title: Molecular targeting of proteins by L-homocysteine: mechanistic implications for vascular disease.
abstract: Hyperhomocysteinemia is an independent risk factor for cardiovascular disease, complications of pregnancy, cognitive impairment, and osteoporosis. That elevated homocysteine leads to vascular dysfunction may be the linking factor between these apparently unrelated pathologies. Although a growing body of evidence suggests that homocysteine plays a causal role in atherogenesis, specific mechanisms to explain the underlying pathogenesis have remained elusive. This review focuses on chemistry unique to the homocysteine molecule to explain its inherent cytotoxicity. Thus, the high pKa of the sulfhydryl group (pKa, 10.0) of homocysteine underlies its ability to form stable disulfide bonds with protein cysteine residues, and in the process, alters or impairs the function of the protein. Studies in this laboratory have identified albumin, fibronectin, transthyretin, and metallothionein as targets for homocysteinylation. In the case of albumin, the mechanism of targeting has been elucidated. Homocysteinylation of the cysteine residues of fibronectin impairs its ability to bind to fibrin. Homocysteinylation of the cysteine residues of metallothionein disrupts zinc binding by the protein and abrogates inherent superoxide dismutase activity. Thus, S-homocysteinylation of protein cysteine residues may explain mechanistically the cytotoxicity of elevated L-homocysteine.
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Case Western Reserve University, Cleveland, Ohio 44195, USA.
authors.forename: Alla V
authors.initials: AV
authors.lastname: Glushchenko
authors.forename: Donald W
authors.initials: DW
authors.lastname: Jacobsen
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D006710:Homocysteine / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D014652:Vascular Diseases / Q000378:metabolism* / Q000473:pathology*
chemical_list: D001798:Blood Proteins; D008565:Membrane Proteins; D006710:Homocysteine