Textbook - BIOLOGICAL CHEMISTRY - Gubsky Yu.I. - 2000

Chapter III. METABOLISM OF MAJOR CLASSES OF BIOMOLECULES

CHAPTER 11. CARBOHYDRATE METABOLISM. I. AEROBIC AND ANAEROBIC OXIDATION OF GLUCOSE

11.2. AEROBIC OXIDATION OF GLUCOSE

Under normal cellular Respiration conditions, aerobic oxidation is predominant for most animal Tissues and represents the most energetically efficient metabolic pathway for glucose.

The overall equation for the aerobic oxidation of glucose to carbon dioxide and Water is as follows:

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The complex multi-step process of aerobic glucose oxidation includes the following stages:

1. Breakdown of glucose to pyruvic acid.

The products of this glycolytic stage of glucose breakdown are Pyruvate, as well as two molecules of reduced NAD⁺ and two molecules of ATP:

The enzymatic reactions leading to The formation of pyruvate from glucose (aerobic Glycolysis) are discussed below. Note that the oxidation in the mitochondrial Respiratory Chain of the two NADH molecules generated at this stage is accompanied by The production of six (2x3) ATP molecules via Oxidative Phosphorylation.

2. Oxidative Decarboxylation of pyruvic acid.

This process yields acetyl-coenzyme A—the primary substrate for oxidation in The Tricarboxylic Acid Cycle—and reduced NAD⁺.

The overall equation for The oxidative decarboxylation of pyruvate:

The oxidative decarboxylation of pyruvate is catalyzed by the pyruvate dehydrogenase complex—a multienzyme system located in the mitochondrial membranes of Eukaryotic Cells and in the Cytoplasm of prokaryotes. This complex comprises three Enzymes that catalyze three successive stages of pyruvate conversion to acetyl-CoA: pyruvate dehydrogenase, dihydrolipoyl acetyltransferase, dihydrolipoyl dehydrogenase, along with five Coenzymes and prosthetic groups: Thiamine diphosphate (TDP), coenzyme A (CoA), Lipoic Acid (LA), NAD+, and FAD.

Enzymatic stages of acetyl-CoA formation from pyruvate.

Stage I — catalyzed by pyruvate dehydrogenase (E₁), which utilizes TDP as a coenzyme. At this stage, pyruvate interacts with the C-2 atom of the thiazole ring of the thiamine molecule; this reaction yields an enzyme-bound hydroxyethyl derivative of thiamine diphosphate:

Stage II — catalyzed by the central enzyme of the complex, dihydrolipoyl acetyltransferase (E₂), which transfers the hydroxyethyl group from TDP (E₁) to the prosthetic group of enzyme E₂ (the oxidized form of lipoic acid, LA). This reaction yields an acetyl thioester of the reduced lipoyl groups of enzyme E₂ containing a high-energy bond:

Stage III — dihydrolipoyl acetyltransferase transfers the acetyl group from reduced lipoic acid to coenzyme A:

Stage IV — oxidation of the reduced form of enzyme E₂ by FAD-dependent dihydrolipoyl dehydrogenase (E₃):

Stage V — transfer of hydrogen atoms from the reduced FAD group of dihydrolipoyl dehydrogenase to NAD⁺, yielding NADH:

The reduced NADH generated during the oxidative decarboxylation of pyruvate is oxidized under aerobic conditions within the Mitochondrial Electron Transport chain, producing six (2x3) ATP molecules.

3. Oxidation of acetyl-CoA to carbon dioxide and water in the tricarboxylic acid cycle.

The tricarboxylic acid cycle, functionally and biochemically coupled with the Electron Transport Chain in the mitochondrial membranes, completes the aerobic oxidation of glucose to CO₂ and H₂O, generating 12 ATP molecules per cleaved molecule of acetyl-CoA.