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Biosynthesis of Long-Chain N-Acyl Amide by a Truncated Polyketide Synthase–Nonribosomal Peptide Synthetase Hybrid Megasynthase in Fungi

Hai, Yang, Tang, Yi
Journal of the American Chemical Society 2018 v.140 no.4 pp. 1271-1274
G-protein coupled receptors, Talaromyces, active sites, bioinformatics, biosynthesis, catalytic activity, enzymes, fungi, genome mining, histidine, lipids, polyketides
Truncated iterative polyketide synthase–nonribosomal peptide synthetase (PKS-NRPS) megasynthases in which only the C domain is present are widespread in fungi, yet nearly all members have unknown functions. Bioinformatics analysis showed that the C domains of such PKS-C enzymes are noncanonical due to substitution at the second histidine in the active site HHxxxDG motif. Here, we used genome mining strategy to characterize a cryptic PKS-C hybrid from Talaromyces wortmanii and discovered the products are reduced long-chain polyketides amidated with a specific ω-amino acid 5-aminopentanoic acid (5PA). The wortmanamides resemble long-chain N-acyl-amide signaling lipids that target diverse receptors including GPCRs. The noncanonical C domain of this PKS-C hybrid was also demonstrated to be a bona fide condensation domain that specifically selects 5PA and catalyzes amidation to release polyketide chain.