Fatty acid synthesis, in eukaryotes

Fatty Acid Synthesis in Eukaryotes Occurs on a Multienzyme Complex... 

Salati LM, Goodridge AG Fatty acid synthesis in eukaryotes. In Biochemistry of Lipids, Lipoproteins and Membranes. Vance DE, Vance JE (editors). Elsevier, 1996. 

The remaining series of reactions of fatty acid synthesis in eukaryotes is catalyzed by fatty acid synthase (FAS) is a homodimeric and multifunctional complex of 250 kDa and contains seven different enzymatic activities plus a domain that covalently binds a molecule of 4 -phosphopantetheine, of the acyl carrier protein (ACP) [105,106]. PA, the most abundant acid, is synthesized de novo firrm acetyl-CoA as a primer, malonyl-CoA as a carbon donor, and NADPH as a reducing equivalent according to the following reaction [104, 105, 107]. 

Eukaryotic cells face a dilemma in providing suitable amounts of substrate for fatty acid synthesis. Sufficient quantities of acetyl-CoA, malonyl-CoA, and NADPH must be generated in the cytosol for fatty acid synthesis. Malonyl-CoA is made by carboxylation of acetyl-CoA, so the problem reduces to generating sufficient acetyl-CoA and NADPH. 

In eukaryotes, the cytoplasm, representing slightly more than 50% of the cell volume, is the most important cellular compartment. It is the central reaction space of the cell. This is where many important pathways of the intermediary metabolism take place—e.g., glycolysis, the pentose phosphate pathway, the majority of gluconeogenesis, and fatty acid synthesis. Protein biosynthesis (translation see p. 250) also takes place in the cytoplasm. By contrast, fatty acid degradation, the tricarboxylic acid cycle, and oxidative phosphorylation are located in the mitochondria (see p. 210). 

All the reactions in the synthetic process are catalyzed by a multienzyme complex, fatty acid synthase. Although the details of enzyme structure differ in prokaryotes such as Escherichia coli and in eukaryotes, the four-step process of fatty acid synthesis is the same in all organisms. We first describe the process as it occurs in A1, coli, then consider differences in enzyme structure in other organisms. 

In nonphotosynthetic eukaryotes, nearly all the acetyl-CoA used in fatty acid synthesis is formed in mito-... 

In prokaryotes, each of the reactions of fatty acid synthesis is catalyzed by a separate enzyme. However, in eukaryotes, the enzymes of the fatty acid synthesis elongation cycle are present in a single polypeptide chain, multifunctional enzyme complex, called fatty acid synthase. The fatty acid synthase complex exists as a dimer, with the ACP moiety shuttling the fatty acyl chain between successive catalytic sites, and from one subunit of the dimer to the other. It is, in effect, a highly efficient production line for fatty acid biosynthesis. 

This separation is necessary for energetic reasons, as will be evident in subsequent chapters. It also facilitates the control of metabolism. In eukaryotes, metabolic regulation and flexibility also are enhanced by compartmentalization. For example, fatty acid oxidation takes place in mitochondria, whereas fatty acid synthesis takes place in the cytosol. 

Although the basic biochemical reactions in fatty acid synthesis are very similar in E. coli and eukaryotes, the structure of the synthase varies considerably. The fatty acid synthases of eukaryotes, in contrast with those of E. coli, have the component enzymes linked in a large polypeptide chain. 

In mammals Fatty Acid Synthase (FAS) catalyzes fatty acid synthesis on a homodimeric enzyme, each monomer of which has seven catalytic activities, and eight sites (In bacteria such as E. colt there are seven separate enzymes plus an acyl-carrier protein. Plants also have individual proteins for the various activities which are associated in a quaternary complex. In eukaryotes other than plants the FAS are complexes of multifunctional proteins. The enzyme weighs approximately 500,000 Daltons. 

Multiprotein complexes are molecular machines. Used by both prokaryotes and eukaryotes, each type of complex efficiently performs a specific biological task. Prominent examples of processes that require the coordinated functioning of large numbers of associated proteins include DNA synthesis, transcription, fatty acid synthesis, and protein degradation. Each element in a multiprotein complex is spatially and temporally positioned to perform a specific operation so that a biological task can be accomplished. In addition to the catalysis of... 

Enzymes. The enzymes that catalyze fatty acid synthesis are significantly different in structure than those in /3-oxidation. In eukaryotes, most of these enzymes are components of a multienzyme complex referred to as fatty acid synthase. 

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