MTHFD1 explained

Methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1) is a gene located in humans on chromosome 14^[1] that encodes a protein, C-1-tetrahydrofolate synthase, cytoplasmic also known as C1-THF synthase, with three distinct enzymatic activities.^{[2] [3] [4]}

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.^{[4] [5]}

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).

References

Further reading

• Schild D, Brake AJ, Kiefer MC, Young D, Barr PJ . 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 . 2183217 . 53804 . 10.1073/pnas.87.8.2916 . free . 1990PNAS...87.2916S .
• Peri KG, Belanger C, Mackenzie RE . Nucleotide sequence of the human NAD-dependent methylene tetrahydrofolate dehydrogenase-cyclohydrolase . Nucleic Acids Research . 17 . 21 . 8853 . November 1989 . 2587219 . 335047 . 10.1093/nar/17.21.8853 .
• MacKenzie RE, Mejia N, Yang XM . Methylenetetrahydrofolate dehydrogenases in normal and transformed mammalian cells . Advances in Enzyme Regulation . 27 . 31–39 . 1989 . 3074630 . 10.1016/0065-2571(88)90007-6 .
• Shannon KW, Rabinowitz JC . 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 . 3528153 . 10.1016/S0021-9258(18)67234-5 . free .
• Mejia NR, MacKenzie RE . NAD-dependent methylenetetrahydrofolate dehydrogenase is expressed by immortal cells . The Journal of Biological Chemistry . 260 . 27 . 14616–14620 . November 1985 . 3877056 . 10.1016/S0021-9258(17)38612-X . free .
• Allaire M, Li Y, MacKenzie RE, Cygler M . The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5 A resolution . Structure . 6 . 2 . 173–182 . February 1998 . 9519408 . 10.1016/S0969-2126(98)00019-7 . free .
• Hol FA, van der Put NM, Geurds MP, Heil SG, Trijbels FJ, Hamel BC, Mariman EC, Blom HJ . 6 . 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 . 9611072 . 10.1111/j.1399-0004.1998.tb02658.x . 42398289 .
• Schmidt A, Wu H, MacKenzie RE, Chen VJ, Bewly JR, Ray JE, Toth JE, Cygler M . 6 . Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase . Biochemistry . 39 . 21 . 6325–6335 . May 2000 . 10828945 . 10.1021/bi992734y .
• Brody LC, Conley M, Cox C, Kirke PN, McKeever MP, Mills JL, Molloy AM, O'Leary VB, Parle-McDermott A, Scott JM, Swanson DA . 6 . 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 . 12384833 . 385099 . 10.1086/344213 .
• Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J . Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides . Nature Biotechnology . 21 . 5 . 566–569 . May 2003 . 12665801 . 10.1038/nbt810 . 23783563 .
• Parle-McDermott A, Mills JL, Kirke PN, Cox C, Signore CC, Kirke S, Molloy AM, O'Leary VB, Pangilinan FJ, O'Herlihy C, Brody LC, Scott JM . 6 . 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 . 15633187 . 10.1002/ajmg.a.30354 . 26023725 .
• Parle-McDermott A, Pangilinan F, Mills JL, Signore CC, Molloy AM, Cotter A, Conley M, Cox C, Kirke PN, Scott JM, Brody LC . 6 . 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 . 16123074 . 10.1093/molehr/gah204 . free .
• Kohlmeier M, da Costa KA, Fischer LM, Zeisel SH . 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 . 16236726 . 1276051 . 10.1073/pnas.0504285102 . free . 2005PNAS..10216025K .
• De Marco P, Merello E, Calevo MG, Mascelli S, Raso A, Cama A, Capra V . Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G>A polymorphism for neural tube defect risk . Journal of Human Genetics . 51 . 2 . 98–103 . 2006 . 16315005 . 10.1007/s10038-005-0329-6 . free .
• Sun J, Xu Y, Zhu Y, Lu H . Methylenetetrahydrofolate reductase gene polymorphism, homocysteine and risk of macroangiopathy in Type 2 diabetes mellitus . Journal of Endocrinological Investigation . 29 . 9 . 814–820 . October 2006 . 17114913 . 10.1007/bf03347376 . 38072740 .
• Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D . 6 . Large-scale mapping of human protein-protein interactions by mass spectrometry . Molecular Systems Biology . 3 . 1 . 89 . 2007 . 17353931 . 1847948 . 10.1038/msb4100134 .

Notes and References

1. Web site: Symbol report for MTHFD1. HUGO. HUGO Gene Nomenclature Committee. 13 March 2024.
2. Hum DW, Bell AW, Rozen R, MacKenzie RE . Primary structure of a human trifunctional enzyme. Isolation of a cDNA encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase . The Journal of Biological Chemistry . 263 . 31 . 15946–15950 . November 1988 . 3053686 . 10.1016/S0021-9258(18)37540-9 . free .
3. Rozen R, Barton D, Du J, Hum DW, MacKenzie RE, Francke U . Chromosomal localization of the gene for the human trifunctional enzyme, methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase . American Journal of Human Genetics . 44 . 6 . 781–786 . June 1989 . 2786332 . 1715669 .
4. Web site: Entrez Gene: MTHFD1 methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase.
5. Watkins D, Schwartzentruber JA, Ganesh J, Orange JS, Kaplan BS, Nunez LD, Majewski J, Rosenblatt DS . 6 . Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband . Journal of Medical Genetics . 48 . 9 . 590–592 . September 2011 . 21813566 . 10.1136/jmedgenet-2011-100286 . 9623450 .