期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 137, 期 50, 页码 15688-15691出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.5b11814
关键词
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资金
- NIH [1R01GM085128, 1DP1GM106413]
- Natural Sciences & Engineering Research Council of Canada (NSERC)
- Canada Research Chair in Bioorganic & Medicinal Chemistry
Highly reducing polyketide synthases (HR-PKSs) from fungi synthesize complex natural products using a single set of domains in a highly programmed, iterative fashion. The most enigmatic feature of HR-PKSs is how tailoring domains function selectively during different iterations of chain elongation to afford structural diversity. Using the lovastatin nonaketide synthase LovB as a model system and a variety of acyl substrates, we characterized the substrate specificity of the LovB methyltransferase (MT) domain. We showed that, while the MT domain displays methylation activity toward different beta-ketoacyl groups, it is exceptionally selective toward its naturally programmed beta-keto-dienyltetraketide substrate with respect to both chain length and functionalization. Accompanying characterization of the ketoreductase (KR) domain displays broader substrate specificity toward different beta-ketoacyl groups. Our studies indicate that selective modifications by tailoring domains, such as the MTs, are achieved by higher kinetic efficiency on a particular substrate relative to the rate of transformation by other competing domains.
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