Homocysteine is a non-proteinogenic

α-amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ami ...

. It is a homologue of the amino acid cysteine, differing by an additional

methylene bridge In organic chemistry, a methylene bridge, methylene spacer, or methanediyl group is any part of a molecule with formula ; namely, a carbon atom bound to two hydrogen atoms and connected by single bonds to two other distinct atoms in the rest of t ...

(-CH₂-). It is biosynthesized from methionine by the removal of its terminal C^ε

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ma ...

. In the body, homocysteine can be recycled into methionine or converted into cysteine with the aid of certain

B-vitamins B vitamins are a class of water-soluble vitamins that play important roles in cell metabolism and synthesis of red blood cells. Though these vitamins share similar names (B1, B2, B3, etc.), they are chemically distinct compounds that often coexist ...

. High levels of homocysteine in the blood (

hyperhomocysteinemia Hyperhomocysteinemia is a medical condition characterized by an abnormally high level of homocysteine in the blood, conventionally described as above 15 μmol/L. As a consequence of the biochemical reactions in which homocysteine is involved ...

) 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 sy ...

, which can result in

ischemic injury Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wit ...

. Therefore, hyperhomocysteinemia is a possible risk factor for coronary artery disease. 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 o ...

, 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 Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo b ...

Structure

Homocysteine exists at neutral pH values as a

zwitterion In chemistry, a zwitterion ( ; ), also called an inner salt or dipolar ion, is a molecule that contains an equal number of positively- and negatively-charged functional groups. : With amino acids, for example, in solution a chemical equilibrium wil ...

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 synthesis,

DNA methyltransferase In biochemistry, the DNA methyltransferase (DNA MTase, DNMT) family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl m ...

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 Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative. Metabolism Human synthesis Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate. It is co ...

(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 to give

cystathionine Cystathionine is an intermediate in the synthesis of cysteine. Cystathionine is produced by the transsulfuration pathway which converts homocysteine into cystathionine. Cystathionine is then used by the enzymes cystathionine gamma-lyase (CTH), ...

. 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 methionine. This process uses N5-methyl tetrahydrofolate as the methyl donor and

cobalamin Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. ...

(vitamin B₁₂)-related enzymes. More detail on these enzymes can be found in the article for

methionine synthase Methionine synthase also known as MS, MeSe, MTR is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the ''MTR'' gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms ...

Other reactions of biochemical significance

Homocysteine can cyclize to give homocysteine thiolactone, a five-membered

heterocycle A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...

. 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 Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

. 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

. 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 (t ...

, 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