Methylenetetrahydrofolate dehydrogenase 2, mitochondrial (MTHFD2)

Methylenetetrahydrofolate dehydrogenase 2, mitochondrial (MTHFD2) is a bifunctional enzyme that plays a critical role in the mitochondrial one-carbon metabolism pathway [UniProt: P13995]. It possesses both NAD-dependent methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, facilitating the conversion of 5,10-methylenetetrahydrofolate to 10-formyltetrahydrofolate [PubMed: 24909970]. This enzyme is essential for providing the one-carbon units required for de novo purine synthesis and for maintaining cellular redox homeostasis through the production of NADPH [PubMed: 28416141]. While MTHFD2 is highly expressed during embryonic development, its expression is remarkably low or absent in most healthy adult tissues, yet it is significantly upregulated in a wide variety of human cancers [PubMed: 30510244]. This differential expression pattern makes it a highly attractive therapeutic target for oncology, as its inhibition can selectively disrupt the metabolic requirements of malignant cells while sparing normal tissue [PubMed: 29335222]. Current drug discovery efforts focus on small-molecule inhibitors, such as DS18561882 and SHIN1, which aim to induce metabolic crisis and apoptosis in cancer cells by blocking these critical folate-mediated reactions [PubMed: 31209035].

Other names

Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrialNAD-dependent methylenetetrahydrofolate dehydrogenaseNADP-dependent methenyltetrahydrofolate cyclohydrolaseMTHFD

Inhibition of the bifunctional dehydrogenase and cyclohydrolase activities of MTHFD2, leading to the depletion of mitochondrial 10-formyltetrahydrofolate, subsequent inhibition of de novo purine synthesis, and disruption of cellular redox balance [PubMed: 29335222].