Unexpected Role of a Short-Chain Dehydrogenase/Reductase Family Protein in Type II Polyketide Biosynthesis

We investigated the biosynthetic pathway of type II polyketide murayaquinone. The murayaquinone biosynthetic cluster contains genes for three putative short-chain dehydrogenase/reductase family enzymes including MrqF and MrqH with known functions and MrqM with unclear function. We report the functional characterization of MrqM for its role in murayaquinone biosynthesis. Our gene deletion experiment and structural elucidation of the accumulated intermediates revealed that MrqM is related with the second polyketide ring cyclization, because the inactivation of mrqM resulted in the accumulation of an off-pathway intermediate SEK43 and disrupted the second and third ring cyclization. Site-directed mutagenesis studies showed that two conserved residues in MrqM and homologous proteins Y151 and K155 are essential for its activity. The previously proposed second/third ring cyclase, MrqD, might instead play another important role in the chain releasing step of the murayaquinone biosynthesis.

Automated summary

The study investigated the biosynthetic pathway of type II polyketide murayaquinone, focusing on the role of MrqM in the second polyketide ring cyclization. Results from gene deletion experiments and structural elucidation of intermediates showed that MrqM is essential for the proper biosynthesis of murayaquinone. Additionally, it was suggested that MrqD, previously thought to be involved in ring cyclization, might actually play a different role in the chain releasing step of murayaquinone biosynthesis.