|CAS number||, (L-isomer)|
|Jmol-3D images||Image 1|
|Molar mass||135.18 g/mol|
| (what is: / ?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Homocysteine [IPA: ˌhəʊməʊˈsɪstiːn] is a protein amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). 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.
While detection of high levels of homocysteine has been linked to cardiovascular disease, lowering homocysteine levels may not improve outcomes.
Health effects 
Elevated levels of homocysteine have been associated with a number of disease states. However, benefits from efforts to lower homocysteine levels are either not supportive or not conclusive. This includes no evidence to support prevention of cardiovascular disease (including in those with kidney disease), tentative but inconclusive evidence for congestive heart failure and bone health.
Elevated homocysteine 
Abnormally high levels of homocysteine in the serum, above 15 µmol/L, are a medical condition called Hyperhomocysteinemia. This condition is a significant risk factor for the development of a wide range of diseases.
Deficiencies of the vitamins folic acid (B9), pyridoxine (B6), or B12 (cobalamin) 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. Chronic consumption of alcohol may also result in increased plasma levels of homocysteine.
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. However, this phenomenon is more readily explained by higher levels of estrogen, which exerts a cardioprotective effect.
|Sex||Age||Lower limit||Upper limit||Unit||Elevated||Therapeutic target|
|Female||12–19 years||3.3||7.2||μmol/L||> 10.4 μmol/L
> 140 μg/dl
|< 6.3 μmol/L
< 85 μg/dL
|Male||12–19 years||4.3||9.9||μmol/L||> 11.4 μmol/L
> 150 μg/dL
Cardiovascular risks 
A high level of blood serum homocysteine ("homocystinemia") is a powerful risk factor for cardiovascular disease. However, 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 (pyridoxine), 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 proteins, i.e., collagen or elastin, or lifelong 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.
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 methylation activity in cells might increase 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.
The VITATOPS trial concluded that B-vitamin supplements, within 2 years, do not seem to significantly reduce subsequent stroke, MI, or vascular death in patients with a history of recent stroke and ischemic attack, despite lowering of homocysteine levels.
Neuropsychiatric illness 
Studies demonstrate the connection between elevated levels of homocysteine (hyperhomocysteinaemia) and occurrence of Alzheimer's disease (AD) besides other cognitive impairments. Researchers suggest that B-group-vitamin supplementation (including folate) may possibly decrease chances to develop AD. Oxidative stress induced by homocysteine may also play a role in schizophrenia.
Bone health 
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  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.
Homocysteine exists at neutral pH values as a zwitterion.
Biosynthesis and biochemical roles 
Homocysteine is not obtained from the diet. 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.
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-ketobutyrate. 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 N5-methyl tetrahydrofolate as the methyl donor and cobalamin (vitamin B12)-related enzymes. More detail on these enzymes can be found in the article for methionine synthase.
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 by reactions generating oxidative stress.
- Martí-Carvajal AJ, Solà I, Lathyris D, Salanti G (2009). "Homocysteine lowering interventions for preventing cardiovascular events". In Martí-Carvajal, Arturo J. Cochrane Database Syst Rev (4): CD006612. doi:10.1002/14651858.CD006612.pub2. PMID 19821378.
- Martí-Carvajal, AJ; Solà, I; Lathyris, D; Salanti, G (2009-10-07). "Homocysteine lowering interventions for preventing cardiovascular events.". Cochrane database of systematic reviews (Online) (4): CD006612. doi:10.1002/14651858.CD006612.pub2. PMID 19821378.
- Jardine, MJ; Kang, A; Zoungas, S; Navaneethan, SD; Ninomiya, T; Nigwekar, SU; Gallagher, MP; Cass, A; Strippoli, G; Perkovic, V (2012-06-13). "The effect of folic acid based homocysteine lowering on cardiovascular events in people with kidney disease: systematic review and meta-analysis.". BMJ (Clinical research ed.) 344: e3533. PMC 3374481. PMID 22695899.
- Vizzardi, E; Bonadei, I; Zanini, G; Frattini, S; Fiorina, C; Raddino, R; Dei Cas, L (2009 Jan). "Homocysteine and heart failure: an overview.". Recent patents on cardiovascular drug discovery 4 (1): 15–21. PMID 19149701.
- Ahmadieh, H; Arabi, A (2011 Oct). "Vitamins and bone health: beyond calcium and vitamin D.". Nutrition Reviews 69 (10): 584–98. doi:10.1111/j.1753-4887.2011.00372.x. PMID 21967159.
- 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 (5): 1033–1039. PMID 8172087.
- Coen DA Stehouwer, Coen van Guldener (2001). "Homocysteine-lowering treatment: an overview". Expert Opinion on Pharmacotherapy 2 (9): 1449–1460. doi:10.1517/14656518.104.22.1689. PMID 11585023.
- 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. SeeCrichton, Michael (March 19, 2006). "This Essay Breaks the Law". The New York Times (The New York Times Company). Retrieved 2006-03-20.
- According to Professor Melinda M. Manore of Oregon State University's Department of Nutrition and Exercise Sciences,http://www.supplementschat.org/homocysteine-b-vitamins-and-heart-disease.html
- Bleich S, Bleich K, Kropp S, et al. (2001). "Moderate alcohol consumption in social drinkers raises plasma homocysteine levels: a contradiction to the 'French Paradox'?". Alcohol Alcohol. 36 (3): 189–92. PMID 11373253.
- Bleich S, Carl M, Bayerlein K, et al. (March 2005). "Evidence of increased homocysteine levels in alcoholism: the Franconian alcoholism research studies (FARS)". Alcohol. Clin. Exp. Res. 29 (3): 334–6. PMID 15770107.
- The Doctor's Doctor: Homocysteine
- Adëeva Nutritionals Canada > Optimal blood test values Retrieved on July 9, 2009
- Derived from molar values using molar massof 135 g/mol
- "B vitamins do not protect hearts". BBC News (BBC). September 6, 2005. Retrieved 2006-03-20.
- Lonn, E; Yusuf, S; Arnold, MJ; Sheridan, P; Pogue, J; Micks, M; McQueen, MJ; Probstfield, J et al. (2006). "Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease" (PDF). N Engl J Med 354 (15): 1567–77. doi:10.1056/NEJMoa060900. PMID 16531613.
- 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.
- 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" (PDF). N Engl J Med 354 (15): 1578–88. doi:10.1056/NEJMoa055227. PMID 16531614.
- Loscalzo J (2006). "Homocysteine Trials — Clear Outcomes for Complex Reasons". N Engl J Med 354 (15): 1629–1632. doi:10.1056/NEJMe068060. PMID 17224870.
- "B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial". The Lancet Neurology 9 (9): 855–865. 2010. doi:10.1016/S1474-4422(10)70187-3.
- Moris, MS. (July 2003). "Homocysteine and Alzheimer's disease.". Lancet Neurology 2 (7): 425–8. PMID 12849121.
- Smach MA, Jacob N, Golmard JL, et al.; Smach MA, Jacob N, Golmard JL, Charfeddine B, Lammouchi T, Ben Othman L, Dridi H, Bennamou S, Limem K. (2011). "Folate and homocysteine in the cerebrospinal fluid of patients with Alzheimer's disease or dementia: a case control study.". European Neurology 65 (5): 270–8. doi:10.1159/000326301. PMID 21474939.
- Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C et al. (2010). "Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial". PLoS ONE 5 (9): e12244. doi:10.1371/journal.pone.0012244. PMC 2935890. PMID 20838622.
- Dietrich-Muszalska A, Malinowska J, Olas B, et al. (May 2012). "The oxidative stress may be induced by the elevated homocysteine in schizophrenic patients". Neurochem. Res. 37 (5): 1057–62. doi:10.1007/s11064-012-0707-3. PMC 3321271. PMID 22270909.
- McLean RR et al. (2004). "Homocysteine as a predictive factor for hip fracture in older persons". New England Journal of Medicine 350 (20): 2042–2049. doi:10.1056/NEJMoa032739. PMID 15141042.Free text after free registration
- van Meurs JB et al. (2004). "Homocysteine levels and the risk of osteoporotic fracture". New England Journal of Medicine 350 (20): 2033–2041. doi:10.1056/NEJMoa032546. PMID 15141041.Free text after free registration
- 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.
- Selhub, J. (1999). "Homocysteine metabolism". Annual Review of Nutrition 19: 217–246. doi:10.1146/annurev.nutr.19.1.217. PMID 10448523.
- Champe, PC and Harvey, RA. "Biochemistry. Lippincott's Illustrated Reviews" 4th ed. Lippincott Williams and Wilkins, 2008
- Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6.
- Sibrian-Vazquez M, Escobedo JO, Lim S, Samoei GK, Strongin RM (January 2010). "Homocystamides promote free-radical and oxidative damage to proteins". Proc. Natl. Acad. Sci. U.S.A. 107 (2): 551–4. doi:10.1073/pnas.0909737107. PMC 2818928. PMID 20080717.
- Prof. David Spence on homocysteine levels, kidney damage, and cardiovascular disease, The Health Report, Radio National, 24 May 2010