Abstract
Aurantinins (ARTs) are antibacterial polyketides featuring a unique 6/7/8/5-fused tetracyclic ring system and a triene side chain with a carboxyl terminus. Here we identify the art gene cluster and dissect ART’s C-methyl incorporation patterns to study its biosynthesis. During this process, an apparently redundant methyltransferase Art28 was characterized as a malonyl-acyl carrier protein O-methyltransferase, which represents an unusual on-line methyl esterification initiation strategy for polyketide biosynthesis. The methyl ester bond introduced by Art28 is kept until the last step of ART biosynthesis, in which it is hydrolyzed by Art9 to convert inactive ART 9B to active ART B. The cryptic reactions catalyzed by Art28 and Art9 represent a protecting group biosynthetic logic to render the ART carboxyl terminus inert to unwanted side reactions and to protect producing organisms from toxic ART intermediates. Further analyses revealed a wide distribution of this initiation strategy for polyketide biosynthesis in various bacteria.
Highlights
Aurantinins (ARTs) are antibacterial polyketides featuring a unique 6/7/8/5-fused tetracyclic ring system and a triene side chain with a carboxyl terminus
Aurantinins (ARTs) are a group of four antibiotics isolated from Bacillus aurantinus strain KM-214 and Bacillus subtilis fmb6015–18 all sharing a unique 6/7/8/5-fused tetracyclic ring system and a triene side chain with an unusual carboxyl terminus, but differing in glycosylation and methylation patterns (Fig. 1a)
Biosynthesis of the long polyketide chain is initiated by the standalone malonyl-coenzyme A (CoA):acyl carrier protein (ACP) acyltransferase Art[6], which loads a malonyl unit to the trans-AT polyketides synthases (PKSs) ACPs including ACPArt[10] in the loading module
Summary
Aurantinins (ARTs) are antibacterial polyketides featuring a unique 6/7/8/5-fused tetracyclic ring system and a triene side chain with a carboxyl terminus. Characterization of Art[28] as a malonyl-acyl carrier protein (ACP) O-MT revealed an alternative initiation strategy for polyketide biosynthesis involving malonyl group transfer to ACPArt[10] followed by on-line methyl esterification to trigger polyketide chain extension. This methyl ester ‘protecting group’ is retained throughout ART biosynthesis and is hydrolyzed by a membrane protein, Art[9], to expose the free carboxyl terminus at the final step. In silico and in vitro analyses of the Art28-like O-MTs revealed that this on-line methyl esterification initiation strategy for polyketide biosynthesis is distributed in different bacteria from four phyla
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