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Homocysteine (; symbol Hcy) is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (). It is biosynthesized from methionine by the removal of its terminal Cε methyl group.
Although the production of homocysteine is a normal part of the metabolism of methionine, an excess of homocysteine can be harmful. There are two primary ways for organisms such as humans to metabolize homocysteine: remethylation and transsulfuration.
Remethylation adds a methyl group to the homocysteine molecule, converting homocysteine back into methionine. There are two known remethylation pathways. One pathway requires Folate (folate) and B12 (cobalamin), which drive the MTR (methionine synthase) and MTRR (methionine synthase reductase) enzymes. The other pathway uses TMG (trimethylglycine) to drive the BHMT (betaine-homocysteine methyltransferase) enzyme.
Transsulfuration converts homocysteine to cystathionine. This pathway requires vitamin B6 to drive the CBS (cystathionine beta synthase) enzyme. Cystathionine is the immediate precursor of the amino acid cysteine, which (along with glutamate and glycine), is incorporated into the tripeptide glutathione, a major antioxidant in the human body.
Homocysteine is therefore an important metabolic substrate. However, excessive levels of homocysteine can result in hyperhomocysteinemia, which is regarded as an indicator of cardiovascular disease risk. Homocysteine likely contributes to atherogenesis, which can result in Ischemia. Therefore, hyperhomocysteinemia is a possible risk factor for coronary artery disease. Coronary artery disease occurs when an atherosclerotic plaque blocks blood flow to the Coronary artery, which supply the heart with oxygenated blood. Hyperhomocysteinemia has also been correlated with the occurrence of blood clots, heart attacks, and strokes, although it is unclear whether hyperhomocysteinemia is an independent risk factor for these conditions. Homocysteine: The Facts, Tufts Health and Nutrition Letter, July 31, 2020 update Hyperhomocysteinemia has also been associated with early-term spontaneous abortions and with neural tube defects.van der Put NJ et al Folate, Homocysteine and Neural Tube Defects: An Overview Exp Biol Med (Maywood) April 2001 vol. 226 no. 4 243-270
Homocysteine also acts as an allosteric antagonist at Dopamine D2 receptors.
It has been proposed that both homocysteine and its thiolactone may have played a significant role in the Abiogenesis on the early Earth.
Common levels in Western populations are 10 to 12 μmol/L, and levels of 20 μmol/L are found in populations with low B-vitamin intakes or in the elderly (e.g., Rotterdam, Framingham).
It is decreased with methyl folate trapping, where it is accompanied by decreased methylmalonic acid, increased folate, and a decrease in formiminoglutamic acid. This is the opposite of MTHFR C677T mutations, which result in an increase in homocysteine.
Typically, hyperhomocysteinemia is managed with vitamin B6, vitamin B9, and vitamin B12 supplementation. However, supplementation with these vitamins does not appear to improve cardiovascular disease outcomes.
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