Cooh

Fig. 2.10 The animal fatty acid synthase model (taken from Joshi and Smith, 1993, with kind permission of the authors and the American Society for Biochemistry and Molecular Biology). The overall shape of the protein (216 A long, 144 A wide, 72 A deep) and the presence of the two 40 A 'holes' is based on electron micrographic evidence. Two identical subunits are juxtaposed head-to-tail. Each subunit consists of two clusters of catalytic domains (KS/MAT/DH and ER/KR/ ACP/TE) separated by a central structural core. The active-site residues of the various catalytic domains, the glycine-rich motifs of the NADPH-binding sites associated with the reductases and the site of attachment of the 4'-phosphopantetheine thiol are shown. A key feature of this model is that two centres for acyl chain assembly and release are formed by co-operation of three catalytic domains (KS/MAT/DH) of one subunit with four catalytic domains (ER/KR/ACP/TE) of the adjacent subunit. KS: ketoacyl synthase; MAT: malonyl/acetyltransferase; DH: dehydrase; ER: enoyl reductase; KR: ketoreductase; ACP: acyl carrier protein; TE: thioesterase. GxGxxG are the amino acids at the catalytic sites of the reductases, where G is glycine and x is any amino acid.

Fig. 2.10 The animal fatty acid synthase model (taken from Joshi and Smith, 1993, with kind permission of the authors and the American Society for Biochemistry and Molecular Biology). The overall shape of the protein (216 A long, 144 A wide, 72 A deep) and the presence of the two 40 A 'holes' is based on electron micrographic evidence. Two identical subunits are juxtaposed head-to-tail. Each subunit consists of two clusters of catalytic domains (KS/MAT/DH and ER/KR/ ACP/TE) separated by a central structural core. The active-site residues of the various catalytic domains, the glycine-rich motifs of the NADPH-binding sites associated with the reductases and the site of attachment of the 4'-phosphopantetheine thiol are shown. A key feature of this model is that two centres for acyl chain assembly and release are formed by co-operation of three catalytic domains (KS/MAT/DH) of one subunit with four catalytic domains (ER/KR/ACP/TE) of the adjacent subunit. KS: ketoacyl synthase; MAT: malonyl/acetyltransferase; DH: dehydrase; ER: enoyl reductase; KR: ketoreductase; ACP: acyl carrier protein; TE: thioesterase. GxGxxG are the amino acids at the catalytic sites of the reductases, where G is glycine and x is any amino acid.

Stuart Smith has now studied the animal fatty acid synthase in much more detail. Various models of this FAS have been proposed but all of them involve two identical antiparallel polypeptide chains that together form two centres for palmitate synthesis at the subunit interface. Essentially in the conventional view of the FAS mechanism, a malonyl residue attached to ACP on one half of the dimer interacts with the acyl chain (originally acetyl) attached to a cysteine at the active site of the

Ketoacyl synthase

Dehydrase

Transferase

Enoyl reductase

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