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The Molecular Basis of Catalysis by SDR Family Members Ketoacyl-ACP Reductase FabG and Enoyl-ACP Reductase FabI in Type-II Fatty Acid Biosynthesis

文献类型：期刊论文

作者Zhou, Jiashen8; Zhang, Lin8; Wang, Yiran6,7; Song, Wenyan8; Huang, Yuzhou8; Mu, Yajuan8; Schmitz, Werner5; Zhang, Shu-Yu4; Lin, Houwen2,3; Chen, Hong-Zhuan1
刊名ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
出版日期2023-10-12
页码12
ISSN号1433-7851
关键词Acyl-ACP Reductases Allosteric Regulation Biosynthesis Enantioselective Reduction Enzyme Catalysis
DOI10.1002/anie.202313109
通讯作者Zhang, Liang(liangzhang2014@sjtu.edu.cn)
英文摘要The short-chain dehydrogenase/reductase (SDR) superfamily members acyl-ACP reductases FabG and FabI are indispensable core enzymatic modules and catalytic orientation controllers in type-II fatty acid biosynthesis. Herein, we report their distinct substrate allosteric recognition and enantioselective reduction mechanisms. FabG achieves allosteric regulation of ACP and NADPH through ACP binding across two adjacent FabG monomers, while FabI follows an irreversible compulsory order of substrate binding in that NADH binding must precede that of ACP on a discrete FabI monomer. Moreover, FabG and FabI utilize a backdoor residue Phe187 or a "rheostat" alpha 8 helix for acyl chain length selection, and their corresponding triad residues Ser142 or Tyr145 recognize the keto- or enoyl-acyl substrates, respectively, facilitating initiation of nucleophilic attack by NAD(P)H. The other two triad residues (Tyr and Lys) mediate subsequent proton transfer and (R)-3-hydroxyacyl- or saturated acyl-ACP production. The distinct substrate allosteric recognition and reduction catalytic mechanisms of ketoacyl-ACP reductase FabG and enoyl-ACP reductase FabI in Type-II fatty acid biosynthesis are reported. The enzymes use alternative catalytic tunnels and core catalytic triads to recognize different ACP, NAD(P)H and fatty acid substrates for asymmetric reduction catalysis.+image
WOS关键词ACYL CARRIER PROTEIN ; CRYSTAL-STRUCTURE ; ESCHERICHIA-COLI ; 6-DEOXYERYTHRONOLIDE B ; SYNTHASE ; MECHANISM ; RESIDUES ; COMPLEX ; INHIBITION ; COFACTOR
资助项目This project was supported by the grants from the National Key Research and Development Program of China (No. 2022YFC2804100 to Liang Zhang), the National Natural Science Foundation of China (Nos. 22077081 to Liang Zhang; 22107067 to Lin Zhang), the Major[2022YFC2804100] ; National Key Research and Development Program of China[91853118] ; National Natural Science Foundation of China[20S11900300] ; National Natural Science Foundation of China[22S11900600] ; Science and Technology Commission of Shanghai Municipality ; Shanghai Education Development Foundation[20SG16] ; Shanghai Municipal Education Commission[SHSMU-ZDCX20212702] ; Innovative Research Team of High-Level Local Universities in Shanghai ; Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases
WOS研究方向Chemistry
语种英语
出版者WILEY-V C H VERLAG GMBH
WOS记录号WOS:001079470500001
源URL[http://119.78.100.183/handle/2S10ELR8/307345]  
专题新药研究国家重点实验室
通讯作者Zhang, Liang
作者单位1.Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Inst Interdisciplinary Integrat Biomed Res, Shanghai 201203, Peoples R China
2.Shenzhen Polytech, Inst Marine Biomed, Shenzhen 518055, Peoples R China
3.Shanghai Jiao Tong Univ, Ren Ji Hosp, Res Ctr Marine Drugs, Sch Med,State Key Lab Oncogene & Related Genes,Dep, Shanghai 200127, Peoples R China
4.Shanghai Jiao Tong Univ, Sch Chem & Chem Engn, Shanghai 200240, Peoples R China
5.Univ Wurzburg, Dept Biochem & Mol Biol, D-97074 Wurzburg, Germany
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
7.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
8.Shanghai Jiao Tong Univ Sch Med, Dept Pharmacol & Chem Biol, State Key Lab Syst Med Canc, Sch Med SJTU SM, Shanghai 200025, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Jiashen,Zhang, Lin,Wang, Yiran,et al. The Molecular Basis of Catalysis by SDR Family Members Ketoacyl-ACP Reductase FabG and Enoyl-ACP Reductase FabI in Type-II Fatty Acid Biosynthesis[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2023:12.
APA Zhou, Jiashen.,Zhang, Lin.,Wang, Yiran.,Song, Wenyan.,Huang, Yuzhou.,...&Zhang, Liang.(2023).The Molecular Basis of Catalysis by SDR Family Members Ketoacyl-ACP Reductase FabG and Enoyl-ACP Reductase FabI in Type-II Fatty Acid Biosynthesis.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,12.
MLA Zhou, Jiashen,et al."The Molecular Basis of Catalysis by SDR Family Members Ketoacyl-ACP Reductase FabG and Enoyl-ACP Reductase FabI in Type-II Fatty Acid Biosynthesis".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2023):12.

入库方式： OAI收割

来源：上海药物研究所

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