MTHFD1

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; OMA:MTHFD1 - orthologs
Gene location (Mouse)
Chr.	Chromosome 12 (mouse)
End	76,366,577 bp
RNA expression pattern
	Top expressed in
	Top expressed in
	More reference expression data
	More reference expression data
Gene ontology
Molecular function
Cellular component
Biological process
	Sources:Amigo / QuickGO
Orthologs
	4522
	108156
	n/a
	ENSMUSG00000021048
	P11586
	Q922D8
	NM_005956; NM_001364837
	NM_138745
	NP_005947; NP_001351766
	NP_620084
	Wikidata
View/Edit Human	View/Edit Mouse

Methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1) is a gene located in humans on chromosome 14^[4] that encodes a protein, C-1-tetrahydrofolate synthase, cytoplasmic also known as C1-THF synthase, with three distinct enzymatic activities.^[5]^[6]^[7]

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]

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).^[8]

References

^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000021048 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Symbol report for MTHFD1". HUGO. HUGO Gene Nomenclature Committee. Retrieved 13 March 2024.
^ Hum DW, Bell AW, Rozen R, MacKenzie RE (November 1988). "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. doi:10.1016/S0021-9258(18)37540-9. PMID 3053686.
^ Rozen R, Barton D, Du J, Hum DW, MacKenzie RE, Francke U (June 1989). "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. PMC 1715669. PMID 2786332.
^ ^a ^b "Entrez Gene: MTHFD1 methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase".
^ ^a ^b Watkins D, Schwartzentruber JA, Ganesh J, Orange JS, Kaplan BS, Nunez LD, et al. (September 2011). "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. doi:10.1136/jmedgenet-2011-100286. PMID 21813566. S2CID 9623450.

Schild D, Brake AJ, Kiefer MC, Young D, Barr PJ (April 1990). "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. Bibcode:1990PNAS...87.2916S. doi:10.1073/pnas.87.8.2916. PMC 53804. PMID 2183217.
Peri KG, Belanger C, Mackenzie RE (November 1989). "Nucleotide sequence of the human NAD-dependent methylene tetrahydrofolate dehydrogenase-cyclohydrolase". Nucleic Acids Research. 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". Advances in Enzyme Regulation. 27: 31–39. doi:10.1016/0065-2571(88)90007-6. PMID 3074630.
Shannon KW, Rabinowitz JC (September 1986). "Purification and characterization of a mitochondrial isozyme of C1-tetrahydrofolate synthase from Saccharomyces cerevisiae". The Journal of Biological Chemistry. 261 (26): 12266–12271. doi:10.1016/S0021-9258(18)67234-5. PMID 3528153.
Mejia NR, MacKenzie RE (November 1985). "NAD-dependent methylenetetrahydrofolate dehydrogenase is expressed by immortal cells". The Journal of Biological Chemistry. 260 (27): 14616–14620. doi:10.1016/S0021-9258(17)38612-X. PMID 3877056.
Allaire M, Li Y, MacKenzie RE, Cygler M (February 1998). "The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5 A resolution". Structure. 6 (2): 173–182. doi:10.1016/S0969-2126(98)00019-7. PMID 9519408.
Hol FA, van der Put NM, Geurds MP, Heil SG, Trijbels FJ, Hamel BC, et al. (February 1998). "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. doi:10.1111/j.1399-0004.1998.tb02658.x. PMID 9611072. S2CID 42398289.
Schmidt A, Wu H, MacKenzie RE, Chen VJ, Bewly JR, Ray JE, et al. (May 2000). "Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase". Biochemistry. 39 (21): 6325–6335. doi:10.1021/bi992734y. PMID 10828945.
Brody LC, Conley M, Cox C, Kirke PN, McKeever MP, Mills JL, et al. (November 2002). "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. doi:10.1086/344213. PMC 385099. PMID 12384833.
Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J (May 2003). "Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides". Nature Biotechnology. 21 (5): 566–569. doi:10.1038/nbt810. PMID 12665801. S2CID 23783563.
Parle-McDermott A, Mills JL, Kirke PN, Cox C, Signore CC, Kirke S, et al. (February 2005). "MTHFD1 R653Q polymorphism is a maternal genetic risk factor for severe abruptio placentae". American Journal of Medical Genetics. Part A. 132A (4): 365–368. doi:10.1002/ajmg.a.30354. PMID 15633187. S2CID 26023725.
Parle-McDermott A, Pangilinan F, Mills JL, Signore CC, Molloy AM, Cotter A, et al. (July 2005). "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. doi:10.1093/molehr/gah204. PMID 16123074.
Kohlmeier M, da Costa KA, Fischer LM, Zeisel SH (November 2005). "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. Bibcode:2005PNAS..10216025K. doi:10.1073/pnas.0504285102. PMC 1276051. PMID 16236726.
De Marco P, Merello E, Calevo MG, Mascelli S, Raso A, Cama A, Capra V (2006). "Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G>A polymorphism for neural tube defect risk". Journal of Human Genetics. 51 (2): 98–103. doi:10.1007/s10038-005-0329-6. PMID 16315005.
Sun J, Xu Y, Zhu Y, Lu H (October 2006). "Methylenetetrahydrofolate reductase gene polymorphism, homocysteine and risk of macroangiopathy in Type 2 diabetes mellitus". Journal of Endocrinological Investigation. 29 (9): 814–820. doi:10.1007/bf03347376. PMID 17114913. S2CID 38072740.
Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 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.

[refGRCm38Ensembl-1] GRCm38: Ensembl release 89: ENSMUSG00000021048 – Ensembl, May 2017

[2] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[3] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Symbol report for MTHFD1". HUGO. HUGO Gene Nomenclature Committee. Retrieved 13 March 2024.

[pmid3053686-5] Hum DW, Bell AW, Rozen R, MacKenzie RE (November 1988). "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. doi:10.1016/S0021-9258(18)37540-9. PMID 3053686.

[pmid2786332-6] Rozen R, Barton D, Du J, Hum DW, MacKenzie RE, Francke U (June 1989). "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. PMC 1715669. PMID 2786332.

[entrez-7] "Entrez Gene: MTHFD1 methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase".

[Watkins_2011-8] Watkins D, Schwartzentruber JA, Ganesh J, Orange JS, Kaplan BS, Nunez LD, et al. (September 2011). "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. doi:10.1136/jmedgenet-2011-100286. PMID 21813566. S2CID 9623450.

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Enzymes: CO CS and CN ligases (EC 6.1-6.3)
6.1: Carbon-Oxygen	Aminoacyl tRNA synthetase Alanine Arginine Asparagine Aspartate Cysteine D-alanine—poly(phosphoribitol) ligase Glutamate Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine
6.2: Carbon-Sulfur	Succinyl coenzyme A synthetase Acetyl—CoA synthetase Long-chain-fatty-acid—CoA ligase
6.3: Carbon-Nitrogen	Glutamine synthetase Ubiquitin ligase Cullin Von Hippel–Lindau tumor suppressor UBE3A Mdm2 Anaphase-promoting complex UBR1 Glutathione synthetase CTP synthetase Adenylosuccinate synthase Argininosuccinate synthase Holocarboxylase synthetase GMP synthase Asparagine synthetase Carbamoyl phosphate synthetase I II Glutamate–cysteine ligase

Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

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