Wikipedia

Homocysteine

Not to be confused withhomocystine.

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]

Homocysteine
Skeletal formula
Ball-and-stick model
Names
IUPAC name
2-Amino-4-sulfanylbutanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.006.567Edit 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-NcheckY
  • 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
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]
Hazards
GHSlabelling:
GHS07: Exclamation mark
Warning
H302
Except where otherwise noted, data are given for materials in theirstandard state(at 25 °C [77 °F], 100 kPa).

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

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Zwitterionicform of (S)-homocysteine (left) and (R)-homocysteine (right)

Homocysteine exists at neutral pH values as azwitterion.

Biosynthesis and biochemical roles

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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 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

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Mammals 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]

MTHFR metabolism: folate cycle, methionine cycle, trans-sulfuration andhyperhomocysteinemia-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

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Homocysteine 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

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Homocysteine 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

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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 informiminoglutamic acid.[19]This is the opposite of MTHFR C677T mutations, which result in an increase in homocysteine.[citation needed]

Blood reference rangesfor 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

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Main article:Hyperhomocysteinemia

Abnormally 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

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  1. ^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.
  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"(PDF).moh.gov.vn.Retrieved5 April2023.
  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.PMID29552692.S2CID3986295.{{cite journal}}:CS1 maint: multiple names: authors list (link)
  5. ^Boudi, Brian F."Noncoronary Atherosclerosis".Medscape.Archivedfrom 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.PMID10725483.S2CID26125655.
  8. ^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
  9. ^Selhub, J. (1999). "Homocysteine metabolism".Annual Review of Nutrition.19:217–246.doi:10.1146/annurev.nutr.19.1.217.PMID10448523.S2CID2335090.
  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.ISBN1-57259-153-6.
  12. ^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.
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  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.PMID16702348.
  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.ISSN0003-9926.PMID9892328.
  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.ISSN0301-0422.PMID11411265.
  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.ISSN0140-6736.PMID6115113.S2CID29977127.
  20. ^abcdefgh"Homocysteine".www.thedoctorsdoctor.com.Archived fromthe originalon 2008-12-05.Retrieved2008-11-22.
  21. ^abAdëeva Nutritionals Canada > Optimal blood test valuesArchived2009-05-29 at theWayback MachineRetrieved on July 9, 2009
  22. ^abcdefghDerived from molar values using molar massof 135 g/mol
  23. ^"Hyperhomocysteinemia - Hematology and Oncology - Merck Manuals Professional Edition".merckmanuals.com.Archivedfrom the original on 2017-06-09.
  24. ^Cattaneo, M (February 1999). "Hyperhomocysteinemia, atherosclerosis and thrombosis".Thrombosis and Haemostasis.81(2): 165–76.doi:10.1055/s-0037-1614438.PMID10063987.S2CID13228673.
  25. ^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.
  26. ^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.
  27. ^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.
  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.PMC3321271.PMID22270909.
  29. ^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.PMID15141042.S2CID22853996.
  30. ^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.
  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.PMID11145936.
  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.Bibcode:2007PNAS..10419995S.doi:10.1073/pnas.0709487104.ISSN0027-8424.PMC2148411.PMID18056804.
  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.PMID11585023.S2CID45945199.
  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.ISSN1469-493X.PMC4164174.PMID25590290.
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