22.1 Triacylglycerols Are Highly Concentrated Energy Stores

Fatty acids are physiologically important as (1) fuel molecules, (2) components of phospholipids and glycolipids, (3) hydrophobic modifiers of proteins, and (4) hormones and intracellular messengers. They are stored in adipose tissue as triacylglycerols (neutral fat).

22.2 The Use of Fatty Acids as Fuel Requires Three Stages of Processing

Triacylglycerols can be mobilized by the hydrolytic action of lipases that are under hormonal control. Glucagon and epinephrine stimulate triacylglycerol breakdown by activating the lipase. Insulin, in contrast, inhibits lipolysis. Fatty acids are activated to acyl CoAs, transported across the inner mitochondrial membrane by carnitine, and degraded in the mitochondrial matrix by a recurring sequence of four reactions: oxidation by FAD, hydration, oxidation by NAD⁺, and thiolysis by coenzyme A. The FADH₂ and NADH formed in the oxidation steps transfer their electrons to O₂ by means of the respiratory chain, whereas the acetyl CoA formed in the thiolysis step normally enters the citric acid cycle by condensing with oxaloacetate.

22.3 Unsaturated and Odd-Chain Fatty Acids Require Additional Steps for Degradation

Fatty acids that contain double bonds or odd numbers of carbon atoms require ancillary steps to be degraded. An isomerase and a reductase are required for the oxidation of unsaturated fatty acids, whereas propionyl CoA derived from chains with odd numbers of carbon atoms requires a vitamin B₁₂-dependent enzyme to be converted into succinyl CoA. Ketone bodies, formed from acetyl CoA, are an important fuel source for some tissues. Mammals are unable to convert fatty acids into glucose, because they lack a pathway for the net production of oxaloacetate, pyruvate, or other gluconeogenic intermediates from acetyl CoA.

673

22.4 Fatty Acids Are Synthesized by Fatty Acid Synthase

Fatty acids are synthesized in the cytoplasm by a different pathway from that of β oxidation. Fatty acid synthase is the enzyme complex responsible for fatty acid synthase. Synthesis starts with the carboxylation of acetyl CoA to malonyl CoA, the committed step. This ATP-driven reaction is catalyzed by acetyl CoA carboxylase, a biotin enzyme. The intermediates in fatty acid synthesis are linked to an acyl carrier protein. Acetyl ACP is formed from acetyl CoA, and malonyl ACP is formed from malonyl CoA. Acetyl ACP and malonyl ACP condense to form acetoacetyl ACP, a reaction driven by the release of CO₂ from the activated malonyl unit. A reduction, a dehydration, and a second reduction follow. NADPH is the reductant in these steps. The butyryl ACP formed in this way is ready for a second round of elongation, starting with the addition of a two-carbon unit from malonyl ACP. Seven rounds of elongation yield palmitoyl ACP, which is hydrolyzed to palmitate. In higher organisms, the enzymes catalyzing fatty acid synthesis are covalently linked in a multifunctional enzyme complex. A reaction cycle based on the formation and cleavage of citrate carries acetyl groups from mitochondria to the cytoplasm. NADPH needed for synthesis is generated in the transfer of reducing equivalents from mitochondria by the combined action of cytoplasmic malate dehydrogenase and malic enzyme and by the pentose phosphate pathway.

22.5 The Elongation and Unsaturation of Fatty Acids Are Accomplished by Accessory Enzyme Systems

Fatty acids are elongated and desaturated by enzyme systems in the endoplasmic reticulum membrane. Desaturation requires NADH and O₂ and is carried out by a complex consisting of a flavoprotein, a cytochrome, and a nonheme iron protein. Mammals lack the enzymes to introduce double bonds distal to C-9, and so they require linoleate and linolenate in their diets.

Arachidonate, an essential precursor of prostaglandins and other signal molecules, is derived from linoleate. This 20:4 polyunsaturated fatty acid is the precursor of several classes of signal molecules— prostaglandins, prostacyclins, thromboxanes, and leukotrienes—that act as messengers and local hormones because of their transience. They are called eicosanoids because they contain 20 carbon atoms. Aspirin (acetylsalicylate), an anti-inflammatory and antithrombotic drug, irreversibly blocks the synthesis of these eicosanoids.

22.6 Acetyl CoA Carboxylase Plays a Key Role in Controlling Fatty Acid Metabolism

Fatty acid synthesis and degradation are reciprocally regulated so that both are not simultaneously active. Acetyl CoA carboxylase, the essential control site, is phosphorylated and inactivated by AMP-activated kinase. The phosphorylation is reversed by a protein phosphatase. Citrate, which signals an abundance of building blocks and energy, partly reverses the inhibition by phosphorylation. Carboxylase activity is stimulated by insulin and inhibited by glucagon and epinephrine. In times of plenty, fatty acyl CoAs do not enter the mitochondrial matrix, because malonyl CoA inhibits carnitine acyltransferase I.

674