Abstract
Homocysteine is a sulfur-containing amino acid derived from the metabolism of methionine, an essential amino acid, and is metabolized by one of two pathways: remethylation or transsulfuration. Abnormalities of these pathways lead to hyperhomocysteinemia. Hyperhomocysteinemia is observed in approximately 5% of the general population and is associated with an increased risk for many disorders, including vascular and neurodegenerative diseases, autoimmune disorders, birth defects, diabetes, renal disease, osteoporosis, neuropsychiatric disorders, and cancer. We review here the correlation between homocysteine metabolism and the disorders described above with genetic variants on genes coding for enzymes of homocysteine metabolism relevant to clinical practice, especially common variants of the MTHFR gene, 677C>T and 1298A>C. We also discuss the management of hyperhomocysteinemia with folic acid supplementation and fortification of folic acid and the impact of a decrease in the prevalence of congenital anomalies and a decline in the incidence of stroke mortality.
Highlights
Homocysteine (Hcy) is the demethylated derivative of methionine, which, after conversion to S-adenosylmethionine, is the most important methyl group donor in the body
The cofactor vitamin B12 participates in the remethylation reaction with 5-methyltetrahydrofolate, whereas the reaction with betaine is restricted to the liver and is independent of vitamin B12
These findings suggest that impaired folic acid metabolism plays a role in Neural tube defects (NTD)
Summary
Homocysteine (Hcy) is the demethylated derivative of methionine, which, after conversion to S-adenosylmethionine, is the most important methyl group donor in the body. Hcy is metabolized by one of the two following pathways, i.e., remethylation or transsulfuration (Figure 1). Hcy is transformed to methionine by the addition of a methyl group from 5-methyltetrahydrofolate or betaine. The cofactor vitamin B12 participates in the remethylation reaction with 5-methyltetrahydrofolate, whereas the reaction with betaine is restricted to the liver and is independent of vitamin B12. Hcy is converted to cystathionine by cystathionine β-synthase and to cysteine using vitamin B6 as a cofactor [1]. Plasma Hcy levels are determined by several factors such as the cofactors vitamin B12, vitamin B6 and folic acid and enzymes involved in methionine metabolism. The remaining 10-20% of total Hcy (tHcy) is acid-soluble free Hcy presenting as Hcy-cysteine mixed disulfide and homocystine (a dimer of Hcy) and less than the remaining 1% is present in the free reduced form [2]
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