Fatty Acid Biosynthesis and Oxidation

This chapter describes the catalytic transformations in the microbial fatty acid biosynthesis (fatty acid synthase, FAS-II) and mammalian fatty acid β-oxidation pathways, and is organized into three sections based around the thiolase, short-chain dehydrogenase reductase (SDR), and crotonase superfamilies. Section 1 discusses the mechanism of the FAS-II β-ketoacyl-ACP synthases and β-oxidation thiolases, and also describes carbon–carbon bond formation reactions catalyzed by other members of the thiolase superfamily including the biosynthetic thiolases, type III polyketide synthases, and HMG-CoA synthase. Section 2 compares and contrasts the mechanism of the dehydrogenase and reductase members of the SDR superfamily with particular emphasis on the FAS-II β-ketoacyl-ACP reductases and the FabI, FabV and FabL enoyl-ACP reductases. This section concludes with a discussion of the acyl-CoA dehydrogenases and hydroxyacyl-CoA dehydrogenase from the β-oxidation pathway. The final section in the chapter is focused on enzymes involved in the hydration and dehydration of fatty acids, and initially focuses on the FabA and FabZ dehydratases in the FAS-II pathway. This is followed by an extensive discussion of the β-oxidation enzyme enoyl-CoA hydratase (crotonase) together with other members of the crotonase superfamily including 4-chlorobenzoyl-CoA dehalogenase, dihydroxynaphthoyl-CoA synthase, BadI and 3-hydroxyisobutyryl-CoA hydrolase. In addition to a discussion of enzyme mechanisms, where relevant there is also a discussion of inhibitor discovery since the FAS-II pathway is a validated target for antimicrobial drug discovery.