pyruvate 17–1). When oxygen is in short supply, mitochondrial dehydrogenase complex, the citric acid cycle, and the reoxidation of NADH formed from NAD+ during gly- respiratory chain. colysis is impaired, and NADH is reoxidized by reduc- Glycolysis is both the principal route for glucose ing pyruvate to lactate, so permitting glycolysis to pro- metabolism and the main pathway for the metabolism ceed (Figure 17–1). While glycolysis can occur under of fructose, galactose, and other carbohydrates derived anaerobic conditions, this has a price, for it limits the from the diet. The ability of glycolysis to provide ATP amount of ATP formed per mole of glucose oxidized, in the absence of oxygen is especially important because so that much more glucose must be metabolized under it allows skeletal muscle to perform at very high levels anaerobic than under aerobic conditions. when oxygen supply is insufficient and because it allows tissues to survive anoxic episodes. However, heart mus- THE REACTIONS OF GLYCOLYSIS cle, which is adapted for aerobic performance, has relatively low glycolytic activity and poor survival under CONSTITUTE THE MAIN PATHWAY conditions of ischemia. Diseases in which enzymes of OF GLUCOSE UTILIZATION glycolysis (eg, pyruvate kinase) are deficient are mainly The overall equation for glycolysis from glucose to lac- seen as hemolytic anemias or, if the defect affects tate is as follows: skeletal muscle (eg, phosphofructokinase), as fatigue. ++→+− ++ In fast-growing cancer cells, glycolysis proceeds at a Glucos e222 ADP Pi L ( ) Lactate 22 ATP H2 O higher rate than is required by the citric acid cycle, forming large amounts of pyruvate, which is reduced to All of the enzymes of glycolysis (Figure 17–2) are lactate and exported. This produces a relatively acidic found in the cytosol. Glucose enters glycolysis by phos- local environment in the tumor which may have impli- phorylation to glucose 6-phosphate, catalyzed by hexo- cations for cancer therapy. The lactate is used for glucokinase, using ATP as the phosphate donor. Under neogenesis in the liver, an energy-expensive process re- physiologic conditions, the phosphorylation of glucose sponsible for much of the hypermetabolism seen in to glucose 6-phosphate can be regarded as irreversible. cancer cachexia. Lactic acidosis results from several Hexokinase is inhibited allosterically by its product, causes, including impaired activity of pyruvate dehy- glucose 6-phosphate. In tissues other than the liver and drogenase. pancreatic B islet cells, the availability of glucose for 136 ch17.qxd 2/13/2003 3:01 PM Page 137

GLYCOLYSIS & THE OXIDATION OF PYRUVATE / 137

Glucose Glycogen This reaction is followed by another phosphorylation C6 (C6 )n with ATP catalyzed by the enzyme phosphofructokinase (phosphofructokinase-1), forming fructose 1,6- bisphosphate. The phosphofructokinase reaction may be considered to be functionally irreversible under physiologic conditions; it is both inducible and subject to allosteric regulation and has a major role in regulat- Hexose phosphates ing the rate of glycolysis. Fructose 1,6-bisphosphate is C6 cleaved by aldolase (fructose 1,6-bisphosphate aldolase) into two triose phosphates, glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Glyceraldehyde 3-phosphate and dihydroxyacetone phosphate are inter- converted by the enzyme phosphotriose isomerase. Glycolysis continues with the oxidation of glycer- Triose phosphate Triose phosphate aldehyde 3-phosphate to 1,3-bisphosphoglycerate. The C C 3 3 enzyme catalyzing this oxidation, glyceraldehyde + NAD H2O 3-phosphate dehydrogenase, is NAD-dependent. Structurally, it consists of four identical polypeptides (monomers) forming a tetramer. SH groups are O NADH 2 1/2O + H+ 2 present on each polypeptide, derived from cysteine residues within the polypeptide chain. One of the CO2 Pyruvate Lactate  + SH groups at the active site of the enzyme (Figure C3 C3 H2O 17–3) combines with the substrate forming a thiohemi- acetal that is oxidized to a thiol ester; the hydrogens re- moved in this oxidation are transferred to NAD+. The − Figure 17–1. Summary of glycolysis. , blocked by thiol ester then undergoes phosphorolysis; inorganic anaerobic conditions or by absence of mitochondria phosphate (Pi) is added, forming 1,3-bisphosphoglycer- containing key respiratory enzymes, eg, as in erythro- ate, and the SH group is reconstituted. cytes. In the next reaction, catalyzed by phosphoglycerate kinase, phosphate is transferred from 1,3-bisphosphoglycerate onto ADP, forming ATP (substrate-level glycolysis (or glycogen synthesis in muscle and lipogen- phosphorylation) and 3-phosphoglycerate. Since two esis in adipose tissue) is controlled by transport into the molecules of triose phosphate are formed per molecule cell, which in turn is regulated by insulin. Hexokinase of glucose, two molecules of ATP are generated at this has a high affinity (low Km) for its substrate, glucose, stage per molecule of glucose undergoing glycolysis. and in the liver and pancreatic B islet cells is saturated The toxicity of arsenic is due to competition of arsenate under all normal conditions and so acts at a constant with inorganic phosphate (Pi) in the above reactions to rate to provide glucose 6-phosphate to meet the cell’s give 1-arseno-3-phosphoglycerate, which hydrolyzes need. Liver and pancreatic B islet cells also contain an spontaneously to give 3-phosphoglycerate plus heat, isoenzyme of hexokinase, glucokinase, which has a Km without generating ATP. 3-Phosphoglycerate is isomer- very much higher than the normal intracellular concen- ized to 2-phosphoglycerate by phosphoglycerate mu- tration of glucose. The function of glucokinase in the tase. It is likely that 2,3-bisphosphoglycerate (diphos- liver is to remove glucose from the blood following a phoglycerate; DPG) is an intermediate in this reaction. meal, providing glucose 6-phosphate in excess of re- The subsequent step is catalyzed by enolase and in- quirements for glycolysis, which will be used for glyco- volves a dehydration, forming phosphoenolpyruvate. gen synthesis and lipogenesis. In the pancreas, the Enolase is inhibited by fluoride. To prevent glycolysis glucose 6-phosphate formed by glucokinase signals in- in the estimation of glucose, blood is collected in creased glucose availability and leads to the secretion of tubes containing fluoride. The enzyme is also depen- insulin. dent on the presence of either Mg2+ or Mn2+. The Glucose 6-phosphate is an important compound at phosphate of phosphoenolpyruvate is transferred to the junction of several metabolic pathways (glycolysis, ADP by pyruvate kinase to generate, at this stage, gluconeogenesis, the pentose phosphate pathway, gly- two molecules of ATP per molecule of glucose oxi- cogenesis, and glycogenolysis). In glycolysis, it is con- dized. The product of the enzyme-catalyzed reaction, verted to fructose 6-phosphate by phosphohexose- enolpyruvate, undergoes spontaneous (nonenzymic) isomerase, which involves an aldose-ketose isomerization. isomerization to pyruvate and so is not available to 5475ch17.qxd_ccII 2/26/03 8:05 AM Page 138

Glycogen

Glucose 1-phosphate HEXOKINASE

CH2OH CH2 O P GLUCOKINASE CH2 O P O O PHOSPHOHEXOSE O H H 2+ H H ISOMERASE CH2OH H Mg H OH H OH H H HO HO OH HO OH H OH

H OH ATP ADP H OH OH H α-D-Glucose α-D-Glucose 6-phosphate D-Fructose 6-phosphate ATP

Mg2+ PHOSPHOFRUCTO- ADP KINASE

CH2 O P O CH* 2 O P

D-Fructose 1,6-bisphosphate H HO H OH ALDOLASE

Iodoacetate HO H CH* 2 O P GLYCERALDEHYDE-3-PHOSPHATE PHOSPHOGLYCERATE CO O DEHYDROGENASE KINASE – COO C O P H C O CH2OH 2+ Mg P i Dihydroxyacetone phosphate H C OH H C OH H C OH

PHOSPHOTRIOSE CH2 O P CH2 O P CH2 O P ATP ADP NADH NAD+ ISOMERASE + 3-Phosphoglycerate 1,3-Bisphosphoglycerate+ H Glyceraldehyde 3-phosphate 1 /2O2 PHOSPHOGLYCERATE MUTASE Mitochondrial respiratory chain H2O COO– 3ATP H C O P 2-Phosphoglycerate 3ADP + P i

CH2OH Anaerobiosis Fluoride Mg2+ H2O ENOLASE

COO– Phosphoenolpyruvate C O P Oxidation in citric CH2 acid cycle ADP Mg2+ PYRUVATE KINASE + + + ATP NADH H NAD COO– COO– COO– Spontaneous C OH CO HO C H

LACTATE CH CH2 CH3 DEHYDROGENASE 3

(Enol) (Keto) L(+)-Lactate Pyruvate Pyruvate

 2− 2− − Figure 17–2. The pathway of glycolysis. ( P , PO3 ; Pi, HOPO3 ; , inhibition.) At asterisk: Carbon atoms 1–3 of fructose bisphosphate form dihydroxyacetone phosphate, whereas carbons 4–6 form glyceraldehyde 3-phosphate. The term “bis-,” as in bisphosphate, indicates that the phosphate groups are separated, whereas diphosphate, as in adenosine diphosphate, indicates that they are joined. 138 ch17.qxd 2/13/2003 3:01 PM Page 139

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S Enz H CO H C OH H COH NAD+ H C OH CH2 O P CH O P Glyceraldehyde 3-phosphate 2 Enzyme-substrate complex HS Enz

NAD+ Bound coenzyme Substrate oxidation O P by bound NAD+ CO

H C OH P i

CH2 O P 1,3-Bisphosphoglycerate

S Enz S Enz

CO CO NADH + H+ NAD* + H C OH H C OH NADH + H+ NAD* + CH2 OOP CH2 P

Energy-rich intermediate

Figure 17–3. Mechanism of oxidation of glyceraldehyde 3-phosphate. (Enz, glyceraldehyde-3-phosphate dehydrogenase.) The enzyme is inhibited by the SH poison iodoacetate, which is thus able to inhibit glycolysis. The NADH produced on the enzyme is not as firmly bound to the enzyme as is NAD+. Consequently, NADH is easily displaced by another molecule of NAD+.

undergo the reverse reaction. The pyruvate kinase re- up into mitochondria for oxidation via one of the two action is thus also irreversible under physiologic con- shuttles described in Chapter 12. ditions. The redox state of the tissue now determines which of two pathways is followed. Under anaerobic condi- Tissues That Function Under Hypoxic tions, the reoxidation of NADH through the respira- Circumstances Tend to Produce Lactate tory chain to oxygen is prevented. Pyruvate is reduced (Figure 17–2) by the NADH to lactate, the reaction being catalyzed by lactate dehydrogenase. Several tissue-specific isoen- This is true of skeletal muscle, particularly the white zymes of this enzyme have been described and have fibers, where the rate of work output—and therefore clinical significance (Chapter 7). The reoxidation of the need for ATP formation—may exceed the rate at NADH via lactate formation allows glycolysis to pro- which oxygen can be taken up and utilized. Glycolysis ceed in the absence of oxygen by regenerating sufficient in erythrocytes, even under aerobic conditions, always NAD+ for another cycle of the reaction catalyzed by terminates in lactate, because the subsequent reactions glyceraldehyde-3-phosphate dehydrogenase. Under aer- of pyruvate are mitochondrial, and erythrocytes lack obic conditions, pyruvate is taken up into mitochon- mitochondria. Other tissues that normally derive much dria and after conversion to acetyl-CoA is oxidized to of their energy from glycolysis and produce lactate in- CO2 by the citric acid cycle. The reducing equivalents clude brain, gastrointestinal tract, renal medulla, retina, from the NADH + H+ formed in glycolysis are taken and skin. The liver, kidneys, and heart usually take up ch17.qxd 2/13/2003 3:01 PM Page 140

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lactate and oxidize it but will produce it under hypoxic HCO Glucose conditions. HCOH

Glycolysis Is Regulated at Three Steps CH2 O P Involving Nonequilibrium Reactions Glyceraldehyde 3-phosphate + Although most of the reactions of glycolysis are re- P i NAD versible, three are markedly exergonic and must there- GLYCERALDEHYDE-3-PHOSPHATE fore be considered physiologically irreversible. These re- DEHYDROGENASE actions, catalyzed by hexokinase (and glucokinase), NADH + H+ phosphofructokinase, and pyruvate kinase, are the O major sites of regulation of glycolysis. Cells that are ca- pable of reversing the glycolytic pathway (gluconeoge- CO P nesis) have different enzymes that catalyze reactions H C OH BISPHOSPHOGLYCERATE which effectively reverse these irreversible reactions. MUTASE The importance of these steps in the regulation of gly- CH2 O P colysis and gluconeogenesis is discussed in Chapter 19. 1,3-Bisphosphoglycerate

In Erythrocytes, the First Site in Glycolysis ADP COO– for ATP Generation May Be Bypassed PHOSPHOGLYCERATE H C O P KINASE In the erythrocytes of many mammals, the reaction cat- CH O P alyzed by phosphoglycerate kinase may be bypassed 2 ATP by a process that effectively dissipates as heat the free 2,3-Bisphosphoglycerate energy associated with the high-energy phosphate of – 1,3-bisphosphoglycerate (Figure 17–4). Bisphospho- COO glycerate mutase catalyzes the conversion of 1,3-bis- H C OH P i phosphoglycerate to 2,3-bisphosphoglycerate, which is 2,3-BISPHOSPHOGLYCERATE CH O P converted to 3-phosphoglycerate by 2,3-bisphospho- 2 PHOSPHATASE glycerate phosphatase (and possibly also phosphoglyc- 3-Phosphoglycerate erate mutase). This alternative pathway involves no net Pyruvate yield of ATP from glycolysis. However, it does serve to Figure 17–4. 2,3-Bisphosphoglycerate pathway in provide 2,3-bisphosphoglycerate, which binds to hemo- erythrocytes. globin, decreasing its affinity for oxygen and so making oxygen more readily available to tissues (see Chapter 6).

THE OXIDATION OF PYRUVATE TO in thiamin deficiency glucose metabolism is impaired ACETYL-CoA IS THE IRREVERSIBLE and there is significant (and potentially life-threatening) lactic and pyruvic acidosis. Acetyl lipoamide reacts with ROUTE FROM GLYCOLYSIS TO THE coenzyme A to form acetyl-CoA and reduced lipoamide. CITRIC ACID CYCLE The cycle of reaction is completed when the reduced Pyruvate, formed in the cytosol, is transported into the lipoamide is reoxidized by a flavoprotein, dihydrolipoyl dehydrogenase, containing FAD. Finally, the reduced mitochondrion by a proton symporter (Figure 12–10). + Inside the mitochondrion, pyruvate is oxidatively decar- flavoprotein is oxidized by NAD , which in turn trans- boxylated to acetyl-CoA by a multienzyme complex that fers reducing equivalents to the respiratory chain. is associated with the inner mitochondrial membrane. + + ++→− +++ This pyruvate dehydrogenase complex is analogous to Pyruvate NAD CoA Acetyl CoA NADH H CO2 the α-ketoglutarate dehydrogenase complex of the citric acid cycle (Figure 16–3). Pyruvate is decarboxylated by The pyruvate dehydrogenase complex consists of a the pyruvate dehydrogenase component of the enzyme number of polypeptide chains of each of the three com- complex to a hydroxyethyl derivative of the thiazole ring ponent enzymes, all organized in a regular spatial con- of enzyme-bound thiamin diphosphate, which in turn figuration. Movement of the individual enzymes ap- reacts with oxidized lipoamide, the prosthetic group of pears to be restricted, and the metabolic intermediates dihydrolipoyl transacetylase, to form acetyl lipoamide do not dissociate freely but remain bound to the en- (Figure 17–5). Thiamin is vitamin B1 (Chapter 45), and zymes. Such a complex of enzymes, in which the sub- ch17.qxd 2/13/2003 3:01 PM Page 141

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CH C COO– + H+ 3 TDP Pyruvate Acetyl lipoamide HS CoA-SH

CH H

3 CS PYRUVATE 2 DEHYDROGENASE CH C CO O 2 2

C H

C H N TDP O

H3COHC Hydroxyethyl

C H H H H C 2 C N DIHYDROLIPOYL Oxidized lipoamide 2 C TRANSACETYLASE SS O Lipoic acid Lysine side chain

O + N NAD H C

FADH2

DIHYDROLIPOYL CH CH CO S CoA DEHYDROGENASE 2 3 Acetyl-CoA SH

Dihydrolipoamide

FAD NADH + H+

Figure 17–5. Oxidative decarboxylation of pyruvate by the pyruvate dehydrogenase complex. Lipoic acid is joined by an amide link to a lysine residue of the transacetylase component of the enzyme complex. It forms a long flexible arm, allowing the lipoic acid prosthetic group to rotate sequentially between the active sites of each of the enzymes of the complex. (NAD+, nicotinamide adenine dinucleotide; FAD, flavin adenine dinucleotide; TDP, thiamin diphosphate.)

strates are handed on from one enzyme to the next, in- lated by phosphorylation by a kinase of three serine creases the reaction rate and eliminates side reactions, residues on the pyruvate dehydrogenase component of increasing overall efficiency. the multienzyme complex, resulting in decreased activity, and by dephosphorylation by a phosphatase that Pyruvate Dehydrogenase Is Regulated causes an increase in activity. The kinase is activated by increases in the [ATP]/[ADP], [acetyl-CoA]/[CoA], by End-Product Inhibition + & Covalent Modification and [NADH]/[NAD ] ratios. Thus, pyruvate dehydrogenase—and therefore glycolysis—is inhibited not only Pyruvate dehydrogenase is inhibited by its products, by a high-energy potential but also when fatty acids are acetyl-CoA and NADH (Figure 17–6). It is also regu- being oxidized. Thus, in starvation, when free fatty acid ch17.qxd 2/13/2003 3:01 PM Page 142

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[ Acetyl-CoA ] [ NADH ] [ ATP ] [ CoA ] [ NAD+ ] [ ADP ]

+ + +

– Dichloroacetate Acetyl-CoA – – Ca2+ PDH KINASE Pyruvate + + 2+ NADH H CO2 Mg ATP ADP

– PDH – PDH-a PDH-b (Active DEPHOSPHO-ENZYME) (Inactive PHOSPHO-ENZYME)

NAD+ CoA

Pi H2O

Pyruvate PDH PHOSPHATASE

+ AB+

Mg2+, Ca2+ Insulin (in adipose tissue) Figure 17–6. Regulation of pyruvate dehydrogenase (PDH). Arrows with wavy shafts indicate allosteric ef- fects. A: Regulation by end-product inhibition. B: Regulation by interconversion of active and inactive forms.

concentrations increase, there is a decrease in the pro- ATP synthase reaction has been calculated as approxi- portion of the enzyme in the active form, leading to a mately 51.6 kJ. It follows that the total energy captured sparing of carbohydrate. In adipose tissue, where glu- in ATP per mole of glucose oxidized is 1961 kJ, or ap- cose provides acetyl CoA for lipogenesis, the enzyme is proximately 68% of the energy of combustion. Most of activated in response to insulin. the ATP is formed by oxidative phosphorylation resulting from the reoxidation of reduced coenzymes by the respiratory chain. The remainder is formed by substrate- Oxidation of Glucose Yields Up to 38 Mol level phosphorylation (Table 17–1). of ATP Under Aerobic Conditions But Only 2 Mol When O2 Is Absent CLINICAL ASPECTS When 1 mol of glucose is combusted in a calorimeter Inhibition of Pyruvate Metabolism to CO2 and water, approximately 2870 kJ are liberated Leads to Lactic Acidosis as heat. When oxidation occurs in the tissues, approximately 38 mol of ATP are generated per molecule of Arsenite and mercuric ions react with the SH groups ∆ glucose oxidized to CO2 and water. In vivo, G for the of lipoic acid and inhibit pyruvate dehydrogenase, as ch17.qxd 2/13/2003 3:01 PM Page 143

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Table 17–1. Generation of high-energy phosphate in the catabolism of glucose.

Number of ~P Formed per Pathway Reaction Catalyzed by Method of ~P Production Mole of Glucose Glycolysis Glyceraldehyde-3-phosphate dehydrogenase Respiratory chain oxidation of 2 NADH 6* Phosphoglycerate kinase Phosphorylation at substrate level 2 Pyruvate kinase Phosphorylation at substrate level 2 10 Allow for consumption of ATP by reactions catalyzed by hexokinase and phosphofructokinase −2 Net 8 Pyruvate dehydrogenase Respiratory chain oxidation of 2 NADH 6 Isocitrate dehydrogenase Respiratory chain oxidation of 2 NADH 6 α-Ketoglutarate dehydrogenase Respiratory chain oxidation of 2 NADH 6 Citric acid cycle Succinate thiokinase Phosphorylation at substrate level 2 Succinate dehydrogenase Respiratory chain oxidation of 2 FADH2 4 Malate dehydrogenase Respiratory chain oxidation of 2 NADH 6 Net 30 Total per mole of glucose under aerobic conditions 38 Total per mole of glucose under anaerobic conditions 2 *It is assumed that NADH formed in glycolysis is transported into mitochondria via the malate shuttle (see Figure 12–13). If the glyc- erophosphate shuttle is used, only 2 ~P would be formed per mole of NADH, the total net production being 26 instead of 38. The calculation ignores the small loss of ATP due to a transport of H+ into the mitochondrion with pyruvate and a similar transport of H+ in the operation of the malate shuttle, totaling about 1 mol of ATP. Note that there is a substantial benefit under anaerobic conditions if glycogen is the starting point, since the net production of high-energy phosphate in glycolysis is increased from 2 to 3, as ATP is no longer required by the hexokinase reaction.

does a dietary deficiency of thiamin, allowing pyru- • It can function anaerobically by regenerating oxidized vate to accumulate. Nutritionally deprived alcoholics NAD+ (required in the glyceraldehyde-3-phosphate de- are thiamin-deficient and may develop potentially fatal hydrogenase reaction) by reducing pyruvate to lactate. pyruvic and lactic acidosis. Patients with inherited • Lactate is the end product of glycolysis under anaero- pyruvate dehydrogenase deficiency, which can be due bic conditions (eg, in exercising muscle) or when the to defects in one or more of the components of the en- metabolic machinery is absent for the further oxida- zyme complex, also present with lactic acidosis, particu- tion of pyruvate (eg, in erythrocytes). larly after a glucose load. Because of its dependence on • Glycolysis is regulated by three enzymes catalyzing glucose as a fuel, brain is a prominent tissue where these nonequilibrium reactions: hexokinase, phosphofruc- metabolic defects manifest themselves in neurologic tokinase, and pyruvate kinase. disturbances. Inherited aldolase A deficiency and pyruvate kinase • In erythrocytes, the first site in glycolysis for genera- deficiency in erythrocytes cause hemolytic anemia. tion of ATP may be bypassed, leading to the forma- The exercise capacity of patients with muscle phos- tion of 2,3-bisphosphoglycerate, which is important phofructokinase deficiency is low, particularly on in decreasing the affinity of hemoglobin for O2. high-carbohydrate diets. By providing an alternative • Pyruvate is oxidized to acetyl-CoA by a multienzyme lipid fuel, eg, during starvation, when blood free fatty complex, pyruvate dehydrogenase, that is dependent acids and ketone bodies are increased, work capacity is on the vitamin cofactor thiamin diphosphate. improved. • Conditions that involve an inability to metabolize pyruvate frequently lead to lactic acidosis. SUMMARY • Glycolysis is the cytosolic pathway of all mammalian REFERENCES cells for the metabolism of glucose (or glycogen) to Behal RH et al: Regulation of the pyruvate dehydrogenase multien- pyruvate and lactate. zyme complex. Annu Rev Nutr 1993;13:497. ch17.qxd 2/13/2003 3:01 PM Page 144

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Boiteux A, Hess B: Design of glycolysis. Phil Trans R Soc London Sols A: Multimodulation of enzyme activity. Curr Top Cell Reg B 1981;293:5. 1981;19:77. Fothergill-Gilmore LA: The evolution of the glycolytic pathway. Srere PA: Complexes of sequential metabolic enzymes. Annu Rev Trends Biochem Sci 1986;11:47. Biochem 1987;56:89. Scriver CR et al (editors): The Metabolic and Molecular Bases of In- herited Disease, 8th ed. McGraw-Hill, 2001.