Molecular Basis for Polyketide Ketoreductase-Substrate Interactions
Shiji Zhao1,2, Fanglue Ni1, Tianyin Qiu1
1Departments of Molecular Biology and Biochemistry, Chemical and Biomolecular Engineering, Materials Science and Engineering, and Biomedical Engineering, University of California, Irvine, CA 92697, USA.
Abstract:
Polyketides are a large class of structurally and functionally diverse natural products with important bioactivities. Many polyketides are synthesized by reducing type II polyketide synthases (PKSs), containing transiently interacting standalone enzymes. During synthesis, ketoreductase (KR) catalyzes regiospecific carbonyl to hydroxyl reduction, determining the product outcome, yet little is known about what drives specific KR-substrate interactions. In this study, computational approaches were used to explore KR-substrate interactions based on previously solved apo and mimic cocrystal structures. We found five key factors guiding KR-substrate binding. First, two major substrate binding motifs were identified. Second, substrate length is the key determinant of substrate binding position. Third, two key residues in chain length specificity were confirmed. Fourth, phosphorylation of substrates is critical for binding. Finally, packing/hydrophobic effects primarily determine the binding stability. The molecular bases revealed here will help further engineering of type II PKSs and directed biosynthesis of new polyketides.
More Related Videos
09:42Unraveling Entropic Rate Acceleration Induced by Solvent Dynamics in Membrane Enzymes
Published on: January 16, 2016
10:33Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
Published on: October 26, 2015
Related Concept Videos
Vicinal Diols via Reductive Coupling of Aldehydes or Ketones: Pinacol Coupling Overview
α-Hydroxy Ketones via Reductive Coupling of Esters: Acyloin Condensation Overview
Protecting Groups for Aldehydes and Ketones: Introduction
Reactions of Aldehydes and Ketones: Baeyer–Villiger Oxidation
The carbonyl center is activated by...
Factors Affecting α-Alkylation of Ketones: Choice of Base
The reaction involving bases like EtO− whose conjugate acid EtOH (pKa = 15.9) is stronger than the ketone (pKa = 19.2) results in an equilibrium mixture with higher ketone concentration. As a consequence,...
Intramolecular Aldol Reaction
