Homocysteine is a naturally occurring amino acid produced as an intermediate in the metabolism of methionine, a process dependent on the B vitamins folic acid (vitamin B9), vitamin B12 (cobalamin) and vitamin B6.

Studies have shown that increased serum homocysteine levels are associated with declining cognitive function and dementia amongst others.

Formation of homocysteine

Methionine and cysteine are amino acid which are necessary for the biosynthesis of proteins. Methionine, an essential amino acid, must be supplied by the diet.

Homocysteine differs from cysteine by having an additional methylene group (-CH2-).

Homocysteine is biosynthesized from methionine and can be either recycled into methionine (the methionine synthase pathway) or irreversibly converted into cysteine (the cystathionine pathway or reverse trans-sulfuration route). The remethylation to methionine requires folate and vitamin B12, the conversion to cysteine requires the action of vitamin B6.

The methionine synthase pathway

This reaction transforms the primary biologically active form of folate (5-methyl tetrahydrofolate or 5-MTHF) into tetrahydrofolate (THF – a derivative of folate) while transferring a methyl group to homocysteine to form methionine. This reaction requires the presence of cobalamin (vitamin B12).

The folate pathway

5-MTHF functions as a methyl donor for homocysteine remethylation to methionine, which releases a THF and the cycle can start again.

If there is not enough vitamin B12 available, the 5-methyltetrahydrofolate (5-MTHF) cannot be converted into THF due to the “methyl trap”. This impairs the folate pathway and leads to an increase in homocysteine which damages cells, even though enough folate or folic acid may be available.

The cystathionine pathway

During this reaction, an enzyme catalyses the transformation of homocysteine to cystathionine with the help of pyridoxine (vitamin B6) as a cofactor. The action of another enzyme transforms than cystathionine to cysteine.

It seems that in most tissues, homocysteine is either remethylated to methionine or transported out of the cell. The liver, thanks to a peculiar set of enzymes, is the main organ enabling the degradation of excess methionine which help maintaining homocysteine at adequate levels.

Factors influencing homocysteine levels

A high plasma level of homocysteine may result from:

  • an inadequate B vitamins status (B9, B6 and B12),
  • rare genetic defects and disease
  • aging
  • specific lifestyle.

The main nutritional cause of elevated plasma homocysteine in most healthy populations is folate, vitamin B12 and, to a lower extent, vitamin B6 insufficiency.

Consequences of hyperhomocysteinemia

Hyperhomocysteinemia is an elevation of the homocysteine level in blood (above 15 micromoles per liter).

High homocysteine levels affect the interior lining of blood vessels, resulting in an increased risk of atherosclerosis or a narrowing of blood vessels.

Studies have shown that high plasma level of homocysteine is related to several age-related pathologies such as osteoporosis, Alzheimer’s disease, Parkinson’s disease, stroke, and cardiovascular disease.


The vitamins folic acid (vitamin B9), vitamin B12 (cobalamin) and vitamin B6 act as cofactors for the enzymes involved in the methionine metabolism, and help maintaining a balanced homocysteine blood level. If the vitamin B concentrations decrease, the plasma homocysteine level will inversely increase.
This raise in homocysteine concentration is associated to a declining cognitive function and to cardiovascular diseases. During pregnancy it may be associated with fetal malformations, pre-eclampsia and to recurrent spontaneous early pregnancy losses.

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