Homocysteine, the New Marker of Disease Risk - An Overview

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Butz and du Vigneaud first described homocysteine in 1932. This sulphur-containing amino acid is closely related to methionine and cysteine. Homocystinuria, a condition in which the homocysteine levels in blood and urine are very high, is caused by some severe enzyme defects. This condition was found to be associated with premature occlusive cardiovascular disease (CVD) and with mental retardation.
In 1969, McCully described the vascular pathology, including smooth muscle proliferation, progressive arterial stenosis and haemostatic changes found in such patients. A large number of epidemiological, case├óÔé¼ÔÇ£control and longitudinal studies have since demonstrated an association between moderately elevated homocysteine levels in the plasma or serum and pregnancy complications, neural tube defects, other birth defects, various neuropsychiatric disorders, cognitive impairment in the elderly and an increased mortality rate, in addition to vascular diseases. Research within the field has been very active during the last decade. About 1,000 scientific reports are now published annually.
This research has been made possible by the development of accurate methods for measuring homocysteine in plasma and serum. The recent introduction of enzyme immunoassays is a further step forward. Automated methods using standard immunoassay equipment have been introduced.


The One-carbon Metabolism
Homocysteine is an intermediate product of the one-carbon metabolism. All homocysteine found in mammals is formed during the metabolism of methionine in the methylation cycle (see Figure 1). Dietary methionine is used either for protein synthesis or the formation of S-adenosylmethionine (SAM), which contains a very reactive methyl group. This is transferred to a large variety of acceptor substrates, including nucleic acids (deoxyribonucleic acid (DNA) and ribonucleic acid), proteins, phospholipids, myelin, polysaccharides, choline, catecholamines and a large number of small molecules. SAM is the principal biological methyl group donor in the organism and the only donor in the central nervous system (CNS). S-adenosyl-l-homocysteine (SAH) is hydrolysed in a reversible reaction to homocysteine, which can be recycled to methionine and SAM or directed toward the transsulphuration pathway.

Figure 1: Homocysteine Metabolism


Three enzymes are involved directly in this metabolism: methionine synthase (MS); betaine homocysteine methyltransferase; and cystathionine ├Ä╦ø-synthase (CBS). Vitamin B12 is a co-factor to MS and vitamin B6 to CBS. Methyl tetrahydrofolate (methylTHF) is a substrate in the MS-mediated reaction. This reaction is also critical for the formation of the active folate forms required for purine and thymidine synthesis and thus for DNA synthesis and repair.

The majority of tissues, including the CNS, are entirely dependent on methyl groups derived from the MS-mediated recycling of homocysteine. This reaction is indirectly regulated by the activity of methyl-enetetrahydrofolate reductase (MTHFR), as this enzyme mediates the formation of methylTHF. This enzyme therefore has a strong, indirect influence on the remethylation of homocysteine. />/>/>



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