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Homocysteine racemic.png
IUPAC name
CAS number 454-29-5 Yes check.svgY,
6027-13-0 (L-isomer)
PubChem 778
EC-number 207-222-9
Molecular formula C4H9NO2S
Molar mass 135.18 g/mol
 Yes check.svgY (what is this?)  (verify)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

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 methionine by the removal of its terminal Cε methyl group. Homocysteine can be recycled into methionine or converted into cysteine with the aid of B-vitamins.



As other amino acids homocysteine exists at neutral pH values as a zwitterion:

Betatine form of (S)-homocysteine (left) and (R)-homocysteine (right)

Biosynthesis and biochemical roles

Homocysteine is not obtained from the diet.[1] Instead, it is biosynthesized from methionine via a multi-step process. First, methionine receives an adenosine group from ATP, a reaction catalyzed by S-Adenosyl-methionine synthetase, to give S-adenosyl methionine ("SAM"). SAM then transfers the methyl group to an acceptor molecule, (i.e. norepinephrine as an acceptor during epinephrine synthesis, DNA methyltransferase as an intermediate acceptor in the process of DNA methylation). The adenosine is then hydrolyzed to yield L-homocysteine. L-homocysteine has two primary fates: conversion via tetrahydrofolate (THF) back into L-methionine or conversion to L-cysteine.[2]


Biosynthesis of cysteine

Mammals biosynthesize the amino acid cysteine via homocysteine. Cystathionine β-synthase catalyses the condensation of homocysteine and serine to give cystathionine. This reaction uses pyridoxine (Vitamin B6) as a cofactor. Cystathionine β-lyase then converts this double amino acid to cysteine, ammonia, and α-ketoglutarate. Bacteria and plants rely on a different pathway to produce cysteine, relying on O-acetylserine.[3]

Methionine salvage

Homocysteine can be recycled into methionine. This process uses N5-methyl tetrahydrofolate as the methyl donor and cobalamin (Vitamin B12)-related enzymes. More detail on those enzymes: Tetrahydrofolate-methyltransferase

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.[4 ] Supplementation with pyridoxine, folic acid, B12 or trimethylglycine (betaine) reduces the concentration of homocysteine in the bloodstream.[5][6] 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.[7]

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). These individuals require adequate dietary riboflavin in order for homocysteine levels to remain normal. 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:
Sex Age Lower limit Upper limit Unit Elevated Therapeutic target
Female 12-19 years 3.3 [8] 7.2[8] μmol/L > 10.4 < 6.3 [9]
(0.85 mg/L)[9]
>60 years 4.9 [8] 11.6 [8] μmol/L
Male 12-19 years 4.3 [8] 9.9 [8] μmol/L > 11.4
>60 years 5.9 [8] 15.3 [8] μmol/L

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.[10] 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 [11] 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 proteins, i.e. collagen or elastin, or life-long proteins, i.e. 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 in patients with pre-existing conditions found no significant benefit nor damage.[11][12 ][13]

Hypotheses have been offered to address the failure of homocysteine-lowering therapies to reduce cardiovascular event frequency.[14] 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.[15][16] 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.[17]

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.


  1. ^ Selhub, J. (1999). "Homocysteine metabolism.". Annual Review of Nutrition 19: 217–246. doi:10.1146/annurev.nutr.19.1.217. PMID 10448523.  
  2. ^ Champe, PC and Harvey, RA. "Biochemistry. Lippincott's Illustrated Reviews" 4th ed. Lippincott Williams and Wilkins, 2008
  3. ^ Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6.
  4. ^ Miller JW, Nadeau MR, Smith D and Selhub J (1994). "Vitamin B-6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats". American Journal of Clinical Nutrition 59: 1033–1039. PMID 8172087.  
  5. ^ Coen DA Stehouwer, Coen van Guldener (2001). "Homocysteine-lowering treatment: an overview". Expert Opinion on Pharmacotherapy 2 (9): 1449–1460. doi:10.1517/14656566.2.9.1449. PMID 11585023.  
  6. ^ Legal note: Metabolite Laboratories is defending a patent as of March 2006 that may cover the mere mention or consideration of the relationship of vitamin B12 and homocysteine levels. See Crichton, Michael (March 19, 2006). "This Essay Breaks the Law". The New York Times (The New York Times Company). Retrieved 2006-03-20.  
  7. ^ According to Professor Melinda M. Manore of Oregon State University's Department of Nutrition and Exercise Sciences,
  8. ^ a b c d e f g h The Doctor's Doctor: Homocysteine
  9. ^ a b Adëeva Nutritionals Canada > Optimal blood test values Retrieved on July 9, 2009
  10. ^ "B vitamins do not protect hearts". BBC News (BBC). September 6, 2005. Retrieved 2006-03-20.  
  11. ^ a b "Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease". N Engl J Med. 2006. PMID [ Full text PDF 16531613 Full text PDF].  
  12. ^ Zoungas S, McGrath BP, Branley P, Kerr PG, Muske C, Wolfe R, Atkins RC, Nicholls K, Fraenkel M, Hutchison BG, Walker R, McNeil JJ (2006). "Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial". J Am Coll Cardiol 47 (6): 1108–16. doi:10.1016/j.jacc.2005.10.064. PMID 16545638.  
  13. ^ Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K (2006). "Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction". N Engl J Med 354: 1578. doi:10.1056/NEJMoa055227. PMID [ Full text PDF 16531614 Full text PDF].  
  14. ^ Loscalzo J (2006). "Homocysteine Trials — Clear Outcomes for Complex Reasons". N Engl J Med 354 (15): 1629–1632. doi:10.1056/NEJMe068060. PMID 17224870.  
  15. ^ McLean RR et al. (2004). "Homocysteine as a predictive factor for hip fracture in older persons.". New England Journal of Medicine 350: 2042–2049. doi:10.1056/NEJMoa032739. PMID 15141042.   Free text after free registration
  16. ^ van Meurs JB et al. (2004). "Homocysteine levels and the risk of osteoporotic fracture.". New England Journal of Medicine 350: 2033–2041. doi:10.1056/NEJMoa032546. PMID 15141041.   Free text after free registration
  17. ^ Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K (March 2005). "Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial". JAMA 293 (9): 1082–8. doi:10.1001/jama.293.9.1082. PMID 15741530.  


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