Biological Chemistry - Berezov T. T., Korovkin B. F. 1998

Carbohydrate Metabolism
Aerobic Metabolism of Pyruvate
Oxidative Decarboxylation of Pyruvic Acid

Cells with an insufficient oxygen supply can rely, partially or fully, on the energy yielded by Glycolysis. However, most animal and plant cells normally exist under aerobic conditions, completely oxidizing their organic "fuel" to СО₂ and Н₂О. Under these conditions, the Pyruvate generated from glucose breakdown is not reduced to lactate; instead, it is progressively oxidized to СО₂ and Н₂О during the aerobic stage of Catabolism. This initially involves The oxidative decarboxylation of pyruvate to yield acetyl-CoA.

The Oxidation of Pyruvate to acetyl-CoA proceeds via a series of Enzymes and Coenzymes structurally organized into a multienzyme system known as the pyruvate dehydrogenase complex.

In Stage I of this process, pyruvate (Fig. 10.8) loses its carboxyl group through interaction with thiamine pyrophosphate (TPP), which is located in the active center of the pyruvate dehydrogenase enzyme (E₁). In stage II, the hydroxyethyl group of the E₁—TPP—CHOH—CH₃ complex is oxidized to an acetyl group, which is simultaneously transferred to lipoamide (a coenzyme) covalently bound to the dihydrolipoyl transacetylase enzyme (E₂). This enzyme catalyzes stage III—The transfer of the acetyl group to coenzyme A (HS-CoA) to form the final product, acetyl-CoA, which is a high-energy (macroergic) compound.

In stage IV, the oxidized form of lipoamide is regenerated from the reduced dihydrolipoyl-lipoamide—E₂ complex. Catalyzed by dihydrolipoyl dehydrogenase (E₃), hydrogen atoms are transferred from the reduced sulfhydryl groups of dihydrolipoyl to FAD, which serves as the tightly bound prosthetic group of this enzyme. In stage V, the reduced FADH₂ of dihydrolipoyl dehydrogenase transfers hydrogen to the coenzyme NAD, yielding NADH + H⁺.

The Oxidative Decarboxylation of pyruvate takes place within the mitochondrial matrix. It involves (as part of a complex multienzyme system) 3 enzymes (pyruvate dehydrogenase, dihydrolipoyl transacetylase, dihydrolipoyl dehydrogenase) and 5 coenzymes (TPP, lipoamide, coenzyme A, FAD, and NAD). Of these, three are relatively tightly bound to the enzymes (TPP-E₁, lipoamide-E₂, and FAD-E₃), while two dissociate readily (HS-CoA and NAD).

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Fig. 10.8. MECHANISM OF ACTION of the pyruvate dehydrogenase complex.

E₁ – pyruvate dehydrogenase; E₂ – dihydrolipoyl transacetylase; E₃ – dihydrolipoyl dehydrogenase; numbers in circles indicate the Stages of the process.

All of these subunit-structured enzymes and coenzymes are organized into a single complex, allowing intermediate products to interact rapidly with one another. It has been shown that The polypeptide chains of the dihydrolipoyl transacetylase subunits form the core of the complex, around which pyruvate dehydrogenase and dihydrolipoyl dehydrogenase are arranged. It is generally accepted that the native enzyme complex is formed via self-assembly.

The overall reaction catalyzed by the pyruvate dehydrogenase complex can be represented as follows:

Pyruvate + NAD⁺ + HS-CoA -> Acetyl-CoA + NADH + H⁺ + СО₂.

This reaction is accompanied by a significant decrease in Standard Free energy and is practically irreversible.

The acetyl-CoA produced during oxidative decarboxylation undergoes further oxidation to yield СО₂ and Н₂О. The Complete oxidation of acetyl-CoA takes place in The Tricarboxylic Acid Cycle (the Krebs cycle). Like the oxidative decarboxylation of pyruvate, this process occurs within the Cell/35.html">Mitochondria of the cells.