Figure 2: Homocysteine metabolism
Normally, homocysteine (Hcy) is maintained at very low levels in serum due to the methionine cycle, which leads to a rapid methyl transfer reaction using the following enzyme substrates: methionine (Met), S-adenosyl-methionine (S-Adenosyl-Met), and S-adenosyl-homocysteine (S-Adenosyl-Hcy). The methionine cycle is controlled by methionine synthase (MS), betaine-Hcy methyltransferase(BHMT), methionine adenosyltransferase (MAT), methyltransferase (MT), and S-Adenosyl-Hcy hydrolase (SAHH). Met and Hcy are also metabolized by methionyl-tRNA synthase (MetRS) to become MettRNA and Hcy-thiolactone (HT). Under normal conditions, Hcy-thiolactone is rapidly converted to Hcy by Hcy-thiolactonase (HTase). However, Hcythiolactone reacts spontaneously with protein ε-lysine residues, leading to formation of N-Hcy-protein. Alternatively, Hcy can enter the transsulfuration pathway. It is then converted to cystathionine (Cyst) by cystathionineβ- synthase (CBS), which is further converted to cysteine (Cys) by cystathionine γ-lyase (CSE). The transsulfuration pathway ends with sulfate. Additionally, vitamins, including: B6, B12, betaine (B10), and tetrahydrofolate (THF, sometimes called B9).