Characterization of a Novel Fatty Acid-Modifying Pathway in the Biosynthesis of Tambjamine BE-18591 in Streptomyces

Tambjamines are a class of bacterial bipyrrolic natural products with potent biological activity. Recently, the first actinomycete biosynthetic gene cluster (BGC) responsible for the production of a tambjamine (BE-18591) was discovered in Streptomyces albus, and bioinformatic analysis suggested the alkylamine tail component is constructed using different biosynthetic logic than employed by Proteobacteria to assemble structurally similar tambjamines YP1 and MYP1. Here, we report the experimental characterization of four novel streptomycete proteins and demonstrate that these enable the unique, late-stage assembly of the alkylamine tail of BE-18951. Specifically, a fatty acyl-carrier protein (TabQ) is loaded with a 12-carbon acyl chain, selected for, in part, through the action of an editing type II thioesterase (TabJ). The resulting C₁₂-TabQ adduct is then processed to an aldehyde by a novel acyl-ACP reductase (TabE) that harbors none of the telltale amino acid signatures that typically identify these proteins. The resulting aldehyde is finally converted to the amine by an ω-transaminase (TabA) that demonstrates some degree of promiscuity. Our findings highlight the disparate chemical logic employed by Proteo- and Actinobacteria for the biosynthesis of the alkylamine components of tambjamine natural products.