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homocysteine - Humpath.com - Human pathology

Home > A. Molecular pathology > homocysteine


Wednesday 15 October 2003

Definition: Homocysteine is a chemical compound with the formula HSCH2CH2CH(NH2)CO2H.

Homocysteine is a homologue of the naturally-occurring amino acid cysteine, differing in that its side-chain contains an additional methylene (-CH2-) group before the thiol (-SH) group.

Alternatively, homocysteine can be derived from methionine by removing the latter’s terminal Cε methyl group.

Elevated homocysteine

As a consequence of the biochemical reactions in which homocysteine is involved, deficiencies of the vitamins folic acid (vitamin B9), pyridoxine (vitamin B6), or viatmin B12 (cyanocobalamin) can lead to high homocysteine levels.

Supplementation with pyridoxine, folic acid, B12 or trimethylglycine (betaine) reduces the concentration of homocysteine in the bloodstream. Increased levels of homocysteine are linked to high concentrations of endothelial asymmetric dimethylarginine.

Elevations of homocysteine also occur in the rare hereditary disease homocystinuria and in the methylene-tetrahydrofolate-reductase polymorphism genetic traits. The latter is quite common (about 10% of the world population) and it is linked to an increased incidence of thrombosis and cardiovascular disease and that occurs more often in people with above minimal levels of homocysteine (about 6 μmol/L).

Common levels in Western populations are 10 to 12 and levels of 20 μmol/L are found in populations with low B-vitamin intakes (New Delhi) or in the older elderly (Rotterdam, Framingham).

Women have 10-15% less homocysteine during their reproductive decades than men which may help explain the fact they suffer myocardial infarction (heart attacks) on average 10 to 15 years later than men.

Methionine regeneration in the folate-homocysteine cycle

Methionine derivative S-adenosyl methionine (SAM) serves as a methyl donor. Methionine is converted to S-adenosylmethionine (SAM) by methionine adenosyltransferase. SAM serves as a methyl-donor in many methyltransferase reactions and is converted to S-adenosylhomocysteine (SAH). Adenosylhomocysteinase converts SAH to homocysteine.

There are two fates of homocysteine:

1. Methionine can be regenerated from homocysteine via methionine synthase. It can also be remethylated using glycine betaine (NNN-trimethyl glycine) to methionine via the enzyme Betaine-homocysteine methyltransferase (E.C., BHMT). Betaine-homocysteine methyltransferase makes up to 1.5% of all the soluble protein of the liver, and recent evidence suggests that it may have a greater influence on methionine and homocysteine homeostasis than methionine synthase.

2. Homocysteine can be converted to cysteine. Cystathionine-β-synthase (a PLP-dependent enzyme) combines homocysteine and serine to produce cystathionine. Instead of degrading cystathionine via cystathionine-β-lyase, as in the biosynthetic pathway, cystathionine is broken down to cysteine and α-ketobutyrate via cystathionine-γ-lyase. α-ketoacid dehydrogenase converts α-ketobutyrate to propionyl-CoA, which is metabolized to succinyl-CoA in a three-step process (see propionyl-CoA for pathway).


- hyperhomocysteinemia

  • hyperhomocysteinemia is an independent risk factor for cardiovascular disease

- anomalies of homocysteine remethylation: risk of spina bifida


- Huhta JC, Hernandez-Robles JA. Homocysteine, folate, and congenital heart defects. Fetal Pediatr Pathol. 2005 Mar-Apr;24(2):71-9. PMID: 16243751

- Ulrey CL, Liu L, Andrews LG, Tollefsbol TO. The impact of metabolism on DNA methylation. Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R139-47. PMID: 15809266


  • Folate-homocysteine pathway