Understanding Programming of Fungal Iterative Polyketide Synthases: the Biochemical Basis for Regioselectivity by the Methyltransferase Domain in the Lovastatin Megasynthase

Details

• Alternative Title:
  J Am Chem Soc
• Personal Author:
  Cacho, Ralph A. ; Thuss, Justin ; Xu, Wei ; Sanichar, Randy ; Gao, Zhizeng ; Nguyen, Allison ; Vederas, John C. ; Tang, Yi
• Description:
  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 β-ketoacyl groups, it is exceptionally selective toward its naturally programmed β-keto-dienyltetraketide substrate with respect to both chain length and functionalization. Accompanying characterization of the ketoreductase (KR) domain displays broader substrate specificity toward different β-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.
• Subjects:
  Article Fungi Lovastatin Methyltransferases Polyketide Synthases
• Source:
  J Am Chem Soc. 137(50):15688-15691
• Pubmed ID:
  26630357
• Pubmed Central ID:
  PMC4906797
• Document Type:
  Journal Article
• Funding:
  DP1 GM106413/GM/NIGMS NIH HHSUnited States/ ; R01 GM085128/GM/NIGMS NIH HHSUnited States/ ; 1DP1GM106413/DP/NCCDPHP CDC HHSUnited States/ ; 1R01GM085128/GM/NIGMS NIH HHSUnited States/
• Volume:
  137
• Issue:
  50
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:23c9005f98cb9fbaa3a40b087a05650c5a16a67e1822427494b403f8197827c6
• Download URL:
  https://stacks.cdc.gov/view/cdc/39903/cdc_39903_DS1.pdf
• File Type:
  [PDF - 419.13 KB ]