Homocysteine Explained

Homocysteine should not be confused with homocystine.

Homocysteine or Hcy: 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. In the body, homocysteine can be recycled into methionine or converted into cysteine with the aid of vitamin B6, B9, and B12.[1]

High levels of homocysteine in the blood (hyperhomocysteinemia) is regarded as a marker of cardiovascular disease, likely working through atherogenesis, which can result in ischemic injury. Therefore, hyperhomocysteinemia is 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.[2] [3]

Hyperhomocysteinemia has been correlated with the occurrence of blood clots, heart attacks, and strokes, although it is unclear whether hyperhomocysteinemia is an independent risk factor for these conditions.[4] Hyperhomocysteinemia also has been associated with early-term spontaneous abortions[5] and with neural tube defects.[6]

Structure

Homocysteine exists at neutral pH values as a zwitterion.

Biosynthesis and biochemical roles

Homocysteine is biosynthesized naturally via a multi-step process.[7] First, methionine receives an adenosine group from ATP, a reaction catalyzed by S-adenosyl-methionine synthetase, to give S-adenosyl methionine (SAM-e). SAM-e 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.[8]

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 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.[9]

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.[10]

Homocysteine also acts as an allosteric antagonist at Dopamine D2 receptors.[11]

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.[12]

Homocysteine levels

Homocysteine levels typically are higher in men than women, and increase with age.[13] [14]

Common levels in Western populations are 10 to 12 μmol/L, and levels of 20 μmol/L are found in populations with low B-vitamin intakes or in the elderly (e.g., Rotterdam, Framingham).[15] [16]

It is decreased with methyl folate trapping, where it is accompanied by decreased methylmalonic acid, increased folate, and a decrease in formiminoglutamic acid.[17] This is the opposite of MTHFR C677T mutations, which result in an increase in homocysteine.

Blood reference ranges for homocysteine:
- SexAgeLower limitUpper limitUnitElevatedTherapeutic target - Female 12–19 years 3.3[18] 7.2 μmol/L > 10.4 μmol/L
or
> 140 μg/dl 		< 6.3 μmol/L[19]
or
< 85 μg/dL 		- 45[20] 100 μg/dL - >60 years 4.9 11.6 μmol/L - 66 160 μg/dL - Male 12–19 years 4.3 9.9 μmol/L > 11.4 μmol/L
or
> 150 μg/dL 		- 60 130 μg/dL - >60 years 5.9 15.3 μmol/L - 80 210 μg/dL -
The ranges above are provided as examples only; test results always should be interpreted using the range provided by the laboratory that produced the result.

Elevated homocysteine

See main article: Hyperhomocysteinemia. Abnormally high levels of homocysteine in the serum, above 15 μmol/L, are a medical condition called hyperhomocysteinemia.[21] This has been claimed to be a significant risk factor for the development of a wide range of diseases, including thrombosis,[22] neuropsychiatric illness,[23] [24] [25] [26] and fractures.[27] [28] It also is found to be associated with microalbuminuria, which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction.[29] Vitamin B12 deficiency, when coupled with high serum folate levels, has been found to increase overall homocysteine concentrations as well.[30]

Typically, hyperhomocysteinemia is managed with vitamin B6, vitamin B9, and vitamin B12 supplementation.[31] However, supplementation with these vitamins does not appear to improve cardiovascular disease outcomes.[32]

External links

Notes and References

  1. Web site: Homocysteine. 5 April 2023. moh.gov.vn.
  2. Kim J, Kim H, Roh H, Kwon Y. Causes of hyperhomocysteinemia and its pathological significance. . Arch Pharm Res . 2018 . 41 . 4 . 372–383 . 29552692 . 10.1007/s12272-018-1016-4 . 3986295 .
  3. Web site: Boudi. Brian F. Noncoronary Atherosclerosis. Medscape. live. https://web.archive.org/web/20130511074608/http://emedicine.medscape.com/article/1950759-overview#aw2aab6b3. 2013-05-11.
  4. Homocysteine: The Facts, Tufts Health and Nutrition Letter, July 31, 2020 update
  5. 10725483 . 95 . 4 . Homocysteine and folate levels as risk factors for recurrent early pregnancy loss . Nelen WL, Blom HJ, Steegers EA, den Heijer M, Thomas CM, Eskes TK . Obstet Gynecol . 519–24 . 10.1016/s0029-7844(99)00610-9. 2000 . 26125655 .
  6. van der Put NJ et al Folate, Homocysteine and Neural Tube Defects: An Overview Exp Biol Med (Maywood) April 2001 vol. 226 no. 4 243-270
  7. Selhub, J. . Homocysteine metabolism . Annual Review of Nutrition . 1999 . 19 . 217–246 . 10448523 . 10.1146/annurev.nutr.19.1.217. 2335090 .
  8. Champe, PC and Harvey, RA. "Biochemistry. Lippincott's Illustrated Reviews" 4th ed. Lippincott Williams and Wilkins, 2008
  9. Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. .
  10. 20080717 . 10.1073/pnas.0909737107 . 107 . 2 . Homocystamides promote free-radical and oxidative damage to proteins . 2818928 . January 2010 . Sibrian-Vazquez M, Escobedo JO, Lim S, Samoei GK, Strongin RM . Proc. Natl. Acad. Sci. U.S.A. . 551–4 . 2010PNAS..107..551S . free .
  11. Agnati. LF. Ferré, S. Genedani, S. Leo, G. Guidolin, D. Filaferro, M. Carriba, P. Casadó, V. Lluis, C. Franco, R. Woods, AS. Fuxe, K. Allosteric modulation of dopamine D2 receptors by homocysteine. Journal of Proteome Research. Nov 2006. 5. 11. 3077–83. 17081059. 10.1021/pr0601382. live. https://web.archive.org/web/20170809142808/http://www.cigs.unimo.it/CigsDownloads/labs/cnf_sp2/pubblicazioni/19-Agnati%20allosteric%20modulation.pdf. 2017-08-09. 10.1.1.625.26.
  12. 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. en. 61. 8–9. 471–478. 10.1387/ijdb.170028yv. 29139533. 0214-6282. free.
  13. Nygård. O. Vollset, SE . Refsum, H . Stensvold, I . Tverdal, A . Nordrehaug, JE . Ueland, M . Kvåle, G . Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA: The Journal of the American Medical Association. Nov 15, 1995. 274. 19. 1526–33. 7474221. 10.1001/jama.274.19.1526.
  14. Refsum. H. Nurk, E . Smith, AD . Ueland, PM . Gjesdal, CG . Bjelland, I . Tverdal, A . Tell, GS . Nygård, O . Vollset, SE . The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. The Journal of Nutrition. June 2006. 136. 6 Suppl. 1731S–1740S. 16702348. 10.1093/jn/136.6.1731S. free.
  15. 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. en. 159. 1. 38–44. 10.1001/archinte.159.1.38. 9892328. 0003-9926. free. 1765/55858. free.
  16. 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. 0301-0422. 11411265.
  17. Scott . JohnM. . Weir . DonaldG. . 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 . 15 August 1981 . 318 . 8242 . 337–340 . 10.1016/S0140-6736(81)90650-4 . 6115113 . 29977127 . 0140-6736.
  18. Web site: Homocysteine. www.thedoctorsdoctor.com. dead. https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm. 2008-12-05. 2008-11-22.
  19. http://www.adeeva.com/resources/bloodtestscomplete.html Adëeva Nutritionals Canada > Optimal blood test values
  20. Derived from molar values using molar massof 135 g/mol
  21. Web site: Hyperhomocysteinemia - Hematology and Oncology - Merck Manuals Professional Edition. merckmanuals.com. live. https://web.archive.org/web/20170609083346/http://www.merckmanuals.com/professional/hematology-and-oncology/thrombotic-disorders/hyperhomocysteinemia#v12779073. 2017-06-09.
  22. Cattaneo. M. Hyperhomocysteinemia, atherosclerosis and thrombosis. Thrombosis and Haemostasis. February 1999. 81. 2. 165–76. 10063987. 10.1055/s-0037-1614438. 13228673.
  23. Morris. MS. Homocysteine and Alzheimer's disease. Lancet Neurology. July 2003. 2. 7. 425–8. 12849121. 10.1016/s1474-4422(03)00438-1. 20443022.
  24. Smach . MA . Jacob . N . Golmard . JL . Charfeddine . B . Lammouchi . T . Ben Othman . L . Dridi . H . Bennamou . S . Limem . K . Folate and homocysteine in the cerebrospinal fluid of patients with Alzheimer's disease or dementia: a case control study . European Neurology . 2011 . 65 . 5 . 270–8 . 21474939 . 10.1159/000326301. 7689901 .
  25. Smith . AD . Smith . SM . de Jager . CA . Whitbread . P . Johnston . C . Agacinski . G . Oulhaj . A . Bradley . KM . Jacoby . R . Refsum . H . Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial . PLOS ONE . Sep 8, 2010 . 5 . 9 . e12244 . 20838622 . 10.1371/journal.pone.0012244 . 2935890. 2010PLoSO...512244S . free .
  26. Dietrich-Muszalska. A. Malinowska, J . Olas, B . Głowacki, R . Bald, E . Wachowicz, B . Rabe-Jabłońska, J . The oxidative stress may be induced by the elevated homocysteine in schizophrenic patients. Neurochemical Research. May 2012. 37. 5. 1057–62. 22270909. 10.1007/s11064-012-0707-3. 3321271.
  27. McLean. RR. Jacques, PF . Selhub, J . Tucker, KL . Samelson, EJ . Broe, KE . Hannan, MT . Cupples, LA . Kiel, DP . Homocysteine as a predictive factor for hip fracture in older persons. The New England Journal of Medicine. May 13, 2004. 350. 20. 2042–9. 15141042. 10.1056/NEJMoa032739. 22853996. free.
  28. 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 . Homocysteine levels and the risk of osteoporotic fracture . The New England Journal of Medicine . May 13, 2004 . 350 . 20 . 2033–41 . 15141041 . 10.1056/NEJMoa032546. 1765/8452 . free .
  29. Jager . A . Kostense . PJ . Nijpels . G . Dekker . JM . Heine . RJ . Bouter . LM . Donker . AJ . Stehouwer . CD . Serum homocysteine levels are associated with the development of (micro)albuminuria: the Hoorn study . Arteriosclerosis, Thrombosis, and Vascular Biology . Jan 2001 . 21 . 1 . 74–81 . 10.1161/01.ATV.21.1.74 . 11145936. free .
  30. 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. 10.1073/pnas.0709487104. 18056804. 2148411. 2007PNAS..10419995S. 0027-8424. free.
  31. 10.1517/14656566.2.9.1449 . 11585023 . Homocysteine-lowering treatment: An overview . Expert Opinion on Pharmacotherapy . 2 . 9 . 1449–60 . 2005 . Stehouwer . Coen DA . Guldener . Coen van . 45945199 .
  32. Martí-Carvajal. Arturo J.. Solà. Ivan. Lathyris. Dimitrios. 15 January 2015. Martí-Carvajal. Arturo J. Homocysteine-lowering interventions for preventing cardiovascular events. The Cochrane Database of Systematic Reviews. 1. CD006612. 10.1002/14651858.CD006612.pub4. 1469-493X. 4164174. 25590290.

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