Homocysteine is a non-proteinogenic amino acid


Homocysteine is a non-proteinogenic amino acid, a homologue of the amino acid cysteine (homologues are the substances that have the same structure but differ from one another in composition by one or more groups -CH2-). In the body homocysteine is produced from methionine and can be converted back into methionine when vitamin B is present. High levels of homocysteine (hyperhomocysteinemia) has negative impact on endothelium (the layer of cells lining the interior surface of the blood vessels and lymphatic vessels). Particularly, it damages the endothelium and results in inflammation of the tissue leading to thrombogenesis, atherosclerosis and related to these conditions ischemic damage. Circulating in the blood stream immune cells bind to the sites of damage in blood vessels and cause inflammation. Cells of the blood vessels actively proliferate to eliminate this damage, which leads to the formation of plaques on the wall of the arteries. In addition, hyperhomocysteinemia promotes oxidation of LDL, endothelial dysfunction, proliferation of smooth muscle cells of blood vessels, activation of platelets and increased thrombogenesis. Thus, elevated homocysteine has negative effect not only on the structure of the vascular wall but also on the blood coagulation system (1).
The methylation potential of a cell is directly related to the SAM-to-SAH (S- Adenosylmethionine to S- adenosylhomocysteine) ratio, where hyperhomocysteinemia shifts it toward decreased methylation potential. Recent studies suggest that homocysteine results in global DNA hypomethylation. Its gene-specific effect on the cells is suppressed transcription of cyclin A – regulatory subunits regulating
cyclin-dependent kinases (Cdks) – in endothelial cells. Homocysteine initiates demethylation of a CpG site in core promoter which then eliminates the binding of methyl CpG-binding protein 2 and HDAC (Histone deacetylases) binding. As a result, gene expression is suppressed due to the accumulation of acetylated histones H3 and H4. Open conformation of transcriptional permissive chromatin that’s linked to both histone acetylation and DNA hypomethylation helps to increase access by repressor proteins, which results in suppressed transcriptional. And vise versa, homocysteine-induced DNA hypomethylation of promoters results in up-reguation of some genes. For instance, expression of the p66shc gene in endothelial cells increases through the homocysteine induction, which results in oxidative stress in those cells by promoting increased levels of reactive oxygen. This process leads to cellular toxicity and misfolding of protein