Chemistry:Homocysteine

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Homocysteine
Skeletal formula
Ball-and-stick model
Names
IUPAC name
2-Amino-4-sulfanylbutanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
EC Number
  • 207-222-9
KEGG
UNII
Properties
C4H9NO2S
Molar mass 135.18 g/mol
Appearance White crystalline powder
Melting point 234–235 °C (453–455 °F; 507–508 K)[2] (decomposes)
soluble
log P -2.56 [1]
Acidity (pKa) 2.25 [1]
Hazards
GHS pictograms GHS07: Harmful
GHS Signal word Warning
H302
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Tracking categories (test):

Homocysteine (/ˌhoʊmoʊˈsɪstiːn/) 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.[3]

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.[4][5]

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.[6] Hyperhomocysteinemia also has been associated with early-term spontaneous abortions[7] and with neural tube defects.[8]

Structure

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

Homocysteine exists at neutral pH values as a zwitterion.

Biosynthesis and biochemical roles

Two of homocysteine's main biochemical roles - (Homocysteine is seen in the left middle of the image.) It can be synthesized from methionine and then converted back to methionine via the SAM cycle or used to create cysteine and alpha-ketobutyrate.

Homocysteine is biosynthesized naturally via a multi-step process.[9] 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.[10]

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.[11]

MTHFR metabolism: folate cycle, methionine cycle, trans-sulfuration and hyperhomocysteinemia - 5-MTHF: 5-methyltetrahydrofolate; 5,10-methyltetrahydrofolate; BAX: Bcl-2-associated X protein; BHMT: betaine-homocysteine S-methyltransferase; CBS: cystathionine beta synthase; CGL: cystathionine gamma-lyase; DHF: dihydrofolate (vitamin B9); DMG: dimethylglycine; dTMP: thymidine monophosphate; dUMP: deoxyuridine monophosphate; FAD+ flavine adenine dicucleotide; FTHF: 10-formyltetrahydrofolate; MS: methionine synthase; MTHFR: mehtylenetetrahydrofolate reductase; SAH: S-adenosyl-L-homocysteine; SAME: S-adenosyl-L-methionine; THF: tetrahydrofolate

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.[12]

Homocysteine also acts as an allosteric antagonist at Dopamine D2 receptors.[13]

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.[14]

Homocysteine levels

Total plasma homocysteine

Homocysteine levels typically are higher in men than women, and increase with age.[15][16]

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).[17][18]

It is decreased with methyl folate trapping, where it is accompanied by decreased methylmalonic acid, increased folate, and a decrease in formiminoglutamic acid.[19] This is the opposite of MTHFR C677T mutations, which result in an increase in homocysteine.[citation needed]

Blood reference ranges for homocysteine:
Sex Age Lower limit Upper limit Unit Elevated Therapeutic target
Female 12–19 years 3.3[20] 7.2[20] μmol/L > 10.4 μmol/L
or
> 140 μg/dl		 < 6.3 μmol/L[21]
or
< 85 μg/dL[21]
45[22] 100[22] μg/dL
>60 years 4.9[20] 11.6[20] μmol/L
66[22] 160[22] μg/dL
Male 12–19 years 4.3[20] 9.9[20] μmol/L > 11.4 μmol/L
or
> 150 μg/dL
60[22] 130[22] μg/dL
>60 years 5.9[20] 15.3[20] μmol/L
80[22] 210[22] 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

Main page: Medicine:Hyperhomocysteinemia

Abnormally high levels of homocysteine in the serum, above 15 μmol/L, are a medical condition called hyperhomocysteinemia.[23] This has been claimed to be a significant risk factor for the development of a wide range of diseases, including thrombosis,[24] neuropsychiatric illness,[25][26][27][28] and fractures.[29][30] It also is found to be associated with microalbuminuria, which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction.[31] Vitamin B12 deficiency, when coupled with high serum folate levels, has been found to increase overall homocysteine concentrations as well.[32]

Typically, hyperhomocysteinemia is managed with vitamin B6, vitamin B9, and vitamin B12 supplementation.[33] However, supplementation with these vitamins does not appear to improve cardiovascular disease outcomes.[34]

References

  1. ↑ 1.0 1.1 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. 
  2. ↑ 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. 
  3. ↑ "Homocysteine". https://dmec.moh.gov.vn/documents/10182/31934092/upload_00034511_1656320270953.pdf?version=1.0&fileId=31960513. 
  4. ↑ Kim J, Kim H, Roh H, Kwon Y (2018). "Causes of hyperhomocysteinemia and its pathological significance.". Arch Pharm Res 41 (4): 372–383. doi:10.1007/s12272-018-1016-4. PMID 29552692. https://pubmed.ncbi.nlm.nih.gov/29552692. 
  5. ↑ Boudi, Brian F. "Noncoronary Atherosclerosis". Medscape. http://emedicine.medscape.com/article/1950759-overview#aw2aab6b3. 
  6. ↑ Homocysteine: The Facts, Tufts Health and Nutrition Letter, July 31, 2020 update
  7. ↑ "Homocysteine and folate levels as risk factors for recurrent early pregnancy loss". Obstet Gynecol 95 (4): 519–24. 2000. doi:10.1016/s0029-7844(99)00610-9. PMID 10725483. 
  8. ↑ 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
  9. ↑ Selhub, J. (1999). "Homocysteine metabolism". Annual Review of Nutrition 19: 217–246. doi:10.1146/annurev.nutr.19.1.217. PMID 10448523. 
  10. ↑ Champe, PC and Harvey, RA. "Biochemistry. Lippincott's Illustrated Reviews" 4th ed. Lippincott Williams and Wilkins, 2008
  11. ↑ Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN:1-57259-153-6.
  12. ↑ "Homocystamides promote free-radical and oxidative damage to proteins". Proc. Natl. Acad. Sci. U.S.A. 107 (2): 551–4. January 2010. doi:10.1073/pnas.0909737107. PMID 20080717. Bibcode: 2010PNAS..107..551S. 
  13. ↑ Agnati, LF; Ferré, S; Genedani, S; Leo, G; Guidolin, D; Filaferro, M; Carriba, P; Casadó, V et al. (Nov 2006). "Allosteric modulation of dopamine D2 receptors by homocysteine". Journal of Proteome Research 5 (11): 3077–83. doi:10.1021/pr0601382. PMID 17081059. http://www.cigs.unimo.it/cigsdownloads/labs/cnf_sp2/pubblicazioni/19-agnati%20allosteric%20modulation.pdf. 
  14. ↑ 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" (in en). International Journal of Developmental Biology 61 (8–9): 471–478. doi:10.1387/ijdb.170028yv. ISSN 0214-6282. PMID 29139533. http://www.ijdb.ehu.es/web/paper/170028yv/at-the-very-beginning-of-life-on-earth-the-thiol-rich-peptide-trp-world-hypothesis. 
  15. ↑ 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. 
  16. ↑ Refsum, H; Nurk, E; Smith, AD; Ueland, PM; Gjesdal, CG; Bjelland, I; Tverdal, A; Tell, GS et al. (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. 
  17. ↑ 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" (in en). Archives of Internal Medicine 159 (1): 38–44. doi:10.1001/archinte.159.1.38. ISSN 0003-9926. PMID 9892328. 
  18. ↑ 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. 
  19. ↑ 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. 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 "Homocysteine". http://www.thedoctorsdoctor.com/labtests/homocysteine.htm. 
  21. ↑ 21.0 21.1 Adëeva Nutritionals Canada > Optimal blood test values Retrieved on July 9, 2009
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 22.6 22.7 Derived from molar values using molar massof 135 g/mol
  23. ↑ "Hyperhomocysteinemia - Hematology and Oncology - Merck Manuals Professional Edition". http://www.merckmanuals.com/professional/hematology-and-oncology/thrombotic-disorders/hyperhomocysteinemia#v12779073. 
  24. ↑ Cattaneo, M (February 1999). "Hyperhomocysteinemia, atherosclerosis and thrombosis". Thrombosis and Haemostasis 81 (2): 165–76. doi:10.1055/s-0037-1614438. PMID 10063987. 
  25. ↑ 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. 
  26. ↑ Smach, MA; Jacob, N; Golmard, JL; Charfeddine, B; Lammouchi, T; Ben Othman, L; Dridi, H; Bennamou, S et al. (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. 
  27. ↑ Smith, AD; Smith, SM; de Jager, CA; Whitbread, P; Johnston, C; Agacinski, G; Oulhaj, A; Bradley, KM et al. (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. PMID 20838622. Bibcode: 2010PLoSO...512244S. 
  28. ↑ 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. PMID 22270909. 
  29. ↑ McLean, RR; Jacques, PF; Selhub, J; Tucker, KL; Samelson, EJ; Broe, KE; Hannan, MT; Cupples, LA et al. (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. 
  30. ↑ van Meurs, JB; Dhonukshe-Rutten, RA; Pluijm, SM; van der Klift, M; de Jonge, R; Lindemans, J; de Groot, LC; Hofman, A et al. (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. PMID 15141041. http://repub.eur.nl/pub/8452. 
  31. ↑ 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. 
  32. ↑ 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. PMID 18056804. Bibcode: 2007PNAS..10419995S. 
  33. ↑ Stehouwer, Coen DA; Guldener, Coen van (2005). "Homocysteine-lowering treatment: An overview". Expert Opinion on Pharmacotherapy 2 (9): 1449–60. doi:10.1517/14656566.2.9.1449. PMID 11585023. 
  34. ↑ Martí-Carvajal, Arturo J.; Solà, Ivan; Lathyris, Dimitrios (15 January 2015). Martí-Carvajal, Arturo J. ed. "Homocysteine-lowering interventions for preventing cardiovascular events". The Cochrane Database of Systematic Reviews 1: CD006612. doi:10.1002/14651858.CD006612.pub4. ISSN 1469-493X. PMID 25590290. 

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