Homocysteine

Homocysteine

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.

Organic chemical properties

The "extra" (relative to cysteine) one carbon methylene group allows this molecule to form a five-membered ring, homocysteine thiolactone. The facility of this reaction precludes the formation of stable peptide bonds. In other words, a protein containing homocysteine would tend to cleave itself.

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.

Elevated homocysteine

As a consequence of the biochemical reactions in which homocysteine is involved, deficiencies of the vitamins folic acid (B9), pyridoxine (B6), or B12 (cyanocobalamin) can lead to high homocysteine levels. Supplementation with pyridoxine, folic acid, B12 or trimethylglycine (betaine) reduces the concentration of homocysteine in the bloodstream. Increased levels of homocysteine are linked to high concentrations of endothelial asymmetric dimethylarginine. Recent research suggests that intense, long duration exercise raises plasma homocysteine levels, perhaps by increasing the load on methionine metabolism.

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.

Cardiovascular risks

A high level of blood serum homocysteine is a powerful risk factor for cardiovascular disease. Unfortunately, one study which attempted to decrease the risk by lowering homocysteine was not fruitful. This study was conducted on nearly 5000 Norwegian heart attack survivors who already had severe, late-stage heart disease. No study has yet been conducted in a preventive capacity on subjects who are in a relatively good state of health.

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.

Bone weakness and breaks

Elevated levels of homocysteine have been linked to increased fractures in elderly persons. Elevated levels may be due to renal or liver disease, deficiency of folic acid, vitamin B6 or vitamin B12. The high level of homocysteine will auto-oxidize and react with reactive oxygen intermediates and damage endothelial cells and has a higher risk to form a thrombus. Homocysteine does not affect bone density. Instead, it appears that homocysteine affects collagen by interfering with the cross-linking between the collagen fibers and the tissues they reinforce. While the HOPE-2 trial [6] showed a reduction in stroke incidence, in those with stroke there is a high rate of hip fractures in the affected side. A trial with 2 homocysteine lowering vitamins (folate and B12) in people with prior stroke, there was an 80% reduction in fractures, mainly hip, after 2 years. Interestingly, also here, bone density (and the number of falls) were identical in the vitamin and the placebo groups.

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.

References

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