The catalytic mechanism of the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2).

ABSTRACT: Methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a new drug target that is expressed in cancer cells but not in normal adult cells, which provides an Achilles heel to selectively kill cancer cells. Despite the availability of crystal structures of MTHFD2 in the inhibitor- and cofactor-bound forms, key information is missing due to technical limitations, including (a) the location of absolutely required Mg2+ ion, and (b) the substrate-bound form of MTHFD2. Using computational modeling and simulations, we propose that two magnesium ions are present at the active site whereby (i) Arg233, Asp225, and two water molecules coordinate [Formula: see text], while [Formula: see text] together with Arg233 stabilize the inorganic phosphate (Pi); (ii) Asp168 and three water molecules c

SUBMITTER: Zhao LN 

PROVIDER: S-EPMC9173628 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature