5l45

Publication Abstract from PubMed

SimC7 is a polyketide ketoreductase involved in biosynthesis of the angucyclinone moiety of the gyrase inhibitor simocyclinone D8 (SD8). SimC7, which belongs to the short-chain dehydrogenase/reductase (SDR) superfamily, catalyzes reduction of the C-7 carbonyl of the angucyclinone, and the resulting hydroxyl is essential for antibiotic activity. SimC7 shares little sequence similarity with characterized ketoreductases, suggesting it might have a distinct mechanism. To investigate this possibility, we determined the structures of SimC7 alone, with NADP(+), and with NADP(+) and the substrate 7-oxo-SD8. These structures show that SimC7 is distinct from previously characterized polyketide ketoreductases, lacking the conserved catalytic triad, including the active-site tyrosine that acts as central acid-base catalyst in canonical SDR proteins. Taken together with functional analyses of active-site mutants, our data suggest that SimC7 catalyzes a substrate-assisted, two-step reaction for reduction of the C-7 carbonyl group involving intramolecular transfer of a substrate-derived proton to generate a phenolate intermediate.

Substrate-Assisted Catalysis in Polyketide Reduction Proceeds via a Phenolate Intermediate.,Schafer M, Stevenson CE, Wilkinson B, Lawson DM, Buttner MJ Cell Chem Biol. 2016 Sep 22;23(9):1091-7. doi: 10.1016/j.chembiol.2016.07.018., Epub 2016 Sep 8. PMID:27617849^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.