Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, some ...

, differing by an additional methylene bridge (-CH₂-). It is biosynthesized from

methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ...

by the removal of its terminal C^ε methyl group. In the body, homocysteine can be recycled into methionine or converted into

with the aid of certain B-vitamins. High levels of homocysteine in the blood ( hyperhomocysteinemia) is regarded as a marker of cardiovascular disease, likely working through

atherogenesis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no ...

, which can result in ischemic injury. Therefore, hyperhomocysteinemia is a possible risk factor for

coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...

. Coronary artery disease occurs when an atherosclerotic plaque blocks blood flow to the

coronary arteries The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ ...

, which supply the heart with oxygenated blood. 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. Hyperhomocysteinemia also has been associated with early-term spontaneous abortions and with neural tube defects.

Structure

Homocysteine exists at neutral pH values as a zwitterion.

Biosynthesis and biochemical roles

Homocysteine is biosynthesized naturally 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-e). SAM-e then transfers the methyl group to an acceptor molecule, (e.g.,

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...

as an acceptor during

epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...

synthesis, DNA methyltransferase as an intermediate acceptor in the process of

DNA methylation DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts ...

). The adenosine is then

hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

to yield L-homocysteine. L-Homocysteine has two primary fates: conversion via tetrahydrofolate (THF) back into L-methionine or conversion to L-cysteine.

Biosynthesis of cysteine

Mammals biosynthesize the amino acid cysteine via homocysteine. Cystathionine β-synthase catalyses the condensation of homocysteine and

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − for ...

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.

Methionine salvage

Homocysteine can be recycled into

. 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 Homocysteine is a non-proteinogenic 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. In t ...

, a five-membered heterocycle. Because of this "self-looping" reaction, homocysteine-containing

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

s tend to cleave themselves by reactions generating oxidative stress. Homocysteine also acts as an allosteric antagonist at Dopamine D₂ receptors. It has been proposed that both homocysteine and its thiolactone may have played a significant role in the appearance of life on the early Earth.

Homocysteine levels

Homocysteine levels typically are higher in men than women, and increase with age. 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). It is decreased with methyl folate trapping, where it is accompanied by decreased methylmalonic acid, increased folate, and a decrease in formiminoglutamic acid. This is the opposite of MTHFR C677T mutations, which result in an increase in homocysteine. 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

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 Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (th ...

, neuropsychiatric illness, and fractures. It also is found to be associated with microalbuminuria, which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction. Vitamin B₁₂ deficiency, when coupled with high serum folate levels, has been found to increase overall homocysteine concentrations as well. Typically, hyperhomocysteinemia is managed with vitamin B₆, vitamin B₉, and vitamin B₁₂ supplementation. However, supplementation with these vitamins does not appear to improve cardiovascular disease outcomes.

References

External links

Homocysteine MS Spectrum
* Homocysteine a
Lab Tests Online

Homocysteine: analyte monograph
- The Association for Clinical Biochemistry and Laboratory Medicine

''The Health Report'', Radio National, 24 May 2010 {{Amino acid metabolism intermediates Sulfur amino acids Thiols Non-proteinogenic amino acids Excitatory amino acids