BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART II GENERATION AND STORAGE OF METABOLIC ENERGY

CHAPTER 17. FATTY ACID METABOLISM

Summary

Fatty acids play a vital physiological role both as components of Phospholipids and Glycolipids and as fuel molecules. They are stored in adipose tissue as triacylglycerols (neutral fat), which can be mobilized by hormonally regulated lipases. Fatty acids are activated by conversion to acyl-CoA, transported across The inner mitochondrial membrane via carnitine, and degraded in the mitochondrial matrix through a repeating sequence of four reactions: 1) FAD-dependent oxidation, 2) Hydration, 3) NAD⁺-dependent oxidation, and 4) CoA-dependent thiolysis. The FADH₂ and NADH formed in the oxidation steps transfer their electrons to O₂ via the Respiratory Chain, whereas the acetyl-CoA produced in the thiolysis step normally enters The Tricarboxylic Acid Cycle by condensing with oxaloacetate. When the concentration of oxaloacetate is insufficiently high, the accumulation of acetyl-CoA leads to elevated levels of acetoacetate and 3-hydroxybutyrate, which normally serve as fuel molecules. During starvation and in diabetes, large quantities of acetoacetate, 3-hydroxybutyrate, and acetone (collectively known as Ketone Bodies) accumulate in the Blood. Mammals are unable to convert fatty acids into glucose because they lack a metabolic pathway that enables the net conversion of acetyl-CoA into oxaloacetate, Pyruvate, or other glycolytic intermediates.

The synthesis of fatty acids in the Cytosol proceeds via reactions distinct from those of β-oxidation. It begins with the carboxylation of acetyl-CoA to malonyl-CoA. This ATP-driven reaction is catalyzed by the biotin-containing enzyme acetyl-CoA carboxylase. This committed step in FATTY ACID Biosynthesis is allosterically stimulated by citrate. The intermediates of fatty acid synthesis are linked to an acyl carrier protein (ACP), specifically to the sulfhydryl terminus of its phosphopantetheine prosthetic group. Acetyl-ACP is formed from acetyl-CoA, and malonyl-ACP from malonyl-CoA. Acetyl-ACP and malonyl-ACP condense to form acetoacetyl-ACP in a reaction driven by the release of CO₂ from the activated malonyl moiety. These steps are followed by reduction, dehydration, and a second reduction. NADPH serves as the reductant in these stages. The resulting butyryl-in can enter a second elongation cycle, which begins with The addition of a two-carbon unit derived from malonyl-ACP. Seven cycles of elongation lead to The formation of palmitoyl-ACP, which is hydrolyzed to palmitate. The synthesis of palmitate requires eight molecules of acetyl-CoA, fourteen NADPH, and seven ATP. In higher organisms, the Enzymes catalyzing fatty acid synthesis are organized into a multienzyme complex. Two Types of polypeptide chains in these complexes harbor seven covalently linked enzymatic activities. A citrate-Cleavage cycle facilitates The transport of acetyl groups from Cell/35.html">Mitochondria to the cytosol and generates a portion of the required NADPH. The remaining NADPH is produced via the Pentose Phosphate Pathway. The Elongation and desaturation of fatty acids are catalyzed by enzyme systems located in The Endoplasmic reticulum membranes. Mammals lack the enzymes capable of introducing double bonds beyond C-9, and therefore must obtain linoleate and linolenate from their diet.