All homocysteine in the body is biosynthesized from methionine, an essential amino acid found abundantly in meats, seafood, dairy products, and eggs. Vegetables, with few exceptions (eg, sesame seeds and Brazil nuts), are low in methionine; even such protein-rich legumes as beans, peas, and lentils contain relatively small amounts of methionine compared to animal-derived foods.
Homocysteine exists in several forms5; the sum of all homocysteine forms is termed ‘total homocysteine.’ Protein-rich diets contain ample amounts of methionine and consequently produce significant levels of homocysteine in the body.6
Homocysteine is metabolized through two pathways: remethylation and transsulfuration. Remethylation requires folate and B12 coenzymes; transsulfuration requires pyridoxal-5’-phosphate, the B6 coenzyme.7
Homocysteine Metabolic Pathways
The remethylation pathway requires vitamin B12, folate, and the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). In kidney and liver, homocysteine is also remethylated by the enzyme betaine homocysteine methyltransferase (BHMT), which transfers a methyl group to homocysteine via the demethylation of betaine to dimethylglycine (DMG). The transsulfuration pathway requires the enzyme cystathionine-synthase (CBS) and vitamin B6 (pyridoxal-5’-phosphate). Once formed from cystathionine, cysteine can be utilized in protein synthesis and glutathione (GSH) production.
Active folate, known as 5-MTHF or 5-methyltetrahydrofolate, works in concert with vitamin B12 as a methyl-group donor in the conversion of homocysteine back to methionine.
Normally, about 50% of homocysteine is remethylated; the remaining homocysteine is transsulfurated to cysteine, which requires vitamin B6 as a co-factor. This pathway yields cysteine, which is then used by the body to make glutathione, a powerful antioxidant that protects cellular components against oxidative damage.
Vitamin B2 (riboflavin) and magnesium are also involved in homocysteine metabolism. Thus, a person needs several different B-vitamins to help keep homocysteine levels low and allow for it to be properly transformed into helpful antioxidants like glutathione. Without B6, B12, B2, folate, and magnesium, dangerous levels of homocysteine may build up in the body.
Blood levels of total homocysteine increase throughout life in men and women.8 Prior to puberty, both sexes enjoy optimally healthy levels (about 6 µmol/L). During puberty, levels rise, more in males than females,9,10 reaching, on average, almost 10 µmol/L in men and more than 8 µmol/L in women. As we age, mean values of homocysteine continue to rise and the concentrations usually remain lower in women than in men.11
The higher total homocysteine concentrations seen in the elderly may be caused by many factors including malabsorption of B12 or a suboptimal intake of B vitamins (especially vitamin B12), reduced kidney function, medications that reduce the absorption of vitamins (as in the case of H2 receptor antagonists or proton-pump inhibitors reducing B12 absorption)12 or increase the catabolism of the vitamins (as in the case of metformin reducing blood levels of B12 and folic acid).13 Certain diseases are associated with higher homocysteine levels, as can such lifestyle factors as smoking,14 coffee consumption,15 and excessive alcohol intake.16 Lack of exercise, obesity, and stress are also associated with hyperhomocysteinemia.