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

Cacho, Ralph A.; Thuss, Justin; Xu, Wei; Sanichar, Randy; Gao, Zhizeng; Nguyen, Allison; Vederas, John C.; Tang, Yi

doi:10.1021/jacs.5b11814

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

Published Date:

Dec 10 2015

Publisher's site:

http://dx.doi.org/10.1021/jacs.5b11814 New Site Icon

Source:

J Am Chem Soc. 137(50):15688-15691.

[PDF-419.13 KB]

Details:

Personal Authors:

Cacho, Ralph A. ; Thuss, Justin ; Xu, Wei ; Sanichar, Randy ; Gao, Zhizeng ; ... More ▼

Keywords:

[+]

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:

Journal Article

Collection(s):

CDC Public Access

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

Supporting Files:

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