Pyruvate

Pyruvate (pyruvic acid 2-oxopropanoic acid alpha-ketopropionic acid aeetylformic acid pyroracemic acid: molecular weight 88) is a keUi-monocarboxylie acid.

Abbreviations

Co A coenzyme A

MCV1 proton/monocarboxylic acid corransporter 1 (SIC16A1) MCT2 proton/monocarboxylic acid corransporter 2 (5LC16A7) PLP pyridoxal S'-phosphace

Nutritional summary

Function: Pyruvate is ihe product of glucose. L-alanine, and L-scrinc breakdown. Food sources: Insignificant amounts are present in foods from both animal and plant sources. In comparison, more than a hundred grams of pyruvate are generated daily from the breakdown of carbohydrates and protein.

Requirements: No dietary intakes are needed. Pyruvate is commercially available as a single compound or in combination with other ingredients.

Deficiency: A lack of intake has no harmful consequences. The efficacy of oral pyruvate supplements to promote weight loss in conjunction with exercise and to improve exercise performance still is uncertain. The intracoronary application for the salvage of ischemic myocardium has been described but requires further evaluation. Excessive intake: The risks associated with use of supplemental pyruvate are not known.

Endogenous sources

Carbohydrates: Several hundred grams of pyruvate are generated during the metabolism of glucose via glycolysis. As a rule of thumb, about one gram of absorbed carbohydrate generates one gram of pyruvate. Asa result of the shuttling of anaerobic glucose metabolites from muscle to liver for complete utilization (Cori cycle) large amounts of pyruvate are generated from S-lactate by NAI il l-dependent L-laetatc dehydrogenase (ECI.K1.27).

Amino acids: Almost all ingested L-alanine is eventually broken down by alanine aminotransferase (EC2.6.1.2) to pyruvate. The L-alanine-pyruvate pair is critical for the transfer of protein-derived carbons for gluconeogensis from muscles to the liver during fasting and severe illness (alanine glucose cycle).

A small proportion of L-senne is converted to pyruvate by the PLP-dependcnt enzymes serine dehydratase (EC4.2.I.13) and threonine dehydratase (EC4.2.L16).

Dietary sources

While many foods contain some pyruvate from the metabolic processes occurring in the food source, the amounts tend to be very small Dietary supplements w ith gram amounts of pyruvate are commercially available.

Digestion and absorption

A proton monocarboxylic acid cot rails porter (MC'fl. SLC16A11 is possibly present in the apical, and certainly in the basolateral membrane (Garcia etui.. I 994: Orsenigo el ul.. 1999; Tamai et ul1999) of the entire intestine, especially the jejunum (Tamai el ul.. 1995). In addition to lactate, acetate, acetoacctale. /S-hydroxybutyrate, propionate. butyrate. and benzoic acid, this transporter mediates uptake of pyruvate both across the brush border membrane and the basolateral membrane. Additional transporters or mechanisms of entry might exist.

Transport and cellular uptake

Blood circulation: Pyruvate is present in blood in free form. Tissues can take it up via several members of the proton monocarboxvlate cotransporter (MCT) family 11 lalestrap and Price. 1999). MCT I is the predominant form responsible for pyruvate uptake from circulation in liver, muscle, and brain. MCT2 (SLCI6A7) is a high-affinity transporter with a preference for pyruvate in many tissues. Expression is especially high in testis and in some neoplastic cells (Lin el ul.. 1998).

Once inside a cell, pyruvate can enter mitochondria via the mitochondrial tricarboxylic carrier, a six-transmembrane helix that is not related to the MCT family of genes (llalestrap and Price, 1999).

Moterno-fctal transfer: Several members of the MCT family contribute to placental transport, but their individual locations still need to be clarified. Blood brain barrier: MCT I is present at both sides of the brain endothelium. Kctosis increases MCT 1 expression in these cells.

Metabolism

Some of the energy content of carbohydrates can be utilized even in the absence of oxygen, especially in strenuously exercised muscle. In this case pyruvate is reduced to

CoA Acetyl-CoA

CoA Acetyl-CoA

Pyruvate

Figure 7.18 A mutii subunn cn/yme cample* o>id(/ci pyruvate

Pyruvate

Figure 7.18 A mutii subunn cn/yme cample* o>id(/ci pyruvate

L-lactate by L-lactate dehydrogenase tit' 1.1.1.27) providing a renewed supply of oxidized NAD for continued glycolysis. The net yield of anaerobic glycolysis is two ATP for eaeli glucose molecule metabolized to L-lactate. The shuttling of L-lactate from muscle to liver, eventual regeneration of pyruvate, glucose synthesis from pyruvate, and return transport of glucose to muscles is referred to as the Cori cycle.

If enough oxygen is available, on the other hand, pyruvate is fully metabolized in mitochondria by oxidative decarboxylation to acetyl-CoA, oxidation in the citric acid cycle, and use of the resulting reductants (NADH and FADH2) for oxidative phosphorylation. A smaller proportion of pyruvate is carboxylated to oxaloacetate in a biotin-dependent reaction. This latter reaction is called anaplerotic (Greek for 'refilling'), because it replenishes the citric acid cycle intermediates and thus sustains their ability to metabolize acetyl-CoA. I he metabolic fate of pyruvate is closely regulated. During glycolysis most pyruvate is metabolized to acetyl-CoA. When the prevailing metabolic direction is towards gluconeogenesis. a large proportion of available pyruvate is converted to oxaloacetate, which is then used to resynthesize glucose. Oxidative decarboxylation: Pyruvate dehydrogenase (EC3.1.3,43) in the mitochondrial matrix comprises multiple copies of three distinct moieties: EI. E2, and E3. Thiamin pyrophosphate is eovalently bound to El. Each subuntt F.2 (dthydrolipoamide S-acety¡transferase: EC2.3.LI2) contains two lipoate molecules, which arc eovalently bound to lysines 94 and 226. These lipoamides serve as acceptors for the acetyl residues from pyruvate, transfer them to acetyl CoA, and reduce lipoamidc to dthydrolipoamide in the process. Another component of the complex, dihydro)ipoamide dehydrogenase

(B3; ECI.8.1.4) transfers ihe hydrogen via FAD to NAD. A single gene encodes the dihydro!ipoamide dehydrogenase of pyruvate dehydrogenase and ihc other two alpha-ketoacid dehydrogenases.

Carboxylation: The biotin-containing enzyme pyruvate carboxylase (ECh.4.1.1) generates oxaloacetate, a pivotal precursor for glucose synthesis in gluconeogenic tissues (liver, kidney). Pyruvate carboxylation is the only anaplerotic (refilling) reaction that can replenish Krebs cycle intermediates without draw ing on L-glutamatc or other amino acids.

Excretion

Pyruvate is recovered from primary filtrate both in proximal renal tubules and collecting ducts. It has been suggested that a sodium-linked carrier, possibly MCT6. is responsible for uptake across the brush border membrane (Halestrap and Price, 1999). MCT1 mediates transport across ba so lateral membranes of proximal tubules. MCT2 performs this function in collecting ducts (Garcia et ul„ 1995).

Regulation

Both synthesis from glycolytic precursors and breakdown to cither acetyl-CoA or oxaloacetate are tightly regulated. Pyruvate dehydrogenase (EC3.I.3.43) is the enzyme that connects glycolysis to the citric acid cycle. This enzyme complex is inactivated by phosphorylation ([pyruvate dehydrogenase (lipoanndc)} kinase; EC2.7.I.99) of three serines in the El subuni! and reactivated by removal of these phosphates by [pyruvate dehydrogenase (lipoamidc)]-phosphatase (EC3,1.3.43). Inactivation is strongly subject to substrate and product feedback: ADP and pyruvate decrease the rate of inactivation. NADU and acetyl-CoA increase it. Activation, on the other hand, is mainly under hormonal control, mediated by calcium.

The activity of pyruvate carboxylase increases with rising acetyl-CoA concentration, which prevents further accumulation from pyruvate metabolism and makes more oxaloacetate available to form citrate condensation with aceiyl-CoA,

Unlike glucose, pyruvate does not stimulate insulin secretion. This dissociation of insulin secretion from mitochondrial substrate oxidation has been called the pyruvate paradox (Ishihara el al., 1499).

Function

Fuel metabolism. As described above, pyruvate is the linchpin between glucose metabolism and the citric acid cycle. Ingested pyruvate provides about 4 kcal g. Its complete oxidation requires adequate supplies of thiamin, riboflavin, niacin, pantothenate, lipoate, ubiquinone, magnesium, and iron.

Amino acid synthesis: L-Alanine aminotransferase lEC2.fi.1.2) uses I -glutamate to transaminate the glycolysis metabolite pyruvate and produce L-alanine. Since the reaction operates near equilibrium, high availability of glucose (and consequently of pyruvate) increases L-alaninc production. During fasting or severe illness ihe alanine- glucose cycle uses pyruvate and the amino groups from protein catabolism to shuttle the gluconeogenesis precursor from extrahcpatic tissues to the liver. Enzyme cofactor: Pyruvate is an essential cofactor of several bacterial enzymes, but no human enzymes with this type of requirement are known.

Performance enhancement: A beneficial effect of pyruvate tm myocardial contractility in patients w ith heart failure has been suggested (Hermann et al., 1999) which might be mediated by an increase of ionized calcium in the sarcoplasmic reticulum (Hermann er«/., 2000). It has also been suggested that supplemental pyruvate (6 gday) in combination with moderate exercise promotes weight loss ( Kaiman et a/., 1999). This type of regimen did not increase short-term strength, however (Stone et ul.. 1999).

References

(jarcia CK. Goldstein iL. Palhak RK, Anderson RG. Brown VIS. Molecular characterization of a membrane transporter for lactate, pyruvate, and other numocarhoxy laics: implications for Ihe Cori cycle. Cell 1994:76:865 7.1 Garcia CK, Brown MS. Pathak RK. Goldstein JL eDNA cloning of MCT2. a second monocarboxylate transporter expressed in different cells than MCT I../ Biol Chem 1995:270:1 «¿3-9

Halestrap AP, Price NT The proton-linked monocarboxylate transporter (MCT) family:

structure, function and regulation. BiochemJ 1999:343:281 49 Hermann HP. I'ieske B, Schwarzmiiller E. et ul. Haemodynamic effects of intra coronary pyruvate in patients with congestive heart failure: an open study. Lancet 1499:353: 1321-3

Hermann IIP. Zeitz O, Kcwcloh B. et ul. Pyruvate potentiates inotropic effects of isoproterenol and Ca:~ in rabbit cardiac muscle preparations. Am ,/ Physiol 2000:279: H702-H708

Ishiharu 11. Wang H, Drewes LR, Wollheim CB. Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in beta cells,,/ Clin invest 1999:104:1621 9 Kaiman ü. Colker CM. Wilets I. Routs .IB. Antonio J. The effects of pyruvate supplementation on body composition in overweight individuals. Nutrition 1999:15:337 -III Lin RY, Vera JC, Chaganti KSK. Golde DW. Human monocarboxylate transporter 2

IMCT2) is a high affinity pyruvate transporter. J Biol Client 1998:273:28959 65 Orsenigo MN. Tosco M. Bazzini C. Laforenza U. Faelli A, A monocarboxylate transporter MCT! is located at the basolateral pole of rat jejunum. Exp Physiol 1999:84: 1033-42

Stone MH. Sanborn K, Smith LL.O'Bryant HS. HokeT, Utter AC. Johnson RL, Boros R, Hruby J, Pierce KC, Stone ML. Garner B. Effects of in-season (5 weeks) creatine and pyruvate supplementation on anaerobic performance and body composition in American football players, fot J Sport Nutr I999;9:I46 65 Tamai 1. Takanaga H. Maeda II, Sai Y. Ogihara T, Higashida II, Tsuji A, Participation of a proton cotransportcr. MCTl, in the intestinal transport of monocarboxylic acids. Biochem Biophys Res Cumm 1995:214:482-9

Tamai 1, Sai Y. Ono A, Kido Y. Yabuuchi 11. Takanaga H, Satoh I . Ogihara 1. Amano O. Izeki S. Tsuji A. ImraunohislochemicaI and functional characterization of pll-depcndent intestinal absorption of weak organic acids hy the monocarboxylic acid transporter MCI 1 .JPharm Pharmacol 1999;51:1113-21

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