期刊
CELL CHEMICAL BIOLOGY
卷 23, 期 9, 页码 1091-1097出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2016.07.018
关键词
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资金
- BBSRC [BB/I002197/1, BB/J004561/1]
- BBSRC [BBS/E/J/000C0665, BB/I002197/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/J/000C0665, BBS/E/J/00000015, BB/I002197/1] Funding Source: researchfish
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 substratederived proton to generate a phenolate intermediate.
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