Pyruvate is transported into the mitochondrion by a proton symporter. It then undergoes oxidative decarboxylation to acetyl-CoA, catalyzed by a multienzyme complex that is associated with the inner mitochondrial membrane. This pyruvate dehydrogenase complexis analogous to the α-ketoglutarate dehydrogenase complex of the citric acid cycle . Pyruvate is decarboxylated by the pyruvate dehydrogenase component of the enzyme complex to a hydroxyethyl derivative of the thiazole ring of enzyme-bound thiamin diphosphate, which in turn reacts with oxidized lipoamide, the prosthetic group of dihydrolipoyl transacetylase, to form acetyl lipoamide (Figure 1). In thiamin (vitamin B1 ) deficiency, pyruvate oxidation is impaired, and there is significant (and potentially life-threatening) lactic and pyruvic acidosis. Acetyl lipoamide reacts with coenzyme A to form acetyl-CoA and reduced lipoamide. The reaction is completed when the reduced lipoamide is reoxidized by a flavoprotein, dihydrolipoyl dehydrogenase, containing flavin adenine dinucleotide (FAD). Finally, the reduced flavoprotein is oxidized by NAD+, which in turn transfers reducing equivalents to the respiratory chain. The overall reaction is:

Pyruvate + NAD⁺ + CoA→Acetyl-CoA + NADH + H⁺+ CO₂

The pyruvate dehydrogenase complex consists of a number of polypeptide chains of each of the three component enzymes and the intermediates do not dissociate, but are channeled from one enzyme site to the next. This increases the rate of reaction and prevents side reactions.

Fig1. 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. (FAD, flavin adenine dinucleotide; NAD+, nicotin amide adenine dinucleotide.)

Pyruvate Dehydrogenase Is Regulated by End-Product Inhibition & Covalent Modification

Pyruvate dehydrogenase is inhibited by its products, acetyl-CoA and NADH (Figure2). It is also regulated by phosphorylation (catalyzed by a kinase) of three serine residues on the pyruvate dehydrogenase component of the multienzyme com plex, resulting in decreased activity and by dephosphorylation (catalyzed by a phosphatase) that causes an increase in activity. The kinase is activated by increases in the [ATP]/[ADP], [acetyl-CoA]/[CoA], and [NADH]/[NAD+] ratios. Thus, pyruvate dehydrogenase, and therefore glycolysis, is inhibited both when there is adequate ATP (and reduced coenzymes for ATP formation) available, and also when fatty acids are being oxidized. In fasting, when nonesterified fatty acid concentrations increase, there is a decrease in the proportion of the enzyme in the active form, decreasing pyruvate oxidation. In adipose tissue, where glucose provides acetyl-CoA for lipogenesis, the enzyme is activated in response to insulin.

Fig2. Regulation of pyruvate dehydrogenase (PDH).Arrows with wavy shafts indicate allosteric effects. (A) Regulation by end product inhibition. (B) Regulation by interconversion of active and inactive forms.

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مواضيع ذات صلة

Cyclic AMP Integrates The Regulation of Glycogenolysis & Glycogenesis

Glycogenolysis is not the Reverse of Glycogenesis, it is A Separate Pathway

Glycogenesis Occurs Mainly in Muscle & Liver

Glycolysis is Regulated at Three Nonequilibrium Reactions

Tissues That Function Under Hypoxic Conditions or have Intrinsically High Rates of Glucose Oxidation Produce Lactate

Glycolysis Constitutes The Main Pathway of Glucose Utilization

Glycolysis Can Function Under Anaerobic Conditions

Regulation of the Citric Acid Cycle Depends Primarily on a Supply of Oxidized Cofactors

The Citric Acid Cycle Takes Part in Fatty Acid Synthesis

The Citric Acid Cycle Takes Part in Gluconeogenesis, Transamination, & Deamination

Reactions of The Citric Acid Cycle Generate Reducing Equivalents & CO2

The Citric Acid Cycle Provides Substrates for The Respiratory Chain