Methylenetetrahydrofolate dehydrogenase 1 and 2 (MTHFD1, MTHFD2)

Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1, cytoplasmic) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2, mitochondrial) are enzymes central to folate-mediated one-carbon metabolism, required for purine, thymidine, and methionine biosynthesis. MTHFD1 is a cytoplasmic, trifunctional enzyme with dehydrogenase, cyclohydrolase, and formyltetrahydrofolate synthetase activity, and is broadly expressed in adult tissues. MTHFD2 is a mitochondrial, bifunctional enzyme (dehydrogenase and cyclohydrolase), uniquely expressed at high levels in embryonic and transformed (cancer) cells but largely absent from most adult tissues. MTHFD2 is highly upregulated in many tumors, where it enables rapid nucleotide synthesis and supports redox balance. Because of its cancer-restricted expression and essential function in tumor cell proliferation, MTHFD2 is a highly attractive target for anticancer drug discovery. If you seek information on only one isoform, MTHFD2 more specifically refers to the cancer-associated mitochondrial bifunctional enzyme, while MTHFD1 is the cytoplasmic, ubiquitously expressed trifunctional enzyme.

Other names

C-1-tetrahydrofolate synthaseNADP-dependent methylenetetrahydrofolate dehydrogenase/cyclohydrolase/formyltetrahydrofolate synthetaseNAD-dependent methylenetetrahydrofolate dehydrogenase/cyclohydrolaseNMDMCMethylenetetrahydrofolate dehydrogenase 2

Inhibitors block the dehydrogenase and/or cyclohydrolase activities, thereby disrupting mitochondrial one-carbon metabolism, depleting nucleotide pools, and impairing redox homeostasis—leading to reduced tumor cell proliferation and survival