Site‐Directed Mutagenesis of Modular Polyketide Synthase Ketoreductase Domains for Altered Stereochemical Control
| Autor: | Constance B. Bailey, Nolan R. Spengler, Elijah G. Hix, Erin E. Drufva |
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| Rok vydání: | 2020 |
| Předmět: |
Stereochemistry
Mutagenesis (molecular biology technique) Context (language use) 010402 general chemistry 01 natural sciences Biochemistry Polyketide synthase ketoreductase Substrate Specificity Polyketide Bacterial Proteins Protein Domains Oxidoreductase Polyketide synthase Site-directed mutagenesis Molecular Biology chemistry.chemical_classification Bacteria biology 010405 organic chemistry Organic Chemistry 0104 chemical sciences Kinetics Enzyme chemistry Polyketides Mutagenesis Site-Directed biology.protein Molecular Medicine Polyketide Synthases NADP |
| Zdroj: | ChemBioChem. 22:1122-1150 |
| ISSN: | 1439-7633 1439-4227 |
| DOI: | 10.1002/cbic.202000613 |
| Popis: | Bacterial modular type I polyketide synthases (PKSs) are complex multidomain assembly line proteins that produce a range of pharmaceutically relevant molecules with a high degree of stereochemical control. Due to their colinear properties, they have been considerable targets for rational biosynthetic pathway engineering. Among the domains harbored within these complex assembly lines, ketoreductase (KR) domains have been extensively studied with the goal of altering their stereoselectivity by site-directed mutagenesis, as they confer much of the stereochemical complexity present in pharmaceutically active reduced polyketide scaffolds. Here we review all efforts to date to perform site-directed mutagenesis on PKS KRs, most of which have been done in the context of excised KR domains on model diffusible substrates such as β-keto N-acetyl cysteamine thioesters. We also discuss the challenges around translating the findings of these studies to alter stereocontrol in the context of a complex multidomain enzymatic assembly line. |
| Databáze: | OpenAIRE |
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