Homocysteine

Homocysteine
Structural formula
Structural formula
Ball-and-stick model
Ball-and-stick model
Names
IUPAC name
2-Amino-4-sulfanylbutanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.006.567 Edit this at Wikidata
EC Number
  • 207-222-9
KEGG
UNII
  • 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
  • C(CS)C(C(=O)O)N
Properties
C4H9NO2S
Molar mass 135.18 g·mol−1
Appearance White crystalline powder
Melting point 234–235 °C (453–455 °F; 507–508 K) (decomposes)
soluble
log P −2.56
Acidity (pKa) 2.25
Hazards
GHS labelling:
GHS07: Exclamation mark
Warning
H302
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X markN verify (what is checkYX markN ?)

Homocysteine (symbol 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.

Although the production of homocysteine is a normal part of the metabolism of methionine, an excess of homocysteine can be harmful. There are two primary ways for organisms such as humans to metabolize homocysteine: remethylation and transsulfuration.

Remethylation adds a methyl group to the homocysteine molecule, converting homocysteine back into methionine. There are two known remethylation pathways. One pathway requires vitamin B9 (folate) and B12 (cobalamin), which drive the MTR (methionine synthase) and MTRR (methionine synthase reductase) enzymes. The other pathway uses TMG (trimethylglycine) to drive the BHMT (betaine-homocysteine methyltransferase) enzyme.

Transsulfuration converts homocysteine to cystathionine. This pathway requires vitamin B6 to drive the CBS (cystathionine beta synthase) enzyme. Cystathionine is the immediate precursor of the amino acid cysteine, which (along with glutamate and glycine), is incorporated into the tripeptide glutathione, a major antioxidant in the human body.

Homocysteine is therefore an important metabolic substrate. However, excessive levels of homocysteine can result in hyperhomocysteinemia, which is regarded as an indicator of cardiovascular disease risk. Homocysteine likely contributes to 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. Hyperhomocysteinemia has also 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. Hyperhomocysteinemia has also been associated with early-term spontaneous abortions and with neural tube defects.

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

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. First, methionine receives an adenosine group from ATP, a reaction catalyzed by S-adenosyl-methionine synthetase, to give S-adenosyl methionine (SAM). SAM is a widely used source of methyl radicals and a cofactor for radical SAM enzymes. Transfer of the methyl group to an acceptor molecule results in the formation of S-adenosyl-homocysteine. Hydrolysis of this thioether gives L-homocysteine. L-Homocysteine reacts with tetrahydrofolate (THF) to give L-methionine.[clarification needed]

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 Pyridoxal phosphate (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.

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 Methylcobalamin (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.

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.

Homocysteine levels

Total plasma homocysteine

Homocysteine levels typically are higher in men than women, and increase with age.

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).

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.[citation needed]

Blood reference ranges for homocysteine:
SexAgeLower limitUpper limitUnitElevatedTherapeutic target
Female12–19 years3.37.2μmol/L> 10.4 μmol/L
or
> 140 μg/dl		< 6.3 μmol/L
or
< 85 μg/dL
45100μg/dL
>60 years4.911.6μmol/L
66160μg/dL
Male12–19 years4.39.9μmol/L> 11.4 μmol/L
or
> 150 μg/dL
60130μg/dL
>60 years5.915.3μmol/L
80210μg/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. This has been claimed to be a significant risk factor for the development of a wide range of diseases, in total more than 100 including thrombosis, neuropsychiatric illness, in particular dementia and fractures. It also is found to be associated with microalbuminuria (moderately increased albuminuria), which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction. Vitamin B12 deficiency, even when coupled with high serum folate levels, has been found to increase overall homocysteine concentrations as well.

Typically, hyperhomocysteinemia is managed with vitamin B6, vitamin B9, and vitamin B12 supplementation. However, supplementation with these vitamins does not appear to improve cardiovascular disease outcomes. An important consideration when specifically supplementing with folic acid (vitamin B9) is to use a lower dosage. Over-supplementation with folic acid may produce negative health effects, including increased risk of cardiovascular disease and the development of cancer. It has been shown that the ideal dose of folic acid for lowering homocysteine levels is up to 1.2 mg per day. Higher dosages do not result in a greater decrease of homocysteine levels in the general population, which excludes individuals with certain mutations in the MTHFR gene.

Certain mutations in the MTR, MTHFR, and MTRR enzymes can cause hyperhomocysteinemia. This can be treated by supplementation with Methylfolate, P5P, and methylcobalamin, which are the bioactive forms of folate, Vitamin B6, and vitamin B12 respectively. This treatment also significantly lowers LDL cholesterol levels in patients with low to moderate cardiovascular disease risk. However, the treatment does not significantly affect HDL cholesterol levels or lipid measurements.

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. Bibcode:1952JAChS..74.3932A. 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. Bibcode:2009AnaCh..81.2506C. doi:10.1021/ac802272u. PMID 19275147.
  3. ↑ "Homocysteine" (PDF). moh.gov.vn. Archived from the original (PDF) on 22 March 2023. Retrieved 5 April 2023.
  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. S2CID 3986295.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ↑ Boudi, Brian F. "Noncoronary Atherosclerosis". Medscape. Archived from the original on 2013-05-11.
  6. ↑ Homocysteine: The Facts, Tufts Health and Nutrition Letter, July 31, 2020 update
  7. ↑ 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.
  8. ↑ 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
  9. ↑ Selhub, J. (1999). "Homocysteine metabolism". Annual Review of Nutrition. 19 (1): 217–246. Bibcode:1999ARNut..19..217S. doi:10.1146/annurev.nutr.19.1.217. PMID 10448523. S2CID 2335090.
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  13. ↑ 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. hdl:11380/307098. PMID 17081059. Archived (PDF) from the original on 2017-08-09. {{cite journal}}: Cite uses deprecated parameter |citeseerx= (help)
  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". International Journal of Developmental Biology. 61 (8–9): 471–478. doi:10.1387/ijdb.170028yv. ISSN 0214-6282. PMID 29139533.
  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; 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.
  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". Archives of Internal Medicine. 159 (1): 38–44. doi:10.1001/archinte.159.1.38. hdl:1765/55858. 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. S2CID 29977127.
  20. 1 2 3 4 5 6 7 8 "Homocysteine". www.thedoctorsdoctor.com. Archived from the original on 2008-12-05. Retrieved 2008-11-22.
  21. 1 2 Adëeva Nutritionals Canada > Optimal blood test values Archived 2009-05-29 at the Wayback Machine Retrieved on July 9, 2009
  22. 1 2 3 4 5 6 7 8 Derived from molar values using molar massof 135 g/mol
  23. ↑ "Hyperhomocysteinemia - Hematology and Oncology - Merck Manuals Professional Edition". merckmanuals.com. Archived from the original on 2017-06-09.
  24. ↑ Smith, A. D.; Refsum, H. (October 2021). "Homocysteine – from disease biomarker to disease prevention". Journal of Internal Medicine. 290 (4): 826–854. doi:10.1111/joim.13279. ISSN 0954-6820. PMID 33660358.
  25. ↑ Cattaneo, M (February 1999). "Hyperhomocysteinemia, atherosclerosis and thrombosis". Thrombosis and Haemostasis. 81 (2): 165–76. doi:10.1055/s-0037-1614438. PMID 10063987. S2CID 13228673.
  26. ↑ 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.
  27. ↑ 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.
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  29. ↑ 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.
  30. ↑ Smith, A. David; Refsum, Helga; Bottiglieri, Teodoro; Fenech, Michael; Hooshmand, Babak; McCaddon, Andrew; Miller, Joshua W.; Rosenberg, Irwin H.; Obeid, Rima (2018). "Homocysteine and Dementia: An International Consensus Statement". Journal of Alzheimer's Disease. 62 (2): 561–570. doi:10.3233/JAD-171042. hdl:10852/67691. ISSN 1387-2877. PMC 5836397. PMID 29480200.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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.
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  37. 1 2 Huang, Xiao; Bao, Huihui; Ding, Congcong; Li, Junpei; Cao, Tianyu; Liu, Lishun; Wei, Yaping; Zhou, Ziyi; Zhang, Nan; Song, Yun; Chen, Ping; Jiang, Chongfei; Xie, Liling; Qin, Xianhui; Zhang, Yan (August 2024). "Optimal folic acid dosage in lowering homocysteine: Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy)". European Journal of Nutrition. 63 (5): 1513–1528. doi:10.1007/s00394-024-03344-8. ISSN 1436-6207. PMC 11329420. PMID 38478042.
  38. ↑ Vezzoli, Alessandra; Dellanoce, Cinzia; Maria Caimi, Teresa; Vietti, Daniele; Montorsi, Michela; Mrakic-Sposta, Simona; Accinni, Roberto (2020-06-30). "Influence of Dietary Supplementation for Hyperhomocysteinemia Treatments". Nutrients. 12 (7): 1957. doi:10.3390/nu12071957. ISSN 2072-6643. PMC 7400212. PMID 32630031.
  39. ↑ Li, Wen-Xing; Dai, Shao-Xing; Zheng, Jun-Juan; Liu, Jia-Qian; Huang, Jing-Fei (2015-08-10). "Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency". Nutrients. 7 (8): 6670–6687. doi:10.3390/nu7085303. ISSN 2072-6643. PMC 4555142. PMID 26266420.
  40. ↑ Pokushalov, Evgeny; Ponomarenko, Andrey; Bayramova, Sevda; Garcia, Claire; Pak, Inessa; Shrainer, Evgenya; Ermolaeva, Marina; Kudlay, Dmitry; Johnson, Michael; Miller, Richard (2024-05-21). "Effect of Methylfolate, Pyridoxal-5′-Phosphate, and Methylcobalamin (SolowaysTM) Supplementation on Homocysteine and Low-Density Lipoprotein Cholesterol Levels in Patients with Methylenetetrahydrofolate Reductase, Methionine Synthase, and Methionine Synthase Reductase Polymorphisms: A Randomized Controlled Trial". Nutrients. 16 (11): 1550. doi:10.3390/nu16111550. ISSN 2072-6643. PMC 11173557. PMID 38892484.