The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health

Abstract

Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid derived in methionine metabolism. The increased level of Hcy in plasma, hyperhomocysteinemia, is considered to be an independent risk factor for cardio and cerebrovascular diseases. However, it is still not clear if Hcy is a marker or a causative agent of diseases. More and more research data suggest that Hcy is an important indicator for overall health status. This review represents the current understanding of molecular mechanism of Hcy metabolism and its link to hyperhomocysteinemia-related pathologies in humans. The aberrant Hcy metabolism could lead to the redox imbalance and oxidative stress resulting in elevated protein, nucleic acid and carbohydrate oxidation and lipoperoxidation, products known to be involved in cytotoxicity. Additionally, we examine the role of Hcy in thiolation of proteins, which results in their molecular and functional modifications. We also highlight the relationship between the imbalance in Hcy metabolism and pathogenesis of diseases, such as cardiovascular diseases, neurological and psychiatric disorders, chronic kidney disease, bone tissue damages, gastrointestinal disorders, cancer, and congenital defects.

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

“…SAM is converted into SAH via an MT‐catalysed methyl transfer reaction. Finally, SAH is rapidly metabolized by SAH hydrolase to adenosine and homocysteine (Skovierova et al ., ). Homocysteine production may be enhanced by increased intake of Met‐rich protein, which results in HHcy.…”

“…Folate in the form of N‐5‐methyl tetrahydrofolate (THF), derived from N ‐5,10‐methylene tetrahydrofolate reductase (MTHFR)‐catalysed THF modification, donates a methyl group to homocysteine in the re‐methylation catalysed by the vitamin B12‐dependent enzyme methionine synthase (MS) (Castro et al ., ). In the other mechanism, betaine derived from choline by betaine–homocysteine S ‐methyltransferase also behaves as a methyl group donor and contributes to the folate/vitamin B12‐independent re‐methylation of homocysteine to form Met (Skovierova et al ., ). Second, homocysteine is resynthesized into SAH through the reversal of SAH hydrolase activity.…”

“…High concentrations of SAH strongly inhibit the transmethylation of Met because SAH is a potent allosteric inhibitor of MT (Kerr, ). Third, homocysteine is metabolized to form Cys via trans‐sulphuration, sequentially catalysed by the vitamin B6‐dependent enzymes cystathionine β‐synthase (CBS) and cystathionine γ‐lyase (CSE) (Skovierova et al ., ). These trans‐sulphuration enzymes CBS and CSE, exhibit other enzymic activities that contribute to the biosynthesis of the gasotransmitter H 2 S, from homocysteine and/or Cys (Weber et al ., ).…”

A Case-Control Study of the Association of the Polymorphisms of <b><i>MTHFR</i></b> and <b><i>APOE</i></b> with Risk Factors and the Severity of Coronary Artery Disease

“…Methylenetetrahydrofolate reductase (MTHFR)is a key enzyme catalyzing the remethylation of homocysteine (Hcy), and mutation of the MTHFR gene has been proved to reduce the enzymatic activity of MTHFR, thus leading to hyperhomocysteinemia [10, 11]. It has been proved through cell culture and animal studies that hyperhomocysteinemia damages arterial endothelial cells, and induces abnormal interaction with platelets and fibrinogen, eventually leading to the process of CAD [12].…”

Capillary electrophoresis coupled with chloroform‐acetonitrile extraction for rapid and highly selective determination of cysteine and homocysteine levels in human blood plasma and urine

“…The quantification of homocysteine (Hcy) and cysteine (Cys) is of prime importance for biological, clinical, and pharmaceutical research . Hcy is considered a risk factor for complications of cardiovascular diseases . The normal Hcy level in blood plasma and urine is 10–15 μM and 0.5–2.5 μM/mM of urine creatinine, respectively .…”