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The β-Ketoacyl-ACP Synthase FabF Catalyzes Carbon-Carbon Bond Formation in a Bimodal Pattern for Fatty Acid Biosynthesis

文献类型：期刊论文

作者Huang, Yuzhou5; Wang, Yiran3,4; Cai, Chang5; Zhang, Lin5; Ye, Fei2; Zhang, Liang1
刊名ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
出版日期2024-10-17
页码11
关键词Fatty acid biosynthesis beta-ketoacyl-ACP synthase Carbon-carbon bond formation Bimodal enzymatic catalysis
ISSN号1433-7851
DOI10.1002/anie.202407921
通讯作者Zhang, Lin(zhanglin777@sjtu.edu.cn) ; Ye, Fei(yefei@zstu.edu.cn) ; Zhang, Liang(liangzhang2014@sjtu.edu.cn)
英文摘要Fatty acids produced by the type-II fatty acid biosynthetic pathway (FAS-II) are essential biomaterials for bacterial membrane construction and numerous metabolic routes. The beta-ketoacyl-ACP synthase FabF catalyzes the key C-C bond formation step for fatty acid elongation in FAS-II. Here, we revealed the substrate recognition and catalytic mechanisms of FabF by determining FabF-ACP complexes. FabF displays a distinctive bimodal catalytic pattern specifically on C6 and C10 acyl-ACP substrates. It utilizes positively charged residues located on the eta 3-helix and loop1 regions near the catalytic tunnel entrance to bind ACP, and two hydrophobic cavities as well as "front", "middle", and "back" door residues to specifically stabilize C6 and C10 acyl substrates for preferential catalysis. Further quantum chemistry calculations suggest that the FabF catalytic residues Lys336 and His304 facilitate proton transfer during condensation catalysis and C-C bond formation. Our results provide key mechanistic insights into the biosynthesis of molecular carbon skeletons based on ketosynthases that are highly conserved through the FAS and polyketide synthase (PKS) analogous biosynthetic routes, broaden the understanding of the tricarboxylic acid cycle that utilizes lipoic acid derived from C8-ACP accumulated due to the FabF distinctive catalytic pattern for oxidative decarboxylations, and may facilitate the development of narrow-spectrum antibacterial drugs. The distinctive bimodal substrate selectivity pattern and carbon-carbon bond formation catalytic mechanism of beta-Ketoacyl-ACP Synthase FabF in Type-II Fatty Acid Biosynthesis pathway was reported. It utilizes three door residues in the substrate tunnel to achieve selective recognition of acyl-ACP with substrates of different chain lengths and catalyzes the transacylation-condensation reaction to complete the carbon chain elongation synthesis of fatty acids. image
WOS关键词CARRIER ; INHIBITOR ; MECHANISM ; KASA
资助项目National Natural Science Foundation of China ; Science and Technology Commission of Shanghai Municipality[22S11900600] ; Shanghai Education Development Foundation ; Shanghai Municipal Education Commission[20SG16] ; Innovative research team of high-level local universities in Shanghai[SHSMU-ZDCX20212702] ; [22477077] ; [22077081] ; [82373729] ; [22107067]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001334148500001
出版者WILEY-V C H VERLAG GMBH
源URL[http://119.78.100.183/handle/2S10ELR8/313814]  
专题新药研究国家重点实验室
通讯作者Zhang, Lin; Ye, Fei; Zhang, Liang
作者单位1.Shanghai Jiao Tong Univ, Sch Chem & Chem Engn, Dept Chem Biol, Shanghai 200240, Shanghai, Peoples R China
2.Zhejiang Sci Tech Univ, Coll Life Sci & Med, Hangzhou 310018, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr,Ctr Chem Biol, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.Shanghai Jiao Tong Univ, Sch Med, Dept Pharmacol & Chem Biol, State Key Lab Syst Med Canc, Shanghai 200025, Peoples R China
推荐引用方式
GB/T 7714		 Huang, Yuzhou,Wang, Yiran,Cai, Chang,et al. The β-Ketoacyl-ACP Synthase FabF Catalyzes Carbon-Carbon Bond Formation in a Bimodal Pattern for Fatty Acid Biosynthesis[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2024:11.
APA Huang, Yuzhou,Wang, Yiran,Cai, Chang,Zhang, Lin,Ye, Fei,&Zhang, Liang.(2024).The β-Ketoacyl-ACP Synthase FabF Catalyzes Carbon-Carbon Bond Formation in a Bimodal Pattern for Fatty Acid Biosynthesis.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,11.
MLA Huang, Yuzhou,et al."The β-Ketoacyl-ACP Synthase FabF Catalyzes Carbon-Carbon Bond Formation in a Bimodal Pattern for Fatty Acid Biosynthesis".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2024):11.

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来源：上海药物研究所

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