Reprogramming of the Aurantinin Polyketide Assembly Line to Synthesize Auritriacids by Excising an Atypical Enoyl-CoA Hydratase Domain.

Abstract

Modular polyketide synthases (PKSs) are capable of synthesizing diverse natural products with fascinating bioactivities. Canonical enoyl-CoA hydratases (ECHs) are components of the β-branching cassette that modifies the polyketide chain by adding a β-methyl branch. Herein, it is demonstrated that the deletion of an atypical ECHQ domain (featuring a Q280 residue) of Art21, a didomain protein contains an ECHQ domain and a thioesterase (TE) domain, reprograms the polyketide assembly line from synthesizing tetracyclic aurantinins (ARTs) to bicyclic auritriacids (ATAs) with much lower antibacterial activities. Genes encoding the ECHQ-TE didomain proteins distribute in many PKS gene clusters from different bacteria. Significantly, the ART PKS machinery can be directed to make ARTs, ATAs, or both of them by employing appropriate ECHQ-TE proteins, implying a great potential for using this reprogramming strategy in polyketide structure diversification.