Homocysteine // is a non-proteinogenic α-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 certain B-vitamins.
3D model (JSmol)
|Molar mass||135.18 g/mol|
|Appearance||White crystalline powder|
|Melting point||234–235 °C (453–455 °F; 507–508 K) (decomposes)|
|log P||-2.56 |
|Acidity (pKa)||2.25 |
|GHS Signal word||Warning|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|what is ?)(|
A high level of homocysteine in the blood (hyperhomocysteinemia) makes a person more prone to endothelial cell injury, which leads to inflammation in the blood vessels, which in turn may lead to atherogenesis, which can result in ischemic injury. Hyperhomocysteinemia is therefore a possible risk factor for coronary artery disease. Coronary artery disease occurs when an atherosclerotic plaque blocks blood flow to the coronary arteries, which supply the heart with oxygenated blood.
Hyperhomocysteinemia has been correlated with the occurrence of blood clots, heart attacks and strokes, though it is unclear whether hyperhomocysteinemia is an independent risk factor for these conditions. Hyperhomocysteinemia has also been associated with early pregnancy loss and with neural tube defects.
Homocysteine exists at neutral pH values as a zwitterion.
Biosynthesis and biochemical rolesEdit
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, (e.g., 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 cysteineEdit
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 γ-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.
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 significanceEdit
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.
Homocysteine also acts as an allosteric antagonist at Dopamine D2 receptors. It has been proposed that both homocysteine and its thiolactone may have played a significant role in the appearance of life on the early Earth.
It is decreased with methyl folate trapping, where it is accompanied by decreased methylmalonic acid, increased folate and a decrease in formiminoglutamic acid. This is the opposite of MTHFR C677T mutations, which result in an increase in homocysteine.
|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
The ranges above are provided as examples only; test results should always be interpreted using the range provided by the laboratory that produced the result.
Abnormally high levels of homocysteine in the serum, above 15 µmol/L, are a medical condition called hyperhomocysteinemia. This has been claimed to be a significant risk factor for the development of a wide range of diseases, including thrombosis, neuropsychiatric illness, and fractures. It is also found to be associated with microalbuminuria which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction. Vitamin B12 deficiency, when coupled with high serum folate levels, has been found to increase overall homocysteine concentrations as well.
- Chalcraft, Kenneth R.; Lee, Richard; Mills, Casandra; Britz-McKibbin, Philip (2009). "Virtual Quantification of Metabolites by Capillary Electrophoresis-Electrospray Ionization-Mass Spectrometry: Predicting Ionization Efficiency Without Chemical Standards". Analytical Chemistry. 81 (7): 2506–2515. doi:10.1021/ac802272u. PMID 19275147.
- Allen, Milton J.; Steinman, Harry G. (1952). "The Electrolytic Reduction of Homocystine at a Controlled Reference Potential". Journal of the American Chemical Society. 74 (15): 3932–3933. doi:10.1021/ja01135a502.
- Boudi, Brian F. "Noncoronary Atherosclerosis". Medscape. Archived from the original on 2013-05-11.
- Nelen WL, Blom HJ, Steegers EA, den Heijer M, Thomas CM, Eskes TK (2000). "Homocysteine and folate levels as risk factors for recurrent early pregnancy loss". Obstet Gynecol. 95 (4): 519–24. doi:10.1016/s0029-7844(99)00610-9. PMID 10725483.
- van der Put NJ et al Folate, Homocysteine and Neural Tube Defects: An Overview Archived 2015-09-16 at the Wayback Machine Exp Biol Med (Maywood) April 2001 vol. 226 no. 4 243-270
- 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.
- Agnati, LF; Ferré, S; Genedani, S; Leo, G; Guidolin, D; Filaferro, M; Carriba, P; Casadó, V; Lluis, C; Franco, R; Woods, AS; Fuxe, K (Nov 2006). "Allosteric modulation of dopamine D2 receptors by homocysteine" (PDF). Journal of Proteome Research. 5 (11): 3077–83. CiteSeerX 10.1.1.625.26. doi:10.1021/pr0601382. PMID 17081059. Archived (PDF) from the original on 2017-08-09.
- Vallee, Yannick; Shalayel, Ibrahim; Ly, Kieu-Dung; Rao, K. V. Raghavendra; Paëpe, Gael De; Märker, Katharina; Milet, Anne (2017-11-08). "At the very beginning of life on Earth: the thiol-rich peptide (TRP) world hypothesis". International Journal of Developmental Biology. 61 (8–9). ISSN 0214-6282.
- Nygård, O; Vollset, SE; Refsum, H; Stensvold, I; Tverdal, A; Nordrehaug, JE; Ueland, M; Kvåle, G (Nov 15, 1995). "Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study". JAMA: The Journal of the American Medical Association. 274 (19): 1526–33. doi:10.1001/jama.274.19.1526. PMID 7474221.
- Refsum, H; Nurk, E; Smith, AD; Ueland, PM; Gjesdal, CG; Bjelland, I; Tverdal, A; Tell, GS; Nygård, O; Vollset, SE (June 2006). "The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease". The Journal of Nutrition. 136 (6 Suppl): 1731S–1740S. doi:10.1093/jn/136.6.1731S. PMID 16702348.
- Bots, Michiel L.; Launer, Lenore J.; Lindemans, Jan; Hoes, Arno W.; Hofman, Albert; Witteman, Jacqueline C. M.; Koudstaal, Peter J.; Grobbee, Diederick E. (1999-01-11). "Homocysteine and Short-term Risk of Myocardial Infarction and Stroke in the Elderly". Archives of Internal Medicine. 159 (1): 38–44. doi:10.1001/archinte.159.1.38. ISSN 0003-9926. PMID 9892328.
- Selhub, J.; Jacques, P. F.; Bostom, A. G.; Wilson, P. W.; Rosenberg, I. H. (2000). "Relationship between plasma homocysteine and vitamin status in the Framingham study population. Impact of folic acid fortification". Public Health Reviews. 28 (1–4): 117–145. ISSN 0301-0422. PMID 11411265.
- Scott, JohnM.; Weir, DonaldG. (15 August 1981). "THE METHYL FOLATE TRAP: A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid-induced exacerbation of subacute combined degeneration in pernicious anaemia". The Lancet. 318 (8242): 337–340. doi:10.1016/S0140-6736(81)90650-4. ISSN 0140-6736. PMID 6115113.
- "Homocysteine". www.thedoctorsdoctor.com. Archived from the original on 2008-12-05.
- Adëeva Nutritionals Canada > Optimal blood test values Archived 2009-05-29 at the Wayback Machine Retrieved on July 9, 2009
- Derived from molar values using molar massof 135 g/mol
- "Hyperhomocysteinemia - Hematology and Oncology - Merck Manuals Professional Edition". merckmanuals.com. Archived from the original on 2017-06-09.
- Cattaneo, M (February 1999). "Hyperhomocysteinemia, atherosclerosis and thrombosis". Thrombosis and Haemostasis. 81 (2): 165–76. doi:10.1055/s-0037-1614438. PMID 10063987.
- Morris, MS (July 2003). "Homocysteine and Alzheimer's disease". Lancet Neurology. 2 (7): 425–8. doi:10.1016/s1474-4422(03)00438-1. PMID 12849121.
- 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; Agacinski, G; Oulhaj, A; Bradley, KM; Jacoby, R; Refsum, H (Sep 8, 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; Głowacki, R; Bald, E; Wachowicz, B; Rabe-Jabłońska, J (May 2012). "The oxidative stress may be induced by the elevated homocysteine in schizophrenic patients". Neurochemical Research. 37 (5): 1057–62. doi:10.1007/s11064-012-0707-3. PMC 3321271. PMID 22270909.
- McLean, RR; Jacques, PF; Selhub, J; Tucker, KL; Samelson, EJ; Broe, KE; Hannan, MT; Cupples, LA; Kiel, DP (May 13, 2004). "Homocysteine as a predictive factor for hip fracture in older persons". The New England Journal of Medicine. 350 (20): 2042–9. doi:10.1056/NEJMoa032739. PMID 15141042.
- van Meurs, JB; Dhonukshe-Rutten, RA; Pluijm, SM; van der Klift, M; de Jonge, R; Lindemans, J; de Groot, LC; Hofman, A; Witteman, JC; van Leeuwen, JP; Breteler, MM; Lips, P; Pols, HA; Uitterlinden, AG (May 13, 2004). "Homocysteine levels and the risk of osteoporotic fracture". The New England Journal of Medicine. 350 (20): 2033–41. doi:10.1056/NEJMoa032546. hdl:1765/8452. PMID 15141041.
- Jager, A; Kostense, PJ; Nijpels, G; Dekker, JM; Heine, RJ; Bouter, LM; Donker, AJ; Stehouwer, CD (Jan 2001). "Serum homocysteine levels are associated with the development of (micro)albuminuria: the Hoorn study". Arteriosclerosis, Thrombosis, and Vascular Biology. 21 (1): 74–81. doi:10.1161/01.ATV.21.1.74. PMID 11145936.
- Selhub, J.; Morris, M. S.; Jacques, P. F. (2007-12-04). "In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations". Proceedings of the National Academy of Sciences. 104 (50): 19995–20000. doi:10.1073/pnas.0709487104. ISSN 0027-8424. PMC 2148411. PMID 18056804.
- Homocysteine MS Spectrum
- Homocysteine at Lab Tests Online
- Homocysteine: analyte monograph[permanent dead link] - The Association for Clinical Biochemistry and Laboratory Medicine
- Prof. David Spence on homocysteine levels, kidney damage, and cardiovascular disease, The Health Report, Radio National, 24 May 2010