title: Dehomocysteinylation is catalysed by the sirtuin-2-like bacterial lysine deacetylase CobB.
abstract: Hyperhomocysteinemia, which is characterized by elevated blood levels of the non-protein amino acid homocysteine (Hcy), is an independent risk factor for many diseases, including cardiovascular diseases, neurodegenerative diseases and birth defects. The incorporation of homocysteine into proteins, known as protein N-homocysteinylation, has been considered a major mechanism that contributes to hyperhomocysteinemia. However, the process of dehomocysteinylation, the N-homocysteinylation substrates and the regulatory enzyme(s) remain largely unknown. In this study, we observed that the dehomocysteinylation reaction is a spontaneous process that can be inhibited by blocking -SH groups, which have been demonstrated to be critical for non-enzymatic dehomocysteinylation reactions. We also report that CobB, a known Sir2-like bacterial lysine deacetylase, catalyzes lysine dehomocysteinylation reactions both in vitro and in vivo. Our work provides insight into how this non-enzymatic modification might be removed from affected proteins, supplies potential targets for developing identification methods for N-homocysteine proteins, and identifies CobB as the first prokaryotic dehomocysteinylation enzyme.
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, China.|Interdisciplinary Center on Biology and Chemistry and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, China.
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Mei
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Xia-Di
authors.initials: XD
authors.lastname: He
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Genetics, Xuzhou Medical University, Jiangsu, China.
authors.forename: Da-Shi
authors.initials: DS
authors.lastname: Qi
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Nie
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Qingdao University of Science and Technology, College of Chemistry and Molecular Engineering, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Si
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Shi-Min
authors.initials: SM
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006710:Homocysteine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D009154:Mutation; D041681:NIH 3T3 Cells; D011499:Protein Processing, Post-Translational; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism; D056565:Sirtuin 2 / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D006710:Homocysteine; D012710:Serum Albumin, Bovine; C007957:homocysteine thiolactone; D002265:Carboxylic Ester Hydrolases; C000619437:CobB protein, Salmonella enterica; C474199:SIRT2 protein, human; D056565:Sirtuin 2; D006655:Histone Deacetylases; D008239:Lysine
keywords: CobB; N-homocysteinylation; dehomocysteinylation; sirtuin; sulfhydryl group