MTHFD1L

Monofunctional C1-tetrahydrofolate synthase, mitochondrial also known as formyltetrahydrofolate synthetase, is an enzyme that in humans is encoded by the MTHFD1L gene (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like).[5][6][7]

MTHFD1L
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2EO2
Identifiers
Aliases	MTHFD1L, FTHFSDC1, MTC1THFS, dJ292B18.2, methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like, methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like
External IDs	OMIM: 611427 MGI: 1924836 HomoloGene: 56706 GeneCards: MTHFD1L
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6q25.1 Start 150,865,549 bp[1] End 151,101,887 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10|10 A1 Start 3,973,118 bp[2] End 4,167,081 bp[2]
Gene ontology Molecular function • nucleotide binding • protein homodimerization activity • methenyltetrahydrofolate cyclohydrolase activity • formate-tetrahydrofolate ligase activity • ligase activity • ATP binding • methylenetetrahydrofolate dehydrogenase (NADP+) activity Cellular component • membrane • mitochondrial matrix • mitochondrion • cytoplasm Biological process • formate metabolic process • embryonic neurocranium morphogenesis • tetrahydrofolate interconversion • tetrahydrofolate metabolic process • neural tube closure • folic acid metabolic process • embryonic viscerocranium morphogenesis • oxidation-reduction process • folic acid-containing compound metabolic process • purine nucleobase biosynthetic process • 10-formyltetrahydrofolate biosynthetic process • one-carbon metabolic process • folic acid-containing compound biosynthetic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	25902	270685
Ensembl	ENSG00000120254	ENSMUSG00000040675
UniProt	Q6UB35 Q4VXM1	Q3V3R1
RefSeq (mRNA)	NM_001242767 NM_001242768 NM_001242769 NM_015440 NM_001350486 NM_001350487 NM_001350488 NM_001350489 NM_001350490 NM_001350491 NM_001350492 NM_001350493	NM_001170785 NM_001170786 NM_172308
RefSeq (protein)	NP_001229696 NP_001229697 NP_001229698 NP_056255 NP_001337415 NP_001337416 NP_001337417 NP_001337418 NP_001337419 NP_001337420 NP_001337421 NP_001337422	NP_001164256 NP_001164257 NP_758512
Location (UCSC)	Chr 6: 150.87 – 151.1 Mb	Chr 10: 3.97 – 4.17 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

One-carbon substituted forms of tetrahydrofolate (THF) are involved in the de novo synthesis of purines and thymidylate and support cellular methylation reactions through the regeneration of methionine from homocysteine. MTHFD1L is an enzyme involved in THF synthesis in mitochondria.[7]

In contrast to MTHFD1 that has trifunctional methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetase enzymatic activities, MTHFD1L only has formyltetrahydrofolate synthetase activity.[8]

Clinical significance

Certain variants of the MTHFD1L are associated neural tube defects.[9] Different alleles of SNP rs7646 in the 3′ UTR of MTHFD1L are differentially regulated by microRNAs affecting MTHFD1L expression.[10]

Model organisms

Mthfd1l knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Abnormal
Recessive lethal study	Abnormal
Fertility	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Plasma immunoglobulins	Normal
Haematology	Normal
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Normal
Skin Histopathology	Normal
Brain histopathology	Normal
Salmonella infection	Normal[11]
Citrobacter infection	Normal[12]
All tests and analysis from[13][14]

Model organisms have been used in the study of MTHFD1L function. A conditional knockout mouse line, called Mthfd1l^{tm1a(EUCOMM)Wtsi}[15][16] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[17][18][19]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[13][20] Twenty six tests were carried out on mutant mice and two significant abnormalities were observed.[13] The homozygous mutant embryos identified during gestation had exencephaly. None survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and no further abnormalities were observed.[13]

References

1. GRCh38: Ensembl release 89: ENSG00000120254 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000040675 - 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. Prasannan P, Pike S, Peng K, Shane B, Appling DR (October 2003). "Human mitochondrial C1-tetrahydrofolate synthase: gene structure, tissue distribution of the mRNA, and immunolocalization in Chinese hamster ovary calls". J. Biol. Chem. 278 (44): 43178–87. doi:10.1074/jbc.M304319200. PMC 1457088. PMID 12937168.
6. Christensen KE, Mackenzie RE (2008). "Mitochondrial methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetases". Vitam. Horm. 79: 393–410. doi:10.1016/S0083-6729(08)00414-7. PMID 18804703.
7. "Entrez Gene: methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like".
8. Christensen KE, Patel H, Kuzmanov U, Mejia NR, MacKenzie RE (March 2005). "Disruption of the mthfd1 gene reveals a monofunctional 10-formyltetrahydrofolate synthetase in mammalian mitochondria". J. Biol. Chem. 280 (9): 7597–602. doi:10.1074/jbc.M409380200. PMID 15611115.
9. Parle-McDermott A, Pangilinan F, O'Brien KK, Mills JL, Magee AM, Troendle J, Sutton M, Scott JM, Kirke PN, Molloy AM, Brody LC (December 2009). "A common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency". Hum. Mutat. 30 (12): 1650–6. doi:10.1002/humu.21109. PMC 2787683. PMID 19777576.
10. Minguzzi, Stefano; Selcuklu, S. Duygu; Spillane, Charles; Parle-McDermott, Anne (2013-12-18). "An NTD-Associated Polymorphism in the 3′ UTR of MTHFD1L can Affect Disease Risk by Altering miRNA Binding". Human Mutation. 35 (1): 96–104. doi:10.1002/humu.22459. ISSN 1059-7794. PMID 24123340. S2CID 6583361.
11. "Salmonella infection data for Mthfd1l". Wellcome Trust Sanger Institute.
12. "Citrobacter infection data for Mthfd1l". Wellcome Trust Sanger Institute.
13. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. S2CID 85911512.
14. Mouse Resources Portal, Wellcome Trust Sanger Institute.
15. "International Knockout Mouse Consortium".
16. "Mouse Genome Informatics".
17. Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M.; Harrow, J.; Cox, T.; Jackson, D.; Severin, J.; Biggs, P.; Fu, J.; Nefedov, M.; De Jong, P. J.; Stewart, A. F.; Bradley, A. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
18. Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
19. Collins FS, Rossant J, Wurst W (2007). "A Mouse for All Reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. S2CID 18872015.
20. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.

Further reading

• McKnight AJ, Maxwell AP, Fogarty DG, et al. (2009). "Genetic analysis of coronary artery disease single-nucleotide polymorphisms in diabetic nephropathy". Nephrol. Dial. Transplant. 24 (8): 2473–6. doi:10.1093/ndt/gfp015. PMID 19336575.
• Bressler J, Folsom AR, Couper DJ, et al. (2010). "Genetic variants identified in a European genome-wide association study that were found to predict incident coronary heart disease in the atherosclerosis risk in communities study". Am. J. Epidemiol. 171 (1): 14–23. doi:10.1093/aje/kwp377. PMC 2800304. PMID 19955471.
• Sugiura T, Nagano Y, Inoue T, Hirotani K (2004). "A novel mitochondrial C1-tetrahydrofolate synthetase is upregulated in human colon adenocarcinoma". Biochem. Biophys. Res. Commun. 315 (1): 204–11. doi:10.1016/j.bbrc.2004.01.035. PMID 15013446.
• Samani NJ, Erdmann J, Hall AS, et al. (2007). "Genomewide association analysis of coronary artery disease". N. Engl. J. Med. 357 (5): 443–53. doi:10.1056/NEJMoa072366. PMC 2719290. PMID 17634449.
• Parle-McDermott A, Pangilinan F, O'Brien KK, et al. (2009). "A common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency". Hum. Mutat. 30 (12): 1650–6. doi:10.1002/humu.21109. PMC 2787683. PMID 19777576.
• Pridgeon JW, Webber EA, Sha D, et al. (2009). "Proteomic analysis reveals Hrs ubiquitin-interacting motif-mediated ubiquitin signaling in multiple cellular processes". FEBS J. 276 (1): 118–31. doi:10.1111/j.1742-4658.2008.06760.x. PMC 2647816. PMID 19019082.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2002). "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. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Walkup AS, Appling DR (2005). "Enzymatic characterization of human mitochondrial C1-tetrahydrofolate synthase". Arch. Biochem. Biophys. 442 (2): 196–205. doi:10.1016/j.abb.2005.08.007. PMID 16171773.
• Fountoulakis M, Gulesserian T, Lubec G (2003). "Overexpression of C1-tetrahydrofolate synthase in fetal Down syndrome brain". J. Neural Transm. Suppl. Journal of Neural Transmission Supplement 67. 67 (67): 85–93. doi:10.1007/978-3-7091-6721-2_7. ISBN 978-3-211-40776-9. PMID 15068241.
• Sowa ME, Bennett EJ, Gygi SP, Harper JW (2009). "Defining the human deubiquitinating enzyme interaction landscape". Cell. 138 (2): 389–403. doi:10.1016/j.cell.2009.04.042. PMC 2716422. PMID 19615732.
• Vieira AR, McHenry TG, Daack-Hirsch S, et al. (2008). "Candidate gene/loci studies in cleft lip/palate and dental anomalies finds novel susceptibility genes for clefts". Genet. Med. 10 (9): 668–74. doi:10.1097/GIM.0b013e3181833793. PMC 2734954. PMID 18978678.
• 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.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.