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Understanding Programming of Fungal Iterative Polyketide Synthases: the Biochemical Basis for Regioselectivity by the Methyltransferase Domain in the Lovastatin Megasynthase
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Details:
  • Pubmed ID:
    26630357
  • Pubmed Central ID:
    PMC4906797
  • 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.

  • Document Type:
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  • Funding:
    DP1 GM106413/GM/NIGMS NIH HHS/United States
    R01 GM085128/GM/NIGMS NIH HHS/United States
    1DP1GM106413/DP/NCCDPHP CDC HHS/United States
    1R01GM085128/GM/NIGMS NIH HHS/United States
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