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Article

Molecular Basis for Polyketide Ketoreductase–Substrate Interactions

1
Departments of Molecular Biology and Biochemistry, Chemical and Biomolecular Engineering, Materials Science and Engineering, and Biomedical Engineering, University of California, Irvine, CA 92697, USA
2
Departments of Molecular Biology and Biochemistry, Chemistry, and Pharmaceutical Sciences, University of California, Irvine, CA 92697, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(20), 7562; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207562
Received: 25 September 2020 / Revised: 11 October 2020 / Accepted: 12 October 2020 / Published: 13 October 2020
(This article belongs to the Collection Computational Studies of Biomolecules)
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. View Full-Text
Keywords: natural products; ketoreductase; polyketides; computational chemistry; molecular dynamics natural products; ketoreductase; polyketides; computational chemistry; molecular dynamics
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MDPI and ACS Style

Zhao, S.; Ni, F.; Qiu, T.; Wolff, J.T.; Tsai, S.-C.; Luo, R. Molecular Basis for Polyketide Ketoreductase–Substrate Interactions. Int. J. Mol. Sci. 2020, 21, 7562. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207562

AMA Style

Zhao S, Ni F, Qiu T, Wolff JT, Tsai S-C, Luo R. Molecular Basis for Polyketide Ketoreductase–Substrate Interactions. International Journal of Molecular Sciences. 2020; 21(20):7562. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207562

Chicago/Turabian Style

Zhao, Shiji, Fanglue Ni, Tianyin Qiu, Jacob T. Wolff, Shiou-Chuan Tsai, and Ray Luo. 2020. "Molecular Basis for Polyketide Ketoreductase–Substrate Interactions" International Journal of Molecular Sciences 21, no. 20: 7562. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207562

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