{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMTHFD1 (5,10‐methylenetetrahydrofolate dehydrogenase 1) is a key trifunctional enzyme in one‐carbon metabolism that catalyzes the interconversion of folate derivatives. Its three enzymatic activities—dehydrogenase, cyclohydrolase, and formyltetrahydrofolate synthetase—integrate single‐carbon units into pathways essential for de novo purine and thymidylate synthesis as well as homocysteine remethylation. Notably, MTHFD1 is not confined to the cytosol; during S-phase, a portion translocates to the nucleus, ensuring that thymidylate production is maintained even under conditions of folate depletion. This dynamic localization and substrate‐dependent stabilization underscore its central role in sustaining nucleotide synthesis and overall genomic stability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA multitude of genetic investigations have revealed that common polymorphisms in MTHFD1—most notably the 1958G>A (R653Q) variant—can markedly influence enzyme function and thereby modulate disease risk and treatment response. Altered MTHFD1 activity, whether through decreased protein stability or impaired catalytic flux, has been linked with an increased risk for neural tube defects, congenital heart anomalies, and adverse pregnancy outcomes, as well as with variable sensitivity to antifolate chemotherapeutics in conditions such as childhood acute lymphoblastic leukemia. Moreover, studies indicate that gene–gene interactions within the folate pathway, in which MTHFD1 plays a pivotal part, contribute to susceptibility to cancers, metabolic imbalances (including choline deficiency), and other folate‐related disorders. Collectively, these findings illuminate how perturbations in MTHFD1 function—not only in its canonical role of supplying one-carbon units for nucleotide biosynthesis but also via its nuclear engagement affecting DNA synthesis and repair—could contribute to genomic instability and diverse disease phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lawrence C Brody, Mary Conley, Christopher Cox, et al. 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