Biology:MTHFD1

Methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1) is a gene located in humans on chromosome 14 that encodes a protein, C-1-tetrahydrofolate synthase, cytoplasmic also known as C1-THF synthase, with three distinct enzymatic activities.

Function

This gene encodes a protein that possesses three distinct enzymatic activities, methylenetetrahydrofolate dehydrogenase (1.5.1.5), methenyltetrahydrofolate cyclohydrolase (3.5.4.9) and formate–tetrahydrofolate ligase (6.3.4.3). Each of these activities catalyzes one of three sequential reactions in the interconversion of 1-carbon derivatives of tetrahydrofolate, which are substrates for methionine, thymidylate, and de novo purine syntheses. The trifunctional enzymatic activities are conferred by two major domains, an aminoterminal portion containing the dehydrogenase and cyclohydrolase activities and a larger synthetase domain.

Clinical significance

Mutations of the MTHFD1 gene may cause methylenetetrahydrofolate dehydrogenase 1 deficiency, also known as combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (CIMAH).

Further reading

• "Cloning of three human multifunctional de novo purine biosynthetic genes by functional complementation of yeast mutations". Proceedings of the National Academy of Sciences of the United States of America 87 (8): 2916–2920. April 1990. doi:10.1073/pnas.87.8.2916. PMID 2183217. Bibcode: 1990PNAS...87.2916S. 
• "Nucleotide sequence of the human NAD-dependent methylene tetrahydrofolate dehydrogenase-cyclohydrolase". Nucleic Acids Research 17 (21): 8853. November 1989. doi:10.1093/nar/17.21.8853. PMID 2587219. 
• "Methylenetetrahydrofolate dehydrogenases in normal and transformed mammalian cells". Advances in Enzyme Regulation 27: 31–39. 1989. doi:10.1016/0065-2571(88)90007-6. PMID 3074630. 
• "Purification and characterization of a mitochondrial isozyme of C1-tetrahydrofolate synthase from Saccharomyces cerevisiae". The Journal of Biological Chemistry 261 (26): 12266–12271. September 1986. doi:10.1016/S0021-9258(18)67234-5. PMID 3528153. 
• "NAD-dependent methylenetetrahydrofolate dehydrogenase is expressed by immortal cells". The Journal of Biological Chemistry 260 (27): 14616–14620. November 1985. doi:10.1016/S0021-9258(17)38612-X. PMID 3877056. 
• "The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5 A resolution". Structure 6 (2): 173–182. February 1998. doi:10.1016/S0969-2126(98)00019-7. PMID 9519408. 
• "Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects". Clinical Genetics 53 (2): 119–125. February 1998. doi:10.1111/j.1399-0004.1998.tb02658.x. PMID 9611072. 
• "Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase". Biochemistry 39 (21): 6325–6335. May 2000. doi:10.1021/bi992734y. PMID 10828945. 
• "A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group". American Journal of Human Genetics 71 (5): 1207–1215. November 2002. doi:10.1086/344213. PMID 12384833. 
• "Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides". Nature Biotechnology 21 (5): 566–569. May 2003. doi:10.1038/nbt810. PMID 12665801. 
• "MTHFD1 R653Q polymorphism is a maternal genetic risk factor for severe abruptio placentae". American Journal of Medical Genetics. Part A 132A (4): 365–368. February 2005. doi:10.1002/ajmg.a.30354. PMID 15633187. 
• "A polymorphism in the MTHFD1 gene increases a mother's risk of having an unexplained second trimester pregnancy loss". Molecular Human Reproduction 11 (7): 477–480. July 2005. doi:10.1093/molehr/gah204. PMID 16123074. 
• "Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans". Proceedings of the National Academy of Sciences of the United States of America 102 (44): 16025–16030. November 2005. doi:10.1073/pnas.0504285102. PMID 16236726. Bibcode: 2005PNAS..10216025K. 
• "Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G>A polymorphism for neural tube defect risk". Journal of Human Genetics 51 (2): 98–103. 2006. doi:10.1007/s10038-005-0329-6. PMID 16315005. 
• "Methylenetetrahydrofolate reductase gene polymorphism, homocysteine and risk of macroangiopathy in Type 2 diabetes mellitus". Journal of Endocrinological Investigation 29 (9): 814–820. October 2006. doi:10.1007/bf03347376. PMID 17114913. 
• "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology 3 (1): 89. 2007. doi:10.1038/msb4100134. PMID 17353931. 

External links

• Overview of all the structural information available in the PDB for UniProt: P11586 (C-1-tetrahydrofolate synthase, cytoplasmic) at the PDBe-KB.