Details:

Alternative Title:
J Am Chem Soc
Publisher's site:
http://dx.doi.org/10.1021/jacs.5b11814
Personal Author:
Cacho, Ralph A. ; Thuss, Justin ; Xu, Wei ; Sanichar, Randy ; Gao, Zhizeng ; ... More +
Cacho, Ralph A. ; Thuss, Justin ; Xu, Wei ; Sanichar, Randy ; Gao, Zhizeng ; Nguyen, Allison ; Vederas, John C. ; Tang, Yi ; Less -
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.
Subject:
[+]
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 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 ;
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 ; Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:23c9005f98cb9fbaa3a40b087a05650c5a16a67e1822427494b403f8197827c6
File Type:

Supporting Files

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