Homocysteine(/ˌhoʊmoʊˈsɪstiːn/) orHcy:is a non-proteinogenicα-amino acid.It is ahomologueof the amino acidcysteine,differing by an additionalmethylene bridge(-CH2-). It is biosynthesized frommethionineby the removal of its terminal Cεmethyl group.In the body, homocysteine can be recycled into methionine or converted intocysteinewith the aid of vitamin B6,B9,and B12.[3]
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IUPAC name
2-Amino-4-sulfanylbutanoic acid
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ECHA InfoCard | 100.006.567 |
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CompTox Dashboard(EPA)
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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 | |
logP | -2.56[1] |
Acidity(pKa) | 2.25[1] |
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H302 | |
Except where otherwise noted, data are given for materials in theirstandard state(at 25 °C [77 °F], 100 kPa).
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High levels of homocysteine in the blood (hyperhomocysteinemia) is regarded as a marker of cardiovascular disease, likely working throughatherogenesis,which can result inischemic injury.Therefore, hyperhomocysteinemia is a possible risk factor forcoronary artery disease.Coronary artery disease occurs when an atherosclerotic plaque blocks blood flow to thecoronary 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 withneural tube defects.[8]
Structure
editHomocysteine exists at neutral pH values as azwitterion.
Biosynthesis and biochemical roles
editHomocysteine is biosynthesized naturally via a multi-step process.[9]First, methionine receives an adenosine group fromATP,a reaction catalyzed byS-adenosyl-methionine synthetase,to giveS-adenosyl methionine(SAM-e). SAM-e then transfers the methyl group to an acceptor molecule, (e.g.,norepinephrineas an acceptor duringepinephrinesynthesis,DNA methyltransferaseas an intermediate acceptor in the process ofDNA methylation). The adenosine is thenhydrolyzedto yieldL-homocysteine.L-Homocysteine has two primary fates: conversion viatetrahydrofolate(THF) back intoL-methionineor conversion toL-cysteine.[10]
Biosynthesis of cysteine
editMammals biosynthesize the amino acid cysteine via homocysteine.Cystathionine β-synthasecatalyses the condensation of homocysteine andserineto givecystathionine.This reaction usespyridoxine(vitamin B6) as a cofactor.Cystathionine γ-lyasethen converts this double amino acid to cysteine, ammonia, and α-ketobutyrate. Bacteria and plants rely on a different pathway to produce cysteine, relying onO-acetylserine.[11]
Methionine salvage
editHomocysteine can be recycled intomethionine.This process uses N5-methyl tetrahydrofolate as the methyl donor andcobalamin(vitamin B12)-related enzymes. More detail on these enzymes can be found in the article formethionine synthase.
Other reactions of biochemical significance
editHomocysteine can cyclize to givehomocysteine thiolactone,a five-memberedheterocycle.Because of this "self-looping" reaction, homocysteine-containingpeptidestend to cleave themselves by reactions generatingoxidative stress.[12]
Homocysteine also acts as anallosteric antagonistat Dopamine D2receptors.[13]
It has been proposed that both homocysteine and its thiolactone may have played a significant role in theappearance of lifeon the early Earth.[14]
Homocysteine levels
editHomocysteine 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 informiminoglutamic acid.[19]This is the opposite of MTHFR C677T mutations, which result in an increase in homocysteine.[citation needed]
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
editAbnormally high levels of homocysteine in the serum, above 15 μmol/L, are a medical condition calledhyperhomocysteinemia.[23]This has been claimed to be a significant risk factor for the development of a wide range of diseases, includingthrombosis,[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 B12deficiency, 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 B12supplementation.[33]However, supplementation with these vitamins does not appear to improve cardiovascular disease outcomes.[34]
References
edit- ^abChalcraft, 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.PMID19275147.
- ^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.
- ^"Homocysteine"(PDF).moh.gov.vn.Retrieved5 April2023.
- ^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.PMID29552692.S2CID3986295.
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:CS1 maint: multiple names: authors list (link) - ^Boudi, Brian F."Noncoronary Atherosclerosis".Medscape.Archivedfrom the original on 2013-05-11.
- ^Homocysteine: The Facts,Tufts Health and Nutrition Letter, July 31, 2020 update
- ^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.PMID10725483.S2CID26125655.
- ^van der Put NJ et alFolate, Homocysteine and Neural Tube Defects: An OverviewArchived2015-09-16 at theWayback MachineExp 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.PMID10448523.S2CID2335090.
- ^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.ISBN1-57259-153-6.
- ^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.Bibcode:2010PNAS..107..551S.doi:10.1073/pnas.0909737107.PMC2818928.PMID20080717.
- ^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.CiteSeerX10.1.1.625.26.doi:10.1021/pr0601382.PMID17081059.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): 471–478.doi:10.1387/ijdb.170028yv.ISSN0214-6282.PMID29139533.
- ^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.PMID7474221.
- ^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.PMID16702348.
- ^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.ISSN0003-9926.PMID9892328.
- ^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.ISSN0301-0422.PMID11411265.
- ^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.ISSN0140-6736.PMID6115113.S2CID29977127.
- ^abcdefgh"Homocysteine".www.thedoctorsdoctor.com.Archived fromthe originalon 2008-12-05.Retrieved2008-11-22.
- ^abAdëeva Nutritionals Canada > Optimal blood test valuesArchived2009-05-29 at theWayback MachineRetrieved on July 9, 2009
- ^abcdefghDerived from molar values using molar massof 135 g/mol
- ^"Hyperhomocysteinemia - Hematology and Oncology - Merck Manuals Professional Edition".merckmanuals.com.Archivedfrom 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.PMID10063987.S2CID13228673.
- ^Morris, MS (July 2003). "Homocysteine and Alzheimer's disease".Lancet Neurology.2(7): 425–8.doi:10.1016/s1474-4422(03)00438-1.PMID12849121.S2CID20443022.
- ^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.PMID21474939.S2CID7689901.
- ^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.PMC2935890.PMID20838622.
- ^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.PMC3321271.PMID22270909.
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- ^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.PMID15141041.
- ^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.PMID11145936.
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External links
edit- Homocysteine MS Spectrum
- Homocysteine atLab Tests Online
- Prof. David Spence on homocysteine levels, kidney damage, and cardiovascular disease,The Health Report,Radio National, 24 May 2010