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Fragment antigen binding domains (F_(ab)s) as tools to study assembly-line polyketide synthases

Synthetic and Systems Biotechnology 2022年第1期7卷 506-512页

作者： Katarina M.Guzman Chaitan Khosla Department of Chemical Engineering Stanford UniversityStanfordCA94305USA Department of Chemistry Stanford ChEM-HStanford UniversityStanfordCA94305USA

The crystallization of proteins remains a bottleneck in our fundamental understanding of their ***,discovering tools that aid crystallization is *** this review,the versatility of fragment-antigen binding domains(F_(ab)s)as protein crystallization chaperones is discussed.F_(ab)s have aided the crystallization of membrane-bound and soluble proteins as well as *** ability to bind three F_(ab)s onto a single protein target has demonstrated their potential for crystallization of challenging *** describe a high-throughput workflow for identifying F_(ab)s to aid the crystallization of a protein of interest(POI)by leveraging phage display technologies and differential scanning fluorimetry(DSF).This workflow has proven to be especially effective in our structural studies of assembly-line polyketide synthases(PKSs),which harbor flexible domains and assume transient *** are of interest to us due to their ability to synthesize an unusually broad range of medicinally relevant *** years of research studying these megasynthases,their overall topology has remained *** F ab in particular,1B2,has successfully enabled X-ray crystallographic and single particle cryo-electron microscopic(cryoEM)analyses of multiple modules from distinct assembly-line *** use has not only facilitated multidomain protein crystallization but has also enhanced particle quality via cryoEM,thereby enabling the visualization of intact PKS modules at near-atomic(3–5Å)*** identification of PKS-binding F_(ab)s can be expected to continue playing a key role in furthering our knowledge of polyketide biosynthesis on assembly-line PKSs.

关键词： Crystallography Cryo-EM polyketide synthases Fragment antigen binding domains

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Virtual Mutation Research of Acyltransferase Domain to Improve Bio-synthetic Activity of polyketide synthases

Virtual Mutation Research of Acyltransferase Domain to Impro...

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2019中国化学会第十五届全国计算（机）化学学术会议

作者：向瑶 Baerlike Wujieti Jinai Gao Mingjuan Ji Wei Cui 中国科学院大学 School of Chemical Sciences University of Chinese Academy of Sciences

The modular polyketide synthases（PKSs） catalyzed the biosynthesis of polyketides, which widely utilized in medicine, agriculture, and industry. The demand for polyketides exceeds the supply, the low catalytic activity of PKSs needs to be improved. But the PKSs is one of the most complex enzymes in eukaryotic cells and its structure too difficult to be modified. Delightfully, the structure and function of the acyltransferase（AT） domain of PKSs similar to malonyl/acyltransferase（MAT） domain of fatty acid synthases（FAS） which acyl transaction rate higher than AT domain. Herein, inspired by the structure of FAS, we perform a rational modification study to improve the enzymatic activity of the rate control domain in PKSs. Based on the comparison between MAT domain and AT domain, the key residues of the AT domain were defined which have significant effects on substrate binding mode. After progressive virtual mutation simulation of the key residues, the binding affinity of the mutants which we were finally designed is more stable than wild types. The results of molecular dynamics simulation of mutants showed that the triple mutation to the binding pocket not only improved the polar interaction at the entrance of pocket, but also changed the shape of the deep pocket, and enhanced the non-polar interactions between acyl group of substrate and residues around catalysis site. By increasing enzyme-substrate binding ability, the rate of acyl transaction catalyzed by AT domain may improve. These results enhance our understanding of the mechanism of the AT domain and can aid future endeavors in PKSs’ enzyme engineering.

关键词： polyketide synthases acyltransferase domain molecular dynamics MM/GBSA progressive virtual mutation

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Tetracycline natural products:discovery,biosynthesis and engineering

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Chinese Journal of Natural Medicines 2022年第10期20卷 773-794页

作者： WANG Haiyan WANG Ljun FAN Keqiang PAN Guohui State Key Laboratory of Microbial Resources Institute of MicrobiologyChinese Academy of SciencesBeijing 10010lChina University of Chinese Academy of Sciences Beijing 100049China

Tetracycline(TC)natural products possess a variety of remarkable bioactivities and diverse *** are an important and fertile source for developing novel *** one of the most successful drug families,TC antibiotics have been in clinical use for over seven decades,and continue to make an important contribution to human health *** date,studies on TC natural products and their biosynthesis have revealed numerous novel biochemical mechanisms and regulatory elements,which facilitates the rational metabolic engineering studies for generating novel bioactive TC analogs and inspires the development of new synthetic biology *** this review,we provide a comprehensive overview on the discovery,biosynthesis,and engineering of the existing TC natural *** analyses will be of great value for the discovery,design and development of novel TC drugs in the future.

关键词： Tetracycline polyketide synthases Biosynthesis Engineering

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