ChemBioChem., published online 27 September 2011, doi: 10.1002/cbic.201100474

The lankacidins are macrocyclic polyketides that contain four carbon-carbon double bonds and are synthesized by hybrid machinery containing both nonribosomal peptide synthetase and polyketide synthase modules. Olefin formation is thought to be catalyzed by a trans-acting dehydratase, LkcB, in tandem with the LkcC subunit, which is responsible for selecting incoming building blocks to lengthen the molecular chain. However, the current biosynthetic proposal, in which the LkcB-LkcC pair function iteratively to complete five steps of the pathway, does not agree with the substrate specificity of the LkcC subunit. In efforts to elucidate the true biosynthetic pathway, Dickschat et al. resequenced the lankacidin-producing Streptomyces rochei var. volubilis ATCC 21250. Analysis of this sequence identified a previously unassigned ∼400-amino-acid segment of LkcC containing both a second dehydratase domain and a putative docking site for a trans-acting acyltransferase. Mutational analysis of both the LkcB and LkcC dehydratases confirmed that their function was necessary for lankacidin production, although the lack of any intermediate lankamycin products precluded revision of the biosynthetic proposal. However, the authors do speculate that, in a process akin to the mechanism used by FabA in fatty acid biosynthesis to determine product outcome, chain-length selectivity of the new dehydratase might determine the reaction course, in this case by dictating a switch between iterative cycles through LkcC and modular steps through other lankamicin subunits.