Homocysteine

Homocysteine
Names
IUPAC name
2-Amino-4-sulfanylbutanoic acid
Identifiers
454-29-5 (racemate) YesY
6027-13-0 (L-isomer) YesY
3D model (Jmol) Interactive image
ChEBI CHEBI:17230 YesY
ChEMBL ChEMBL310604 YesY
ChemSpider 757 YesY
ECHA InfoCard 100.006.567
EC Number 207-222-9
KEGG C05330 YesY
PubChem 778
UNII S7IJP4A89K (racemate) YesY
0LVT1QZ0BA (L-isomer) YesY
Properties
C4H9NO2S
Molar mass 135.18 g/mol
Appearance White crystalline powder
Melting point 234–235 °C (453–455 °F; 507–508 K)[1] (decomposes)
soluble
log P -2.56 [2]
Acidity (pKa) 2.25 [2]
Hazards
GHS pictograms
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).
YesY verify (what is YesYN ?)
Infobox references

Homocysteine /ˌhoʊmoʊˈsɪstiːn/ is a non-protein 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. Homocysteine can be recycled into methionine or converted into cysteine with the aid of certain B-vitamins.

A high level of homocysteine in the blood (hyperhomocysteinemia) makes a person more prone to endothelial cell injury, which leads to inflammation in the blood vessels, which in turn may lead to atherogenesis, which can result in ischemic injury.[3] Hyperhomocysteinemia is therefore 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 been correlated with the occurrence of blood clots, heart attacks and strokes, though it is unclear whether hyperhomocysteinemia is an independent risk factor for these conditions. Hyperhomoscyteinemia has also been associated with early pregnancy loss[4] and with neural tube defects.[5]

Structure

Betatine 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 not obtained from the diet.[6] Instead, it is biosynthesized from methionine 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 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.[7]

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.[8]

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.[9]

Homocysteine also acts as an allosteric antagonist at Dopamine D2 receptors.[10]

Homocysteine levels

Total plasma homocysteine

Homocysteine levels are typically higher in men than women, and increase with age.[11][12]

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 older elderly (e.g., Rotterdam, Framingham).

Blood reference ranges for homocysteine:
SexAgeLower limitUpper limitUnitElevatedTherapeutic target
Female 12–19 years 3.3[13] 7.2[13] μmol/L > 10.4 μmol/L
or
> 140 μg/dl 		< 6.3 μmol/L[14]
or
< 85 μg/dL[14]
45[15] 100[15] μg/dL
>60 years 4.9[13] 11.6[13] μmol/L
66[15] 160[15] μg/dL
Male 12–19 years 4.3[13] 9.9[13] μmol/L > 11.4 μmol/L
or
> 150 μg/dL
60[15] 130[15] μg/dL
>60 years 5.9[13] 15.3[13] μmol/L
80[15] 210[15] μg/dL

The ranges above are provided as examples only; test results should always be interpreted using the range provided by the laboratory that produced the result.

Elevated homocysteine

Main article: Hyperhomocysteinemia

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, including thrombosis,[16] neuropsychiatric illness,[17][18][19][20] and fractures.[21][22] It is also found to be associated with microalbuminuria which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction.[23]

Additionally, elevated homocystine is found in megaloblastic anemia.

References

  1. ↑ Allen, Milton J.; Steinman, Harry G. "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. "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.
  3. ↑ Boudi, Brian F. "Noncoronary Atherosclerosis". Medscape.
  4. ↑ Homocysteine and folate levels as risk factors for recurrent early pregnancy lossMartí-Carvajal, AJ; Solà, I; Lathyris, D (January 15, 2015). "Homocysteine-lowering interventions for preventing cardiovascular events". Heart Group. Cochrane Database of Systematic Reviews. John Wiley & Sons (1): Art. No. CD006612. doi:10.1002/14651858.CD006612.pub4. Retrieved 18 January 2015 – via The Cochrane Library. (subscription required (help)).
  5. ↑ 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
  6. ↑ Selhub, J. (1999). "Homocysteine metabolism". Annual Review of Nutrition. 19: 217–246. doi:10.1146/annurev.nutr.19.1.217. PMID 10448523.
  7. ↑ Champe, PC and Harvey, RA. "Biochemistry. Lippincott's Illustrated Reviews" 4th ed. Lippincott Williams and Wilkins, 2008
  8. ↑ Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6.
  9. ↑ 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. doi:10.1073/pnas.0909737107. PMC 2818928Freely accessible. PMID 20080717.
  10. ↑ 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.". Journal of Proteome Research. 5 (11): 3077–83. doi:10.1021/pr0601382. PMID 17081059.
  11. ↑ 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.
  12. ↑ 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. PMID 16702348.
  13. 1 2 3 4 5 6 7 8 The Doctor's Doctor: Homocysteine
  14. 1 2 Adëeva Nutritionals Canada > Optimal blood test values Retrieved on July 9, 2009
  15. 1 2 3 4 5 6 7 8 Derived from molar values using molar massof 135 g/mol
  16. ↑ Cattaneo, M (February 1999). "Hyperhomocysteinemia, atherosclerosis and thrombosis.". Thrombosis and haemostasis. 81 (2): 165–76. PMID 10063987.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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. doi:10.1371/journal.pone.0012244. PMC 2935890Freely accessible. PMID 20838622.
  20. ↑ 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 3321271Freely accessible. PMID 22270909.
  21. ↑ 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.
  22. ↑ 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. PMID 15141041.
  23. ↑ 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.
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