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A unified mechanism for plant polyketide biosynthesis derived from in silico modeling.

ABSTRACT: The polyketide synthases found in a variety of plants and fungi provide a varied source of biologically active compounds of pharmacological and medicinal interest. Stilbene synthase and chalcone synthase catalyze the formation of a common tetraketide intermediate, but use different cyclization mechanisms to produce distinct and separate natural products. While key structural differences have been identified to explain this functional diversity, a fuller explication of the factors responsible for this mechanistic disparity is required. Based on the energetics of our models of the bound tetraketides, and our structural analysis of the active sites we propose that a key tautomeric conversion provides a mechanistic framework common to both cyclizations. A previously unidentified active water molecule facilitates cyclization in chalcone synthase through a Claisen mechanism. Such a "Claisen switch" is comparable to the previously characterized "aldol switch" mechanism proposed for the biosynthesis of resveratrol in stilbene synthase.

SUBMITTER: Healy EF

PROVIDER: S-EPMC6051414 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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A unified mechanism for plant polyketide biosynthesis derived from in silico modeling.

Healy Eamonn F EF Cervantes Luis L Nabona Barret B Williams Jacob J

Biochemical and biophysical research communications 20180226 4

The polyketide synthases found in a variety of plants and fungi provide a varied source of biologically active compounds of pharmacological and medicinal interest. Stilbene synthase and chalcone synthase catalyze the formation of a common tetraketide intermediate, but use different cyclization mechanisms to produce distinct and separate natural products. While key structural differences have been identified to explain this functional diversity, a fuller explication of the factors responsible for ...[more]

PMID: 29496450

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Project description:In recent years, remarkable versatility of polyketide synthases (PKSs) has been recognized; both in terms of their structural and functional organization as well as their ability to produce compounds other than typical secondary metabolites. Multifunctional Type I PKSs catalyze the biosynthesis of polyketide products by either using the same active sites repetitively (iterative) or by using these catalytic domains only once (modular) during the entire biosynthetic process. The largest open reading frame in Mycobacterium tuberculosis, pks12, was recently proposed to be involved in the biosynthesis of mannosyl-beta-1-phosphomycoketide (MPM). The PKS12 protein contains two complete sets of modules and has been suggested to synthesize mycoketide by five alternating condensations of methylmalonyl and malonyl units by using an iterative mode of catalysis. The bimodular iterative catalysis would require transfer of intermediate chains from acyl carrier protein domain of module 2 to ketosynthase domain of module 1. Such bimodular iterations during PKS biosynthesis have not been characterized and appear unlikely based on recent understanding of the three-dimensional organization of these proteins. Moreover, all known examples of iterative PKSs so far characterized involve unimodular iterations. Based on cell-free reconstitution of PKS12 enzymatic machinery, in this study, we provide the first evidence for a novel "modularly iterative" mechanism of biosynthesis. By combination of biochemical, computational, mutagenic, analytical ultracentrifugation and atomic force microscopy studies, we propose that PKS12 protein is organized as a large supramolecular assembly mediated through specific interactions between the C- and N-terminus linkers. PKS12 protein thus forms a modular assembly to perform repetitive condensations analogous to iterative proteins. This novel intermolecular iterative biosynthetic mechanism provides new perspective to our understanding of polyketide biosynthetic machinery and also suggests new ways to engineer polyketide metabolites. The characterization of novel molecular mechanisms involved in biosynthesis of mycobacterial virulent lipids has opened new avenues for drug discovery.

Dataset Information

A unified mechanism for plant polyketide biosynthesis derived from in silico modeling.

Publications

A unified mechanism for plant polyketide biosynthesis derived from in silico modeling.

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