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Crystal structures of the acyl transferases involved in the human cytosolic and mitochondrial fatty acid synthase
Author(s) -
Misquitta Stephanie A.,
Bunkoczi Gabor,
Wu Xiaoqiu,
Kavanagh Kathryn L.,
Hozjan Viktoria,
Oppermann Udo,
Smith Stuart
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1012.1
Subject(s) - biochemistry , residue (chemistry) , stereochemistry , active site , chemistry , enzyme , arginine , hydrolase , serine , histidine , fatty acid synthase , cysteine , amino acid
The objective was to determine the structural basis for the specificities of acyl transferases involved in substrate loading from CoA thioester to the acyl carrier proteins of the type I cytosolic and type II mitochondrial fatty acid synthases. The type I enzyme (MAT) loads both the chain extender malonyl and acetyl primer substrate whereas the type II enzyme (MT) loads only malonyl moieties. Both transferases are characterized by a α/β ‐like hydrolase domain and a smaller domain with a ferredoxin‐like fold. The active‐site, located in a gorge between the two domains, is characterized by a serine nucleophile, supported by a histidine residue, an oxyanion hole and an arginine residue that anchors the 3‐carboxylate of the malonyl moiety. Replacement of the arginine residue severely compromises activity towards malonyl‐CoA but in MT induces activity toward acetyl‐CoA and in MAT induces activity toward acyl‐CoAs containing 2‐10 C‐atoms. Substrate docking experiments confirm the roles of the active site residues and reveal a cryptic acyl binding pocket in MAT that accommodates medium‐length acyl chains in mutants lacking the conserved arginine. Although the two enzymes share similar structural features, the MT more closely resembles its prokaryotic counterparts, consistent with the endosymbiotic theory of mitochondrial origin. Supported by NIH, DK16073 & GM069717. The SGC is supported by public and private sponsors.