Homocysteine is a chemical compound with the formula HSCH2CH2CH(NH2)CO2H. It is a homologue of the naturally-occurring amino acid cysteine, differing in that its side-chain contains an additional methylene (-CH2-) group before the thiol (-SH) group. Alternatively, homocysteine can be derived from methionine by removing the latter's terminal Cε methyl group.
The 4 carbon homocysteine is (only) made from the 5 carbon methionine, an essential amino acid, in a multi step reaction via S-adenosyl methionine. Homocysteine can be recycled back into methionine or it can be permanently converted to cysteine via the transsulfuration pathway. Homocysteine is not obtained from the diet; it is a normal temporary and chemically reactive reaction product that can be measured in blood. Due to its high reactivity to proteins, it is almost always bound to proteins, 'thiolating' (and thus degrading) most notably the lysine and cysteine components thereof. This can permanently affect protein function. In blood, it is found bound to albumin and to hemoglobin. It affects enzymes with cysteine-containing active sites; for example, it inhibits lysyl oxidase a key enzyme in the production of collagen and elastin, two main structural proteins in artery, bone and skin.
Elevations of homocysteine also occur in the rare hereditary disease homocystinuria and in the methylene-tetrahydrofolate-reductase polymorphism genetic traits. The latter is quite common (about 10% of the world population) and it is linked to an increased incidence of thrombosis and cardiovascular disease and that occurs more often in people with above minimal levels of homocysteine (about 6 μmol/L). Common levels in Western populations are 10 to 12 and levels of 20 μmol/L are found in populations with low B-vitamin intakes (New Delhi) or in the older elderly (Rotterdam, Framingham). Women have 10-15% less homocysteine during their reproductive decades than men which may help explain the fact they suffer myocardial infarction (heart attacks) on average 10 to 15 years later than men.
Studies reported in 2006 have shown that giving vitamins [folic acid, B6 and B12] to reduce homocysteine levels may not quickly offer benefit, however a significant 25% reduction in stroke was found in the HOPE-2 study even in patients mostly with existing serious arterial decline although the overall death rate was not significantly changed by the intervention in the trial. Clearly, reducing homocysteine does not quickly repair existing structural damage of the artery architecture. However, the science is strongly supporting the biochemistry that homocysteine degrades and inhibits the formation of the three main structural components of the artery, collagen, elastin and the proteoglycans. Homocysteine permanently degrades cysteine [disulfide bridges] and lysine amino acid residues in proteins, gradually affecting function and structure. Simply put, homocysteine is a 'corrosive' of long-living [collagen, elastin] or life-long proteins [fibrillin]. These long-term effects are difficult to establish in clinical trials focusing on groups with existing artery decline. The main role of reducing homocysteine is possibly in 'prevention' but studies thus far have not found benefits from it, and some have actually seen increased risks from consuming B vitamins, leading them to conclude that supplementation is not recommended.
Hypotheses have been offered to address the failure of homocysteine-lowering therapies to reduce cardiovascular event frequency. One suggestion is that folic acid may directly cause an increased build-up of arterial plaque, independent of its homocysteine-lowering effects. Alternatively, folic acid and vitamin B12 may cause an overall change in gene methlyation levels in vascular cells, which may also promote plaque growth. Finally, altering methlyation activity in cells might increases methylation of l-arginine to asymmetric dimethylarginine which can increase the risk of vascular disease. Thus alternative homocysteine-lowering therapies may yet be developed which show greater effects on development and progression of cardiovascular disease.
Vitamin supplements counter the deleterious effects of homocysteine on collagen. As B12 is inefficiently absorbed from food by elderly persons, they may benefit from taking higher doses orally such as 100 mcg/day (found in some multivitamins) or by intramuscular injection.