Homocysteine

Homocysteine
Names
IUPAC name
2-Amino-4-sulfanylbutanoic acid
Identifiers
CAS Number
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.006.567
Edit this at Wikidata
EC Number
  • 207-222-9
KEGG
PubChem CID
UNII
InChI
  • InChI=1S/C4H9NO2S/c5-3(1-2-8)4(6)7/h3,8H,1-2,5H2,(H,6,7) checkY
    Key: FFFHZYDWPBMWHY-UHFFFAOYSA-N checkY
  • InChI=1/C4H9NO2S/c5-3(1-2-8)4(6)7/h3,8H,1-2,5H2,(H,6,7)
    Key: FFFHZYDWPBMWHY-UHFFFAOYAS
SMILES
  • C(CS)C(C(=O)O)N
Properties
Chemical formula
 C4H9NO2S
Molar mass 135.18 g/mol
Appearance White crystalline powder
Melting point 234–235 °C (453–455 °F; 507–508 K)[1] (decomposes)
Solubility in water
 soluble
log P -2.56 [2]
Acidity (pKa) 2.25 [2]
Hazards
GHS labelling:
Pictograms
Signal word
 Warning
Hazard statements
 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

Homocysteine /ˌhoʊmoʊˈsɪstiːn/ 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 certain B-vitamins.

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.[3] [4]

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

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.[8] 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.[9]

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.[10]

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.[11]

Homocysteine also acts as an allosteric antagonist at Dopamine D2 receptors.[12]

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.[13]

Homocysteine levels

Total plasma homocysteine

Homocysteine levels typically are higher in men than women, and increase with age.[14][15]

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).[16][17]

It is decreased with methyl folate trapping, where it is accompanied by decreased methylmalonic acid, increased folate, and a decrease in formiminoglutamic acid.[18] This is the opposite of MTHFR C677T mutations, which result in an increase in homocysteine.

Blood reference ranges for homocysteine:
SexAgeLower limitUpper limitUnitElevatedTherapeutic target
Female12–19 years3.3[19]7.2[19]μmol/L> 10.4 μmol/L
or
> 140 μg/dl		< 6.3 μmol/L[20]
or
< 85 μg/dL[20]
45[21]100[21]μg/dL
>60 years4.9[19]11.6[19]μmol/L
66[21]160[21]μg/dL
Male12–19 years4.3[19]9.9[19]μmol/L> 11.4 μmol/L
or
> 150 μg/dL
60[21]130[21]μg/dL
>60 years5.9[19]15.3[19]μmol/L

+ |-

80[21]210[21]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

Abnormally high levels of homocysteine in the serum, above 15 μmol/L, are a medical condition called hyperhomocysteinemia.[22] This has been claimed to be a significant risk factor for the development of a wide range of diseases, including thrombosis,[23] neuropsychiatric illness,[24][25][26][27] and fractures.[28][29] It also is found to be associated with microalbuminuria, which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction.[30] Vitamin B12 deficiency, when coupled with high serum folate levels, has been found to increase overall homocysteine concentrations as well.[31]

Typically, Hyperhomocysteinemia is managed with vitamin B6, vitamin B9, and vitamin B12 supplementation.[32] However, supplementation with these vitamins does not appear to improve cardiovascular disease outcomes.[33]

References

  1. ↑ 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.
  2. 1 2 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.
  3. ↑ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ↑ Boudi, Brian F. "Noncoronary Atherosclerosis". Medscape. Archived from the original on 2013-05-11.
  5. ↑ Homocysteine: The Facts, Tufts Health and Nutrition Letter, July 31, 2020 update
  6. ↑ 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. S2CID 26125655.
  7. ↑ 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
  8. ↑ Selhub, J. (1999). "Homocysteine metabolism". Annual Review of Nutrition. 19: 217–246. doi:10.1146/annurev.nutr.19.1.217. PMID 10448523. S2CID 2335090.
  9. ↑ Champe, PC and Harvey, RA. "Biochemistry. Lippincott's Illustrated Reviews" 4th ed. Lippincott Williams and Wilkins, 2008
  10. ↑ Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6.
  11. ↑ 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. Bibcode:2010PNAS..107..551S. doi:10.1073/pnas.0909737107. PMC 2818928. PMID 20080717.
  12. ↑ 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.
  13. ↑ 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): 471–478. doi:10.1387/ijdb.170028yv. ISSN 0214-6282. PMID 29139533.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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. S2CID 29977127.
  19. 1 2 3 4 5 6 7 8 "Homocysteine". www.thedoctorsdoctor.com. Archived from the original on 2008-12-05. Retrieved 2008-11-22.
  20. 1 2 Adëeva Nutritionals Canada > Optimal blood test values Archived 2009-05-29 at the Wayback Machine Retrieved on July 9, 2009
  21. 1 2 3 4 5 6 7 8 Derived from molar values using molar massof 135 g/mol
  22. ↑ "Hyperhomocysteinemia - Hematology and Oncology - Merck Manuals Professional Edition". merckmanuals.com. Archived from the original on 2017-06-09.
  23. ↑ Cattaneo, M (February 1999). "Hyperhomocysteinemia, atherosclerosis and thrombosis". Thrombosis and Haemostasis. 81 (2): 165–76. doi:10.1055/s-0037-1614438. PMID 10063987.
  24. ↑ 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. S2CID 20443022.
  25. ↑ 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. S2CID 7689901.
  26. ↑ 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. Bibcode:2010PLoSO...512244S. doi:10.1371/journal.pone.0012244. PMC 2935890. PMID 20838622.
  27. ↑ 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.
  28. ↑ 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. S2CID 22853996.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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. Bibcode:2007PNAS..10419995S. doi:10.1073/pnas.0709487104. ISSN 0027-8424. PMC 2148411. PMID 18056804.
  32. ↑ 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. S2CID 45945199.
  33. ↑ 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. PMC 4164174. PMID 25590290.
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