MTHFD1

MTHFD1 is a gene located in humans on chromosome 14 that encodes for a protein with three distinct enzymatic activities. C-1-tetrahydrofolate synthase, cytoplasmic also known as C1-THF synthase is an enzyme that in humans is encoded by the MTHFD1 (methylenetetrahydrofolate dehydrogenase 1) gene.[5][6][7]

MTHFD1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1A4I, 1DIA, 1DIB, 1DIG
Identifiers
Aliases	MTHFD1, MTHFC, MTHFD, C1-THF-Synthase, methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1, CIMAH
External IDs	OMIM: 172460 MGI: 1342005 HomoloGene: 55940 GeneCards: MTHFD1
Gene location (Human) Chr. Chromosome 14 (human)[1] Band 14q23.3 Start 64,388,031 bp[1] End 64,463,457 bp[1]
Gene location (Mouse) Chr. Chromosome 12 (mouse)[2] Band 12|12 C3 Start 76,255,298 bp[2] End 76,319,803 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • nucleotide binding • methylenetetrahydrofolate dehydrogenase (NADP+) activity • methylenetetrahydrofolate dehydrogenase (NAD+) activity • ligase activity • methylenetetrahydrofolate dehydrogenase [NAD(P)+ activity] • catalytic activity • oxidoreductase activity • ATP binding • hydrolase activity • GO:0001948 protein binding • formate-tetrahydrofolate ligase activity • methenyltetrahydrofolate cyclohydrolase activity Cellular component • membrane • mitochondrion • extracellular exosome • cytoplasm • cytosol Biological process • purine nucleotide biosynthetic process • transsulfuration • neutrophil homeostasis • one-carbon metabolic process • serine family amino acid metabolic process • embryonic neurocranium morphogenesis • tetrahydrofolate interconversion • histidine biosynthetic process • cellular amino acid biosynthetic process • somite development • serine family amino acid biosynthetic process • methionine biosynthetic process • heart development • methionine metabolic process • neural tube closure • folic acid metabolic process • embryonic viscerocranium morphogenesis • metabolism • oxidation-reduction process • purine nucleobase biosynthetic process • 10-formyltetrahydrofolate biosynthetic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4522	108156
Ensembl	ENSG00000100714	ENSMUSG00000021048
UniProt	P11586	Q922D8
RefSeq (mRNA)	NM_005956 NM_001364837	NM_138745
RefSeq (protein)	NP_005947 NP_001351766	NP_620084
Location (UCSC)	Chr 14: 64.39 – 64.46 Mb	Chr 12: 76.26 – 76.32 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[7][8]

References

1. GRCh38: Ensembl release 89: ENSG00000100714 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000021048 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Hum DW, Bell AW, Rozen R, MacKenzie RE (Dec 1988). "Primary structure of a human trifunctional enzyme. Isolation of a cDNA encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase". J Biol Chem. 263 (31): 15946–50. PMID 3053686.
6. Rozen R, Barton D, Du J, Hum DW, MacKenzie RE, Francke U (Jun 1989). "Chromosomal localization of the gene for the human trifunctional enzyme, methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase". Am J Hum Genet. 44 (6): 781–6. PMC 1715669. PMID 2786332.
7. "Entrez Gene: MTHFD1 methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase".
8. Watkins D, Schwartzentruber JA, Ganesh J, Orange JS, Kaplan BS, Nunez LD, Majewski J, Rosenblatt DS (September 2011). "Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband". J. Med. Genet. 48 (9): 590–2. doi:10.1136/jmedgenet-2011-100286. PMID 21813566.

Further reading

• Schild D, Brake AJ, Kiefer MC, et al. (1990). "Cloning of three human multifunctional de novo purine biosynthetic genes by functional complementation of yeast mutations". Proc. Natl. Acad. Sci. U.S.A. 87 (8): 2916–20. doi:10.1073/pnas.87.8.2916. PMC 53804. PMID 2183217.
• Peri KG, Belanger C, Mackenzie RE (1989). "Nucleotide sequence of the human NAD-dependent methylene tetrahydrofolate dehydrogenase-cyclohydrolase". Nucleic Acids Res. 17 (21): 8853. doi:10.1093/nar/17.21.8853. PMC 335047. PMID 2587219.
• MacKenzie RE, Mejia N, Yang XM (1989). "Methylenetetrahydrofolate dehydrogenases in normal and transformed mammalian cells". Adv. Enzyme Regul. 27: 31–9. doi:10.1016/0065-2571(88)90007-6. PMID 3074630.
• Shannon KW, Rabinowitz JC (1986). "Purification and characterization of a mitochondrial isozyme of C1-tetrahydrofolate synthase from Saccharomyces cerevisiae". J. Biol. Chem. 261 (26): 12266–71. PMID 3528153.
• Mejia NR, MacKenzie RE (1985). "NAD-dependent methylenetetrahydrofolate dehydrogenase is expressed by immortal cells". J. Biol. Chem. 260 (27): 14616–20. PMID 3877056.
• Allaire M, Li Y, MacKenzie RE, Cygler M (1998). "The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5 A resolution". Structure. 6 (2): 173–82. doi:10.1016/S0969-2126(98)00019-7. PMID 9519408.
• Hol FA, van der Put NM, Geurds MP, et al. (1998). "Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects". Clin. Genet. 53 (2): 119–25. doi:10.1111/j.1399-0004.1998.tb02658.x. PMID 9611072.
• Schmidt A, Wu H, MacKenzie RE, et al. (2000). "Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase". Biochemistry. 39 (21): 6325–35. doi:10.1021/bi992734y. PMID 10828945.
• Brody LC, Conley M, Cox C, et al. (2003). "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". Am. J. Hum. Genet. 71 (5): 1207–15. doi:10.1086/344213. PMC 385099. PMID 12384833.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Gevaert K, Goethals M, Martens L, et al. (2004). "Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides". Nat. Biotechnol. 21 (5): 566–9. doi:10.1038/nbt810. PMID 12665801.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Parle-McDermott A, Mills JL, Kirke PN, et al. (2005). "MTHFD1 R653Q polymorphism is a maternal genetic risk factor for severe abruptio placentae". Am. J. Med. Genet. A. 132 (4): 365–8. doi:10.1002/ajmg.a.30354. PMID 15633187.
• Parle-McDermott A, Pangilinan F, Mills JL, et al. (2005). "A polymorphism in the MTHFD1 gene increases a mother's risk of having an unexplained second trimester pregnancy loss". Mol. Hum. Reprod. 11 (7): 477–80. doi:10.1093/molehr/gah204. PMID 16123074.
• Kohlmeier M, da Costa KA, Fischer LM, Zeisel SH (2005). "Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans". Proc. Natl. Acad. Sci. U.S.A. 102 (44): 16025–30. doi:10.1073/pnas.0504285102. PMC 1276051. PMID 16236726.
• De Marco P, Merello E, Calevo MG, et al. (2006). "Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G>A polymorphism for neural tube defect risk". J. Hum. Genet. 51 (2): 98–103. doi:10.1007/s10038-005-0329-6. PMID 16315005.
• Sun J, Xu Y, Zhu Y, Lu H (2007). "Methylenetetrahydrofolate reductase gene polymorphism, homocysteine and risk of macroangiopathy in Type 2 diabetes mellitus". J. Endocrinol. Invest. 29 (9): 814–20. doi:10.1007/bf03347376. PMID 17114913.
• Ewing RM, Chu P, Elisma F, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. 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.