Pyruvate dehydrogenase inhibitors

Aicher, T.D., Anderson, R.C., Bebernitz, G.R.,ei al. (1999) (/ )-3,3,3-Trifluoro-2-hydroxy-2-methylpropiona-mides are orally active inhibitors of pyruvate dehydrogenase kinase. Journal of Medicinal Chemistry, 42, 2741-2746. 

Fig. 9. A schematic drawing of a possible mechanism for the reaction catalyzed by the pyruvate dehydrogenase complex. The three enzymes Elf E2, and E3 are located so that lipoic acid covalently linked to E2 can rotate between the active sites containing thiamine pyrophosphate (TPP) and pyruvate (Pyr) on Elt CoA on E2, and FAD on E3. Acetyl-CoA and GTP are allosteric effectors of E, and NAD+ is an inhibitor of the overall reaction.

Reactions of the TCA cycle Enzyme that oxidatively decarboxylates pyruvate, its coenzymes, activators, and inhibitors REACTIONS OF THE TRICARBOXYLIC ACID CYCLE (p. 107) Pyruvate is oxidatively decarboxylated by pyruvate dehydrogenase complex producing acetyl CoA, which is the major fuel for the tricarboxylic acid cycle (TCA cycle). The irreversible set of reactions catalyzed by this enzyme complex requires five coenzymes thiamine pyrophosphate, lipoic acid, coenzyme A (which contains the vitamin pantothenic acid), FAD, and NAD. The reaction is activated by NAD, coenzyme A, and pyruvate, and inhibited by ATP, acetyl CoA, and NADH. 

Pyruvate produced by the glycolytic pathway may be transported into the mitochondria (via an antiport with OH"), where it is converted to acetyl-CoA by the action of the enzyme complex pyruvate dehydrogenase. The pertinent enzyme activities are pyruvate dehydrogenase (PD), lipoic acid acetyltransferase, and dihydrolipoic acid dehydrogenase. In addition, several cofactors are utilized thiamine pyrophosphate (TPP), lipoic acid, NAD+, Co A, and FAD. Only Co A and NAD+ are used in stoichiometric amounts, whereas the others are required in catalytic amounts. Arsenite and Hg2+ are inhibitors of this system. The overall reaction sequence may be represented by Figure 18.5. The NADH generated may enter the oxidative phosphorylation pathway to generate three ATP molecules per NADH molecule reduced. The reaction is practically irreversible its AGq = -9.4 kcal/mol. 

DCA is an inhibitor of pyruvate dehydrogenase kinase, the enzyme that regulates pyruvate dehydrogenase (PDH) activity by phosphorylation of the Ex subunit, leading to a decrease in PDH activity (see Chapter 7). DCA has been used to lower lactate levels in some patients with MELAS. Stimulation of PDH activity reduces the release of lactate from peripheral tissues and enhances its metabolism by the liver. Since prolonged use of DCA may lead to sensory neuropathy, treatment must be closely monitored. 

Regulation of Pyruvate Dehydrogenase Activity Pyruvate dehydrogenase is the key enzyme that commits pyruvate (and hence the products of carbohydrate metabolism) to complete oxidation (via the tricarboxyUc acid cycle) or lipogenesis. It is subject to regulation by both product inhibition and a phosphorylation/dephosphorylation mechanism. Acetyl CoA and NADH are both inhibitors, competing with coenzyme A and NAD+. 

Over the years, squaric acid and its derivatives have found several uses in medicinal chemistry Squaric acid inhibits glyoxy-lase I (45) semisquaric acid (3-hydroxy-3-cyclobutenedione) is an inhibitor of pyruvate dehydrogenase and transketolase (46) and other derivatives serve as antagonists of the N -methyl-D-... 

A potent inhibitor. Thiamine thiazolone pyrophosphate binds to pyruvate dehydrogenase about 20,000 times as strongly as does thiamine pyrophosphate, and it competitively inhibits the enzyme. Why ... 

Figure 4-11. The TCA cycle and the precursors of acetyl CoA. ICDH = isocitrate dehydrogenase PDH= pyruvate dehydrogenase ETC = electron transport chain = activator 0 = inhibitor. The ( ) indicates that the thioesters acetyl CoA and succinyl CoA are high-energy compounds.

A. Insulin stimulates activation of pyruvate kinase, pyruvate dehydrogenase, and phospho-fructokinase 2 (PFK2). PFK2 then catalyzes formation of fructose 2,6-bisphosphate, which is an activator of PFK1 and an inhibitor of fructose 1,6-bisphosphatase, a gluconeogenic enzyme. 

The pyruvate dehydrogenase complex catalyzes an irreversible reaction that is the entry point of pyruvate into the TCA cycle (see below) and is under complex regulation by allosteric and covalent modification of the pyruvate dehydrogenase component of the complex. The end products of the overall reaction (NADH and acetyl-CoA) are potent allosteric inhibitors of the pyruvate dehydrogenase... 

R)- and (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (Fig. 4) are intermediates for the synthesis of a number of potential pharmaceuticals, which include ATP-sensitive potassium channel openers for the treatment of incontinence [11], and inhibitors of pyruvate dehydrogenase kinase for the treatment of diabetes [12]. 

Arjunan, P, Chandrasekhar, K., Sax, M., et al. (2004) Structural determinants of enzyme binding affinity The El component of pyruvate dehydrogenase from Escherichia coli in complex with the inhibitor thiamin thiazolone diphosphate. Biochemistry 43,2405-2411. 

Both enzymes mentioned previously pertain to the tricarboxylic acid cycle proper, and are apparently vital to sustaining respiration. Accordingly, inhibitors can lead to undesirable and sometimes life-threatening consequences. Enzyme inhibitors for pyruvate dehydrogenase are more commonly known, those for a-ketoglutarate dehydrogenase less so. In the Jain reference respiration inhibitors are treated as a special category. 

Acetyl CoA, which can arise from fatty-acid metabolism as well as from pyruvate, is a required activator of pyruvate carboxylase and an inhibitor of pyruvate dehydrogenase. 

Mann, W.R. Dragland, C.J. Vinluan, C.C. Vedananda, T.R. Bell, P.A. Aicher, T.D. Diverse mechanisms of inhibition of pyruvate dehydrogenase kinase by structurally distinct inhibitors. Biochim. Biophys. Acta, 1480, 283-292 (2000)... 

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