InterPro domain: IPR003171

This represents the catalytic domain of 5,10-methylenetetrahydrofolate reductase from prokaryotes and methylenetetrahydrofolate reductase (MTHFR) from eukaryotes ( 1.5.1.20 ). Both convert 5-methyltetrahydrofolate to 5,10-methylenetetrahydrofolate.

Mammalian and yeast MTHFRs are homodimers in which each subunit contains an N-terminal catalytic domain, and a C-terminal regulatory domain to which the allosteric inhibitor adenosylmethionine binds [ 1 ]. NADPH is the preferred reductant. In humans, there are several clinically significant mutations in MTHFR that result in hyperhomocysteinemia, which is a risk factor for the development of cardiovascular disease [ 2 ].

The bacterial enzyme is a homotetramer. MTHFRs of enteric bacteria comprise shorter chains around 300 residues in length. Their sequences can be aligned with the N-terminal catalytic domains of the eukaryotic MTHFRs [ 3 ]. Escherichia coli MTHFR, along with plant MTHFRs, prefer NADHs as the source of reducing equivalents [ 3 ]. The structure of E. coli MTHFR is known to be a TIM barrel [ 3 ].

1. Functional role for the conformationally mobile phenylalanine 223 in the reaction of methylenetetrahydrofolate reductase from Escherichia coli. Biochemistry 48, 7673-85
2. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat. Struct. Biol. 6, 359-65