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

Chapter III. METABOLISM OF MAJOR CLASSES OF BIOMOLECULES

CHAPTER 14. LIPID METABOLISM. I. CATABOLISM OF TRIACYLGLYCEROLS AND FATTY ACIDS

14.3. OXIDATION OF FATTY ACIDS AND GLYCEROL

The products of lipolysis of triacylglycerols and other glycerides are Fatty acids and glycerol, which are capable of undergoing oxidation to generate a significant amount of ATP.

Class="center">Fatty acid oxidation

Fatty acid oxidation takes place in the mitochondrial matrix through a cyclic process that involves the successive Cleavage of two-carbon fragments from long-chain saturated fatty acid molecules with an even number of carbon atoms (such as palmitic — C₁₆, stearic — C₁₈, etc.) — known as the β-oxidation cycle.

As in glucose METABOLISM, a prerequisite for a fatty acid to enter the oxidation pathway is its enzymatic activation, which means its conversion into an active derivative via an ATP-requiring reaction.

Fatty acid activation occurs in the Cytoplasm with the participation of specific Enzymes called acyl-CoA synthetases (thiokinases), which form CoA-derivatives of fatty acids:

ENZYMATIC REACTIONS OF Fatty Acid β-Oxidation

1. Dehydrogenation of fatty acid CoA-derivatives involving the FAD-dependent enzyme acyl-CoA dehydrogenase.

This reaction yields a trans-unsaturated (at positions 2,3 or α, β) CoA-derivative of the fatty acid:

2. Hydration of the unsaturated acyl-CoA by the enzyme enoyl-CoA hydratase, producing a hydroxylated acyl-CoA derivative — 3-hydroxyacyl-CoA (β-hydroxyacyl-CoA):

3. Dehydrogenation of the hydroxyacyl-CoA derivative by the NAD-dependent enzyme 3-hydroxyacyl-CoA dehydrogenase. The reaction product is 3-ketoacyl-CoA (β-ketoacyl-CoA):

4. Thiolytic cleavage of 3-ketoacyl-CoA through interaction with a CoA molecule in the presence of the enzyme β-ketoacyl-CoA thiolase. This reaction yields a fatty acid CoA-derivative shortened by two carbon atoms, along with acetyl-CoA:

During a single cycle of β-oxidation, one molecule of acetyl-CoA is released from the fatty acid molecule, and consequently, the original acyl-CoA molecule is shortened by two carbon atoms. It is easy to see that for the complete degradation of any even-chain fatty acid molecule with (n) carbon atoms into acetyl-CoA, (n/2 - 1) cycles of β-oxidation are required.

Based on this, the overall equation for the β-oxidation of palmitic acid, which is common in natural triacylglycerols, is as follows:

The General scheme of the saturated fatty acid β-oxidation cycle is shown in Fig. 14.3.

Fig. 14.3. Metabolic map of fatty acid β-oxidation.

The Role of carnitine in fatty acid oxidation

The enzymes responsible for fatty acid β-oxidation are localized within the Cell/35.html">Mitochondria; however, The inner mitochondrial membrane is impermeable to long-chain acyl-CoA derivatives. Therefore, a specialized transport system operates at the inner mitochondrial membrane, involving the amino alcohol carnitine, which facilitates The transport of acyl-CoA molecules into the mitochondrial matrix.

The transport function of carnitine operates via a shuttle mechanism (Fig. 14.4):

Fig. 14.4. The role of carnitine in the transport of long-chain fatty acids across the inner mitochondrial membrane. E₁ — carnitine acyltransferase I; E₂ — carnitine acyltransferase II; T — translocase.

a) on the outer surface of the inner mitochondrial membrane, the enzyme carnitine acyltransferase I catalyzes The formation of the acylcarnitine ester:

b) the transport protein carnitine-acylcarnitine translocase transports acylcarnitine across the mitochondrial membrane;

c) on the inner surface of the membrane, the enzyme carnitine acyltransferase II cleaves acylcarnitine in the following reaction:

Acyl-S-CoA enters the β-oxidation pathway, while free carnitine returns to the intermembrane space/Cytosol to participate in transporting a new fatty acid molecule.

Energetics of fatty acid β-oxidation

1. Each cycle of β-oxidation releases one molecule of acetyl-CoA, The oxidation of which in The Tricarboxylic Acid Cycle yields 12 ATP molecules (Chapter 10). The β-oxidation of palmitate (see above) results in the formation of 8 acetyl-CoA molecules, the Complete oxidation of which to CO₂ and H₂O yields 96 (12x8) ATP molecules.

2. In each cycle of β-oxidation, two molecules of reduced Coenzymes—FADH₂ and NADH—are produced. These can donate their reducing equivalents to the Mitochondrial Electron Transport chain, driving the generation of 2 (FADH₂) and 3 (NADH) ATP molecules, respectively, via Oxidative Phosphorylation, totaling 5 ATP molecules per cycle. For the complete oxidation of palmitate across 7 cycles of β-oxidation, this mechanism yields 35 (5x7) ATP molecules.

Accounting for the consumption of 1 ATP molecule during the fatty acid activation stage, the total net yield of ATP synthesized upon complete oxidation of a palmitate molecule to carbon dioxide and Water is 130 (96+35-1). Based on this, the overall equation for the oxidation of palmitic acid in mitochondria can be represented as follows:

Glycerol oxidation

Glycerol, produced during The breakdown of triacylglycerols or Glycerophospholipids, can enter the catabolic (oxidation) pathway or be reused for The Biosynthesis of various glyceride classes (Chapter 15).

1. The entry of glycerol into metabolic pathways is preceded by its activation, which involves its ATP-dependent conversion into glycerol-3-phosphate (α-glycerophosphate) via the action of the enzyme glycerol kinase.

2. α-Glycerophosphate can be oxidized by the mitochondrial enzyme α-glycerophosphate dehydrogenase to yield glyceraldehyde-3-phosphate (G-3-P).

Glyceraldehyde-3-phosphate is a central metabolite of glycolytic glucose oxidation. The subsequent metabolism of G-3-P derived from glycerol oxidation follows the same pathway as the Catabolism of glycolytic G-3-P (Chapter 11):