SUMMARY

• 28.1 Fatty Acid Synthesis Takes Place in Three Stages

  Fatty acids are synthesized in the cytoplasm by a different pathway from that of β oxidation. 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 concerted action of malate dehydrogenase and NADP⁺-linked malate enzyme, as well as by the pentose phosphate pathway.

  Synthesis starts with the carboxylation of acetyl CoA to malonyl CoA, the committed step. This ATP-driven reaction is catalyzed by acetyl CoA carboxylase 1, 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.

• 28.2 Additional Enzymes Elongate and Desaturate Fatty Acids

  Fatty acids are elongated and desaturated by enzyme systems in the endoplasmic reticulum membrane. Desaturation requires NADH (or NADPH) and O₂. 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, an anti-inflammatory and antithrombotic drug, irreversibly blocks the synthesis of these eicosanoids.

• 28.3 Acetyl CoA Carboxylase Is a Key Regulator of Fatty Acid Metabolism

  Fatty acid synthesis and degradation are reciprocally regulated so that both are not simultaneously active. Acetyl CoA carboxylase 1, 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 synthesized by mitochondrial acetyl CoA carboxylase 2 inhibits carnitine acyltransferase I.

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• 28.4 Metabolism in Context: Ethanol Alters Energy Metabolism in the Liver

  Ethanol cannot be excreted and thus must be metabolized. Ethanol metabolism generates large quantities of NADH. The NADH glut inhibits fatty acid degradation and stimulates fatty acid synthesis, leading to an accumulation of fat in the liver. Excess ethanol is metabolized to acetyl CoA, which results in ketosis, and acetaldehyde, a reactive compound that modifies proteins and impairs their function.