Homocysteine: Function & Diseases

Homocysteine is a non-proteinogenic sulfur-containing alpha-amino acid that is formed by releasing the methyl group (-CH3) as an intermediate from methionine. For further processing of homocysteine, an adequate supply of vitamins B12 and B6 as well as folic acid or betaine as a supplier of methyl groups is necessary. An elevated concentration of homocysteine in blood plasma is associated with damage to blood vessel walls, dementia, and depression.

What is homocysteine?

Homocysteine, in its bioactive L form, is a non-proteinogenic amino acid. It is unable to be a building block of a protein because of its tendency to form a heterocyclic ring due to its additional CH2 group compared to cysteine, which does not allow for stable peptide bonding. Therefore, the incorporation of homocysteine into a protein would cause the protein to disintegrate soon. The chemical molecular formula C4H9NO2S shows that the amino acid consists exclusively of substances that are available in abundant quantities almost everywhere. Trace elements, rare minerals and metals are not necessary for its construction. Homocysteine is a zwitterion because it has two functional groups, each with a positive and a negative charge, which are electrically balanced overall. At room temperature, homocysteine exists as a crystalline solid with a melting point of about 230 to 232 degrees Celsius. The body can break down an elevated level of homocysteine in the blood by allowing two homocysteine molecules to join together to form homocystine via the formation of a disulfide bridge, and can be excreted in this form by the kidneys.

Function, effects, and roles

The main role and function of L-homocysteine is to assist in the synthesis of proteins and to be converted into S-adenosylmethionine (SAM) in cooperation with some co-enzymes. SAM, with three methyl groups (-CH3), is the major methyl group donor of cellular metabolism. SAM is involved in many biosyntheses and in detoxification reactions. The methyl groups of certain neurotransmitters such as adrenaline, choline and creatine originate from SAM. After releasing a methyl group, SAM gives rise to S-adenosylmethionine (SAH), which is converted back to adenosine or back to L-homocysteine by hydrolysis. As important as the supporting function of homocysteine is for certain metabolic processes, it is also important that homocysteine, as an intermediate product of these biochemical reaction and synthesis chains, does not appear in abnormal concentrations in the blood, because it then exerts harmful effects. Excess homocysteine that is not needed to support the conversions in methionine metabolism described above is therefore normally broken down further with the participation of vitamin B6 (pyridoxine) and excreted via the kidneys after the formation of homocystine. In order for homocysteine to perform its metabolic tasks, it is important to provide the body with sufficient amounts of vitamins B6, B12 and folic acid.

Formation, occurrence, properties and optimal values

Homocysteine is formed in the body as a short-lived intermediate within the complex metabolism of methionine. The alternative name (S)-2-amino-4-mercaptobutanoic acid indicates the structure of homocysteine. Accordingly, it is a monocarboxylic acid with the characteristic carboxy group (-COOH) and at the same time a simple fatty acid. Homocysteine is not absorbed through food, but is produced exclusively temporarily in the body. Although the bioactive L-cysteine plays an important role in protein synthesis and in the formation of SAM, the optimal and at the same time tolerable concentration in the blood is within narrow limits of only 5 to 10 µmol/liter. Higher homocysteine levels indicate certain metabolic disorders and lead to the clinical picture of hyperhomocysteinemia. An optimal concentration of the amino acid is likely to depend on the respective mental and physical activity and is difficult to define. It seems more reasonable to define a tolerable upper limit of homocysteine levels, which should be 10 µmol/liter.

Diseases and disorders

When the concentration of homocysteine exceeds the tolerable limit, acquired or genetically determined metabolic disorders in methionine balance are usually present. Often, there is simply a lack of the necessary vitamins B6 (pyridoxine), B9 (folic acid), and B12 (cobalamin), which are needed as coenzymes or catalysts within the biochemical conversion chain.A total of about 230 – albeit rarely occurring – gene mutations are known to lead to a disorder of methionine metabolism. The pathological increase in homocysteine is called homocystinuria. The most common gene mutation causing the disease is located at gene locus 21q22.3. The mutation is autosomal recessive and causes the formation of a defective enzyme needed for the degradation and conversion process of homocysteine. The mutations known so far involve the omission (deletion) or addition (insertion) of nucleic bases on the corresponding DNA strands. Unfavorable living conditions and habits can also cause increased homocysteine levels. These include excessive alcohol consumption, nicotine abuse, obesity and lack of exercise. Excessive homocysteine levels can lead to damage to the endothelium, the inner wall of the blood vessels, and promote arteriosclerosis, for example. The veins become inelastic and cause a number of secondary diseases such as high blood pressure. They also carry the risk of forming thrombi, which cause coronary heart disease and strokes. Neurological diseases such as depression and senile dementia are also associated with elevated homocysteine levels. In children suffering from genetic homocystinuria, the symptoms of the disease vary widely. The spectrum of symptoms ranges from barely detectable disease features to the occurrence of almost all possible symptoms. The first symptoms usually appear after reaching the second year of life. At most, a slowing of psychomotor development can be seen during the first two years of life. In many cases, the first symptom of genetic homocystinuria is a prolapse of the crystalline lens.