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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 |
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| Authors: | Jiashen Zhou Lin Zhang Yiran Wang Wenyan Song Yuzhou Huang Yajuan Mu Werner Schmitz Shu-Yu Zhang Houwen Lin Hong-Zhuan Chen Fei Ye Liang Zhang |
| Institution: | 1. Department of Pharmacology and Chemical Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China;2. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024 China
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China These authors contributed equally to this work.;3. Department of Pharmacology and Chemical Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China These authors contributed equally to this work.;4. Department of Biochemistry and Molecular Biology, University of Würzburg, Würzburg, 97074 Germany;5. School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, 200240 China;6. Research Centre for Marine Drugs, State Key Laboratory of Oncogene and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 China Institute of Marine Biomedicine, Shenzhen Polytechnic, Shenzhen, 518055 China;7. Institute of Interdisciplinary Integrative Biomedical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China;8. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024 China |
| Abstract: | 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” α8 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. |
| Keywords: | Acyl-ACP Reductases Allosteric Regulation Biosynthesis Enantioselective Reduction Enzyme Catalysis |