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Homocysteine
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Homocysteine is an amino acid with the formula HSCH2CH2CH(NH2)CO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene (-CH2-) group. It is biosynthesized from the methionine by the removal of its terminal Ce methyl group. Homocysteine can be recycled into methionine or converted into cysteine with the aid of B-vitamins.
cysteine is not obtained from the diet.
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Encyclopedia
Homocysteine is an amino acid with the formula HSCH2CH2CH(NH2)CO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene (-CH2-) group. It is biosynthesized from the methionine by the removal of its terminal Ce methyl group. Homocysteine can be recycled into methionine or converted into cysteine with the aid of B-vitamins.
Biosynthesis and biochemical roles
Homocysteine is not obtained from the diet. Instead, it is biosynthesized from the methionine via a multi-step process. First, methionine is alkylated by ATP to give S-adenosyl methionine ("SAM"). Catalyzed by the enzyme cytosine-5-methyl transferase, SAM then transfers the methyl group to cytosine in DNA to give adenosylhomocysteine. The enzyme adenosylhomocysteinase then catalyzes the hydrolysis of this intermediate to give homocysteine.
Biosynthesis of cysteine
Mammals biosynthesize the amino acid cysteine via homocysteine. Cystathionine ß-synthase catalyses the condensation of homocysteine and serine to give cystathionine. Cystathionine ß-lyase then converts this double amino acid to cysteine, ammonia, and a-ketoglutarate. Bacteria and plants rely on a different pathway to produce cysteine, relying on O-acetylserine.
Methionine salvage
Homocysteine can be recycled into methionine. This process uses folate as the methyl donor and B12-related enzymes.
Other reactions of biochemical significance
Homocysteine can cyclize to give homocysteine thiolactone, a five-membered) heterocycle. Because of this "self-looping" reaction, homocysteine-containing peptides tend to cleave themselves.
Influence, proposed and verified, of homocysteine on human health
Elevated homocysteine
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, which 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 (e.g., New Delhi) or in the older elderly (e.g., 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.
|+Blood reference ranges for homocysteine:
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|Patient type||Lower limit||Upper limit||Unit||Comment
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| Female 12-19 years || 3.3 || 7.2 || µmol/L ||rowspan=2| Elevated at:
10.4 umol/L
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| Female >60 years || 4.9 || 11.6 || µmol/L
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| Male 12-19 years || 4.3 || 9.9 || µmol/L ||rowspan=2| Elevated at:
11.4 umol/L
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| Male >60 years || 5.9 || 15.3 || µmol/L
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|}
Cardiovascular risks and related medical studies
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 methylation 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. 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. Whereas 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 they inefficiently absorb B12 from food, elderly persons may benefit from taking higher doses orally such as 100 mcg/day (found in some multivitamins) or by intramuscular injection.
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