reading 3

Reading 3 - RESEARCH ARTICLES The Crystal Structure of a Mammalian Fatty Acid Synthase Timm Maier Marc Leibundgut Nenad Ban Mammalian fatty acid

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The Crystal Structure of a Mammalian Fatty Acid Synthase Timm Maier, Marc Leibundgut, Nenad Ban * Mammalian fatty acid synthase is a large multienzyme that catalyzes all steps of fatty acid synthesis. We have determined its crystal structure at 3.2 angstrom resolution covering five catalytic domains, whereas the flexibly tethered terminal acyl carrier protein and thioesterase domains remain unresolved. The structure reveals a complex architecture of alternating linkers and enzymatic domains. Substrate shuttling is facilitated by flexible tethering of the acyl carrier protein domain and by the limited contact between the condensing and modifying portions of the multienzyme, which are mainly connected by linkers rather than direct interaction. The structure identifies two additional nonenzymatic domains: (i) a pseudo-ketoreductase and (ii) a peripheral pseudo-methyltransferase that is probably a remnant of an ancestral methyltransferase domain maintained in some related polyketide synthases. The structural comparison of mammalian fatty acid synthase with modular polyketide synthases shows how their segmental construction allows the variation of domain composition to achieve diverse product synthesis. F atty acids fulfill a variety of vital functions: They are central constituents of biological membranes, serve as energy storage com- pounds, and act as second messengers or as co- valent modifiers governing the localization of proteins. In bacteria and plants, fatty acid bio- synthesis is accomplished by a series of mono- functional proteins in a dissociated type II fatty acid synthase (FAS) system ( 1 ). In contrast, the type I FASs of fungi and animals are huge mul- tifunctional polypeptides that integrate all steps of fatty acid synthesis into large macromolecular assemblies. Fungal FAS is a 2.6-MD a 6 b 6 - heterododecamer with the catalytic domains dis- tributed over two polypeptides ( 2 4 ), whereas mammalian FAS (mFAS) consists of a 270-kD polypeptide chain (comprising all seven required domains) that assembles into homodimers for enzymatic activity ( 5 , 6 ). Despite this variation in structural organiza- tion, all organisms employ a conserved set of chemical reactions for fatty acid biosynthesis ( 1 , 6 8 ). Stepwise elongation of precursors is achieved by cyclic decarboxylative condensation of acyl-coenzyme A (CoA) with the elongation substrate malonyl-CoA, initiated by the starter substrate acetyl-CoA. In the priming step, the acetyl transferase loads acetyl-CoA onto the terminal thiol of the phosphopantheteine cofactor of the acyl carrier protein (ACP), which passes the acetyl moiety over to the active site cysteine of the b -ketoacyl synthase (KS). Malonyl trans- ferase (MT) transfers the malonyl group of malonyl-CoA to ACP, and the KS catalyzes the decarboxylative condensation of the acetyl and malonylmoieties to an ACP-bound b -ketoacyl intermediate. The b -carbon position is then mod- ified by sequential action of the NADPH (the reduced form of nicotinamide adenine dinucleotide,
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This note was uploaded on 10/28/2010 for the course CHEM 157 taught by Professor burkart during the Spring '07 term at UCSD.

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Reading 3 - RESEARCH ARTICLES The Crystal Structure of a Mammalian Fatty Acid Synthase Timm Maier Marc Leibundgut Nenad Ban Mammalian fatty acid

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