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.

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: 58630; GeneCards: MTHFD1; OMA:MTHFD1 - orthologs
Gene location (Mouse) Chr. Chromosome 12 (mouse) Band 12|12 C3 Start 76,302,072 bp End 76,366,577 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver gastrocnemius muscle Achilles tendon adipose tissue ganglionic eminence subcutaneous adipose tissue caudate nucleus nucleus accumbens right coronary artery kidney Top expressed in Paneth cell primitive streak right lobe of liver left lobe of liver right kidney epiblast Epithelium of choroid plexus human kidney left lung right lung lobe More reference expression data BioGPS 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 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 purine nucleobase biosynthetic process 10-formyltetrahydrofolate biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4522 108156 Ensembl n/a ENSMUSG00000021048 UniProt P11586 Q922D8 RefSeq (mRNA) NM_005956 NM_001364837 NM_138745 RefSeq (protein) NP_008637 NP_001351766 NP_620084 Location (UCSC) n/a Chr 12: 76.3 – 76.37 Mb PubMed search
Wikidata
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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

• 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)95007-6. 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.