{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nA careful review of the provided abstracts reveals an extensive discussion of folate‐mediated one‐carbon metabolism, with a particular focus on the multifunctional enzyme MTHFD1. MTHFD1 plays a pivotal role in the conversion, interconversion, and transfer of one‐carbon units required for de novo purine and thymidylate synthesis as well as for cellular methylation reactions. These studies demonstrate that alterations in MTHFD1 activity—whether by genetic inactivation, polymorphism, or subcellular redistribution—profoundly affect embryonic development, DNA stability, and tumorigenic processes by modulating the availability of folate‐activated one‐carbon cofactors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOther reports highlight the compartmentalization of folate metabolism—with particular emphasis on nuclear versus cytoplasmic flux—and the enzyme’s dynamic translocation into the nucleus during S-phase. Such redistribution helps prioritize thymidylate synthesis over other one‑carbon dependent processes, especially under conditions of folate deficiency, thereby safeguarding DNA replication and repair. In addition, genetic studies link MTHFD1 mutations or loss‐of-function variants with increased risks for adverse pregnancy outcomes, colorectal cancer progression, and even subtle cognitive and behavioral alterations, underscoring how perturbations in one‑carbon metabolism can impact diverse physiological processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIt is important to note that despite the original query referring to SNORA37, none of the provided abstracts discuss this small nucleolar RNA. Instead, they collectively focus on MTHFD1 and its central role in folate-dependent one‑carbon reactions. In summary, while MTHFD1 is established as an enzyme crucial for maintaining nucleotide pools, methylation capacity, and redox homeostasis in various cellular and developmental contexts, the function of SNORA37 in these processes remains unaddressed in the current literature. Further investigation will be necessary to elucidate whether SNORA37 plays a direct or regulatory role in folate metabolism or in any related pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Harshila Patel, Karen E Christensen, Narciso Mejia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mammalian mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase derived from a trifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase-synthetase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Biochem Biophys (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0003-9861(02)00203-5"}], "href": "https://doi.org/10.1016/S0003-9861(02"}, {"type": "t", "text": "00203-5) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12061812"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12061812"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Karen E Christensen, Harshila Patel, Uros Kuzmanov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Disruption of the mthfd1 gene reveals a monofunctional 10-formyltetrahydrofolate synthetase in mammalian mitochondria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M409380200"}], "href": "https://doi.org/10.1074/jbc.M409380200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15611115"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15611115"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Amanda J MacFarlane, Cheryll A Perry, Hussein H Girnary, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mthfd1 is an essential gene in mice and alters biomarkers of impaired one-carbon metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M808281200"}], "href": "https://doi.org/10.1074/jbc.M808281200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19033438"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19033438"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Amanda J MacFarlane, Cheryll A Perry, Michael F McEntee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mthfd1 is a modifier of chemically induced intestinal carcinogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgq270"}], "href": "https://doi.org/10.1093/carcin/bgq270"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21156972"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21156972"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Anna E Beaudin, Cheryll A Perry, Sally P Stabler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Maternal Mthfd1 disruption impairs fetal growth but does not cause neural tube defects in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Clin Nutr (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3945/ajcn.111.030783"}], "href": "https://doi.org/10.3945/ajcn.111.030783"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22378735"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22378735"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Martha S Field, Kelsey S Shields, Elena V Abarinov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduced MTHFD1 activity in male mice perturbs folate- and choline-dependent one-carbon metabolism as well as transsulfuration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Nutr (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3945/jn.112.169821"}], "href": "https://doi.org/10.3945/jn.112.169821"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23190757"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23190757"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "J A Ash, X Jiang, O V Malysheva, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dietary and genetic manipulations of folate metabolism differentially affect neocortical functions in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurotoxicol Teratol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ntt.2013.05.002"}], "href": "https://doi.org/10.1016/j.ntt.2013.05.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23684804"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23684804"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Martha S Field, Elena Kamynina, Olufunmilayo C Agunloye, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.599589"}], "href": "https://doi.org/10.1074/jbc.M114.599589"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25213861"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25213861"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Karen E Christensen, Liyuan Deng, Renata H Bahous, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MTHFD1 formyltetrahydrofolate synthetase deficiency, a model for the MTHFD1 R653Q variant, leads to congenital heart defects in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Birth Defects Res A Clin Mol Teratol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/bdra.23451"}], "href": "https://doi.org/10.1002/bdra.23451"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26408344"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26408344"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Nancy Lévesque, Karen E Christensen, Lauren Van Der Kraak, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Murine MTHFD1-synthetase deficiency, a model for the human MTHFD1 R653Q polymorphism, decreases growth of colorectal tumors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Carcinog (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/mc.22568"}], "href": "https://doi.org/10.1002/mc.22568"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27597531"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27597531"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Karen E Christensen, Wenyang Hou, Renata H Bahous, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Moderate folic acid supplementation and MTHFD1-synthetase deficiency in mice, a model for the R653Q variant, result in embryonic defects and abnormal placental development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Clin Nutr (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3945/ajcn.116.139519"}], "href": "https://doi.org/10.3945/ajcn.116.139519"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27707701"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27707701"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Eneda Pjetri, Steven H Zeisel "}, {"type": "b", "children": [{"type": "t", "text": "Deletion of one allele of Mthfd1 (methylenetetrahydrofolate dehydrogenase 1) impairs learning in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Behav Brain Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbr.2017.05.051"}], "href": "https://doi.org/10.1016/j.bbr.2017.05.051"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28559181"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28559181"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Karen E Christensen, Renata H Bahous, Wenyang Hou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Low Dietary Folate Interacts with MTHFD1 Synthetase Deficiency in Mice, a Model for the R653Q Variant, to Increase Incidence of Developmental Delays and Defects."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Nutr (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/jn/nxy013"}], "href": "https://doi.org/10.1093/jn/nxy013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29659962"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29659962"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Minhye Shin, Amanda Vaughn, Jessica Momb, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deletion of neural tube defect-associated gene Mthfd1l causes reduced cranial mesenchyme density."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Birth Defects Res (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/bdr2.1591"}], "href": "https://doi.org/10.1002/bdr2.1591"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31518072"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31518072"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Jinqiu Guan, Mengzhen Li, Yi Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MTHFD1 regulates the NADPH redox homeostasis in MYCN-amplified neuroblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-024-06490-3"}], "href": "https://doi.org/10.1038/s41419-024-06490-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38336749"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38336749"}]}]}]}