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methylation cycle


Role of Homocysteine in the Ischemic Stroke and Development of Ischemic Tolerance

  • Homocysteine (Hcy) is a toxic, sulfur-containing intermediate of methionine metabolism. Hyperhomocysteinemia (hHcy), as a consequence of impaired Hcy metabolism or defects in crucial co-factors that participate in its recycling, is assumed as an independent human stroke risk factor. Neural cells are sensitive to prolonged hHcy treatment, because Hcy cannot be metabolized either by the transsulfuration pathway or by the folate/vitamin B12 independent remethylation pathway.
  • "reactive oxygen species (ROS) and posttranslational modifications of proteins via homocysteinylation and thiolation"


Homocysteine is nonspecifically activated by methionyl-tRNA synthetase; however, it is not transferred to tRNA and incorporated into proteins, but is transformed to a cyclic thioester, homocysteine thiolactone. HCTL is highly reactive and acylates free amino groups of protein lysine residues, the process referred to as protein N-homocysteinylation.@{16106241}


  • Various plasma proteins are homocysteinylated in vitro and in vivo. Homocysteinylation results in the incorporation of additional thiol groups which may alter the physicochemical properties and biological activity of proteins.@{16106241}
  • In particular, homocysteinylation of low-density lipoproteins (LDLs) increases their susceptibility to oxidation and accelerates their uptake by macrophages.@{16106241}
  • In addition, homocysteinylated LDL elicit humoral immune response. Anti-homocysteinyllysine antibodies are detected in plasma of healthy humans and their titer is elevated in patients with ischemic heart disease or ischemic cerebral stroke.@{16106241}
  • Homocysteine significantly induced mRNA and protein expressions of CRP in VSMCs both in vitro and in vivo [16]. Homocysteine augmented NR1 subunit (of N-methyl-D-aspartate receptor (NMDAr)) expression, while MK-801 reduced homocysteine induced CRP expression in VSMCs. The study demonstrated that homocysteine is capable of initiating an inflammatory response in vascular smooth muscle cells by stimulating CRP production, which is mediated through NMDAr-ROS-ERK1/2/p38-NF-κB signal pathway.@{PMC5120102}
  • Hcy suppresses NO production by endothelial cells and platelets and increases generation of reactive oxygen species (ROS) by the release of arachidonic acid from the platelets.@{PMC5120102}
  • It also inhibits glutathione peroxidase and thus stimulates proliferation of endothelial cells (see Petras et al., 2014, for review).@{PMC5120102}
  • In addition, Hcy has been shown to inhibit methyltransferases, to suppress DNA repair and to facilitate apoptosis when accumulated inside the cells.@{PMC5120102}
  • Autooxidation of Hcy metabolites results in H202 accumulation (Boldyrev et al., 2013) and challlenging neurons to Hcy metabolites for longer period leads to necrotic cell death (Ziemińska et al., 2003).@{PMC5120102}


  • Efficient recycling through cobalamin dependent methionine synthase (given an adequate supply of cobalamine and folate) ....@{PMC5120102}
  • This outcome to some extent may be a result of dietary deficiency of folate, vitamin B12 or choline (a betaine precursor necessary for folate-independent methylation of homocysteine) since these are essential for methylation reactions that may epigenetically direct gene expression@{PMC5120102}
    • get enough B12, Folate, and either choline or betaine


Vegetarians may be at a higher risk of hyperhomocysteinemia due to low plasma B12 levels but the difference is likely to be insignificant@{PMC5120102}

high protein

  • @{PMC5120102}
    • High protein increases methionine, which would result in higher homocysteine


Protein homocysteinylation: a new mechanism of atherogenesis?
Role of Homocysteine in the Ischemic Stroke and Development of Ischemic Tolerance