InterPro domain: IPR017226

Betaine-homocysteine methyltransferase (BHMT) is involved in the regulation of homocysteine metabolism. It converts betaine and homocysteine to dimethylglycine and methionine, respectively. This reaction is also required for the irreversible oxidation of choline. BHMT requires a thiol reducing agent for its activity. The catalytic zinc of BHMT is bound by three thiolates and one hydroxyl group. A disulphide bond is formed between two of the three zinc-binding ligands when BHMT is inactive [ 1 ].

BHMT regulates homocysteine levels in the liver. The BHMT/betaine system directly protects hepatocytes from homocysteine-induced injury, but not tunicamycin-induced injury, including an endoplasmic reticulum stress response, lipid accumulation, and cell death. It also has a generalized effect on liver lipids by inducing ApoB expression and increasing S-adenosylmethionine/S-adenosylhomocysteine [ 2 ]. However, the peripheral metabolism of homocysteine protects the liver without the direct action of BHMT in the liver [ 3 ].

The human betaine-homocysteine methyltransferase-2 is also a zinc metalloenzyme that uses S-methylmethionine (SMM) as a methyl donor for the methylation of homocysteine. Unlike the highly homologous BHMT, BHMT-2 cannot use betaine as a substrate [ 4 ].

This entry also includes homocysteine S-methyltransferase ( 2.1.1.10 ), which converts S-adenosylmethionine to methionine [ 5 ]; selenocysteine methyltransferase ( 2.1.1.280 ), which methylates DL- and L-selenocysteine, DL-homocysteine, and DL- and L-cysteine [ 6 ]; and S-methylmethionine--homocysteine S-methyltransferase BHMT2 (also 2.1.1.10 ), which converts converts homocysteine to methionine [ 7 ].

1. Liver betaine-homocysteine S-methyltransferase activity undergoes a redox switch at the active site zinc. Arch. Biochem. Biophys. 472, 26-33
2. Mechanisms of protection by the betaine-homocysteine methyltransferase/betaine system in HepG2 cells and primary mouse hepatocytes. Hepatology 46, 1586-96
3. Effect of transgenic extrahepatic expression of betaine-homocysteine methyltransferase on alcohol or homocysteine-induced fatty liver. Alcohol. Clin. Exp. Res. 32, 1049-58
4. Betaine-homocysteine S-methyltransferase-2 is an S-methylmethionine-homocysteine methyltransferase. J. Biol. Chem. 283, 8939-45
5. Reverse methionine biosynthesis from S-adenosylmethionine in eukaryotic cells. J. Biol. Chem. 275, 40718-24
6. Molecular and biochemical characterization of the selenocysteine Se-methyltransferase gene and Se-methylselenocysteine synthesis in broccoli. Plant Physiol. 138, 409-20