Homocysteine (; symbol Hcy) is a non-proteinogenic

α-amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

. It is a homologue of the amino acid

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

, differing by an additional

methylene bridge In chemistry, a methylene bridge is part of a molecule with formula . The carbon atom is connected by single bonds to two other distinct atoms in the rest of the molecule. A methylene bridge is often called a methylene group or simply methylene, ...

(). It is biosynthesized from

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

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 (whereas normal methane has the formula ). In formulas, the group is often abbreviated a ...

. In the body, homocysteine can be recycled into methionine or converted into cysteine with the aid of vitamin B₆, B₉, and B₁₂. High levels of homocysteine in the blood ( hyperhomocysteinemia) is regarded as a marker of cardiovascular disease, likely working through atherogenesis, 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), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...

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

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

, 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 has also 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 embry ...

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). SAM is widely used source of methyl radicals as a cofactor for radical SAM enzymes. Transfer of the methyl group to an acceptor molecule gives S-adenosyl-homocysteine.

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

of this thioether gives L-homocysteine. L-Homocysteine reacts with tetrahydrofolate (THF) to give L-methionine.

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 − ...

to give cystathionine. This reaction uses

pyridoxine Pyridoxine (PN) is a form of vitamin B6 found commonly in food and used as a dietary supplement. As a supplement it is used to treat and prevent pyridoxine deficiency, sideroblastic anaemia, pyridoxine-dependent epilepsy, certain metaboli ...

(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, also known as cobalamin, is a water-soluble vitamin involved in metabolism. One of eight B vitamins, it serves as a vital cofactor (biochemistry), cofactor in DNA synthesis and both fatty acid metabolism, fatty acid and amino a ...

(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 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 organic chemistry is the branch of organic chemistry dealing with the synthesis, proper ...

. Because of this "self-looping" reaction, homocysteine-containing

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

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 hyperhomocysteinemia. This has been claimed to be a significant risk factor for the development of a wide range of diseases, in total more than 100 including

thrombosis Thrombosis () is the formation of a Thrombus, 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 (thrombocytes) and fib ...

, neuropsychiatric illness, in particular dementia and fractures. It also is found to be associated with microalbuminuria ( moderately increased albuminuria), which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction. Vitamin B₁₂ deficiency, even 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
''The Health Report'', Radio National, 24 May 2010 {{Authority control Alpha-Amino acids Sulfur amino acids Thiols Non-proteinogenic amino acids Excitatory amino acids