title: Cyclic AMP Inhibits the Activity and Promotes the Acetylation of Acetyl-CoA Synthetase through Competitive Binding to the ATP/AMP Pocket.
abstract: The high-affinity biosynthetic pathway for converting acetate to acetyl-coenzyme A (acetyl-CoA) is catalyzed by the central metabolic enzyme acetyl-coenzyme A synthetase (Acs), which is finely regulated both at the transcriptional level via cyclic AMP (cAMP)-driven trans-activation and at the post-translational level via acetylation inhibition. In this study, we discovered that cAMP directly binds to Salmonella enterica Acs (SeAcs) and inhibits its activity in a substrate-competitive manner. In addition, cAMP binding increases SeAcs acetylation by simultaneously promoting Pat-dependent acetylation and inhibiting CobB-dependent deacetylation, resulting in enhanced SeAcs inhibition. A crystal structure study and site-directed mutagenesis analyses confirmed that cAMP binds to the ATP/AMP pocket of SeAcs, and restrains SeAcs in an open conformation. The cAMP contact residues are well conserved from prokaryotes to eukaryotes, suggesting a general regulatory mechanism of cAMP on Acs.
authors.affiliation: From the Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China.|the University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Xiaobiao
authors.initials: X
authors.lastname: Han
authors.affiliation: the Key Laboratory of Synthetic Biology, Chinese Academy of Sciences Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Shen
authors.affiliation: the Department of Medical Microbiology and Parasitology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Qijun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: From the Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
authors.forename: Xufeng
authors.initials: X
authors.lastname: Cen
authors.affiliation: From the Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: the Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.affiliation: From the Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: From the Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China, wzhao@sibs.ac.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: the Key Laboratory of Synthetic Biology, Chinese Academy of Sciences Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China, zhang-yu@sibs.ac.cn.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: the Key Laboratory of Synthetic Biology, Chinese Academy of Sciences Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China, gpzhao@sibs.ac.cn.|the State Key Lab of Genetic Engineering & Institutes of Biomedical Sciences, Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.|the Shanghai-MOST Key Laboratory of Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China.|the Department of Microbiology and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China, and.
authors.forename: Guoping
authors.initials: G
authors.lastname: Zhao
mesh_terms: D000249:Adenosine Monophosphate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D003066:Coenzyme A Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019779:Salmonella enterica / Q000201:enzymology* / Q000235:genetics
chemical_list: D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D003066:Coenzyme A Ligases; C101958:acetate-CoA ligase (ADP-forming)
keywords: acetyl-CoA synthetase; acetylation; crystal structure; cyclic AMP (cAMP); post-translational modification (PTM)