Assembly of poly--keto-acyl-CoAs

Extensive purification of 6-methylsalicylate synthetase from Penicil-lium patulum has been carried out. It is distinct from fatty acid synthetase, separable from it, and of half the molecular weight both enzymes are complexes of several enzymes. One molecule of 6-methylsalicylic acid is generated by 6-methylsalicylate synthetase from one molecule of acetyl-CoA and three of malonyl-CoA in the presence of one molecule of NADPH. as coenzyme no free intermediates can be detected. In the absence of NADPH, triacetic acid lactone 3.15) is formed as the sole product. The same lactone is 

C-Methylation occurs before release of the completed polyketide from the synthetase complex. The evidence for this conclusion comes in part from the failure of unmethylated compounds to serve as precursors, e.g. orsellenic acid 3.4) is not a precursor for atranorin 3.16) [18]. Similarly 5-methylorcylaldehyde 3.18), and not orcyl-dehyde 3.17), is a precursor for gliorosein 3.19) and related compounds [19]. Barnol 3.20) is interesting in that one methyl group 

Incorporation of [ H3]methionine into gliorosein 3.19) occurs with retention of all the deuterium atoms [21] arguing for methylation by a simple nucleophilic displacement on 5-adenosylmethionine [see 3.22)1 

The biosynthesis of the aromatic metabolite, 6-methylsalicylic acid [3.14), has been discussed above. This acid is the source of a variety of metabolites in which hydroxylation and oxidation of the aromatic nucleus and side-chain methyl group occur in major pathways [4] following decarboxylation to m-cresol [3.42). A terminus in this set of oxidative reactions is patulin [3.45). 

The [l- C]acetate labelling in patulin is shown ( ). No regular polyketide chain is apparent but the incorporation of radioactive 6-methylsalicylic acid [3.14) and other related compounds indicate that [3.45) arises by cleavage of an aromatic ring [see dotted line in [3.44)1 

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