Homocysteine

Homocysteine
Names
IUPAC name
2-Amino-4-sulfanylbutanoic acid
Identifiers
454-29-5 (racemate) Yes
6027-13-0 (L-isomer) Yes
ChEBI CHEBI:17230 Yes
ChEMBL ChEMBL310604 Yes
ChemSpider 757 Yes
EC-number 207-222-9
Jmol-3D images Image
KEGG C05330 Yes
PubChem 778
UNII 0LVT1QZ0BA Yes
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 noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 Yes verify (what is: Yes/?)
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.

While detection of high levels of homocysteine has been linked to cardiovascular disease, there is no evidence that treatment with B-complex vitamin supplements to lower homocysteine levels improves outcomes.

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]

Structure

Homocysteine exists at neutral pH values as a zwitterion.

Betatine form of (S)-homocysteine (left) and (R)-homocysteine (right)

Biosynthesis and biochemical roles

Homocysteine is not obtained from the diet.[5] 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.[6]

Folate cycle, methionine cycle, trans-sulfuration and hyperhomocysteinemia

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.[7]

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-ketobuterate.

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.[8]

Homocysteine also acts as an allosteric antagonist at Dopamine D2 receptors.[9]

Homocysteine levels

Total plasma homocysteine

Homocysteine levels are typically higher in men than women, and increase with age.[10][11]

Common levels in Western populations are 10 to 12, 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[12] 7.2[12] μmol/L > 10.4 μmol/L
or
> 140 μg/dl 		< 6.3 μmol/L[13]
or
< 85 μg/dL[13]
45[14] 100[14] μg/dL
>60 years 4.9[12] 11.6[12] μmol/L
66[14] 160[14] μg/dL
Male 12–19 years 4.3[12] 9.9[12] μmol/L > 11.4 μmol/L
or
> 150 μg/dL
60[14] 130[14] μg/dL
>60 years 5.9[12] 15.3[12] μmol/L
80[14] 210[14] 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, neuropsychiatric illness, and fractures. It is also found to be associated with microalbuminuria which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction.[15]

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. ↑ 2.0 2.1 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. ↑ Selhub, J. (1999). "Homocysteine metabolism". Annual Review of Nutrition 19: 217–246. doi:10.1146/annurev.nutr.19.1.217. PMID 10448523.
  6. ↑ Champe, PC and Harvey, RA. "Biochemistry. Lippincott's Illustrated Reviews" 4th ed. Lippincott Williams and Wilkins, 2008
  7. ↑ Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6.
  8. ↑ 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 2818928. PMID 20080717.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 The Doctor's Doctor: Homocysteine
  13. ↑ 13.0 13.1 Adëeva Nutritionals Canada > Optimal blood test values Retrieved on July 9, 2009
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 14.7 Derived from molar values using molar massof 135 g/mol
  15. ↑ 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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