MTHFD1L explained

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).^{[1] [2] [3]}

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.^[3]

In contrast to MTHFD1 that has trifunctional methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetase enzymatic activities, MTHFD1L only has formyltetrahydrofolate synthetase activity.^[4]

Clinical significance

Certain variants of the MTHFD1L are associated neural tube defects.^[5] Different alleles of SNP rs7646 in the 3′ UTR of MTHFD1L are differentially regulated by microRNAs affecting MTHFD1L expression.^[6]

Further reading

• McKnight AJ, Maxwell AP, Fogarty DG, etal . Genetic analysis of coronary artery disease single-nucleotide polymorphisms in diabetic nephropathy. . Nephrol. Dial. Transplant. . 24 . 8 . 2473–6 . 2009 . 19336575 . 10.1093/ndt/gfp015 . free .
• Bressler J, Folsom AR, Couper DJ, etal . 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 . 2010 . 19955471 . 10.1093/aje/kwp377 . 2800304.
• Sugiura T, Nagano Y, Inoue T, Hirotani K . A novel mitochondrial C1-tetrahydrofolate synthetase is upregulated in human colon adenocarcinoma. . Biochem. Biophys. Res. Commun. . 315 . 1 . 204–11 . 2004 . 15013446 . 10.1016/j.bbrc.2004.01.035 .
• Samani NJ, Erdmann J, Hall AS, etal . Genomewide association analysis of coronary artery disease. . N. Engl. J. Med. . 357 . 5 . 443–53 . 2007 . 17634449 . 10.1056/NEJMoa072366 . 2719290.
• Parle-McDermott A, Pangilinan F, O'Brien KK, etal . A common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency. . Hum. Mutat. . 30 . 12 . 1650–6 . 2009 . 19777576 . 10.1002/humu.21109 . 2787683.
• Pridgeon JW, Webber EA, Sha D, etal . Proteomic analysis reveals Hrs ubiquitin-interacting motif-mediated ubiquitin signaling in multiple cellular processes. . FEBS J. . 276 . 1 . 118–31 . 2009 . 19019082 . 10.1111/j.1742-4658.2008.06760.x . 2647816.
• Strausberg RL, Feingold EA, Grouse LH, etal . 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 . 2002 . 12477932 . 10.1073/pnas.242603899 . 139241. 2002PNAS...9916899M . free .
• Walkup AS, Appling DR . Enzymatic characterization of human mitochondrial C1-tetrahydrofolate synthase. . Arch. Biochem. Biophys. . 442 . 2 . 196–205 . 2005 . 16171773 . 10.1016/j.abb.2005.08.007 .
• Book: Fountoulakis M, Gulesserian T, Lubec G . Overexpression of C1-tetrahydrofolate synthase in fetal Down Syndrome brain . Advances in Down Syndrome Research . Journal of Neural Transmission. Supplementum . 67. 67 . 85–93 . 2003 . 15068241 . 10.1007/978-3-7091-6721-2_7. Journal of Neural Transmission Supplement 67 . 978-3-211-40776-9 .
• Sowa ME, Bennett EJ, Gygi SP, Harper JW . Defining the human deubiquitinating enzyme interaction landscape. . Cell . 138 . 2 . 389–403 . 2009 . 19615732 . 10.1016/j.cell.2009.04.042 . 2716422.
• Vieira AR, McHenry TG, Daack-Hirsch S, etal . Candidate gene/loci studies in cleft lip/palate and dental anomalies finds novel susceptibility genes for clefts. . Genet. Med. . 10 . 9 . 668–74 . 2008 . 18978678 . 10.1097/GIM.0b013e3181833793 . 2734954.
• Ewing RM, Chu P, Elisma F, etal . Large-scale mapping of human protein-protein interactions by mass spectrometry. . Mol. Syst. Biol. . 3 . 1. 89 . 2007 . 17353931 . 10.1038/msb4100134 . 1847948.

Notes and References

1. Prasannan P, Pike S, Peng K, Shane B, Appling DR . 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 . October 2003 . 12937168 . 1457088 . 10.1074/jbc.M304319200 . free .
2. Christensen KE, Mackenzie RE . Mitochondrial methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetases . Vitam. Horm. . 79 . 393–410 . 2008 . 18804703 . 10.1016/S0083-6729(08)00414-7 .
3. Web site: Entrez Gene: methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like.
4. Christensen KE, Patel H, Kuzmanov U, Mejia NR, MacKenzie RE . Disruption of the mthfd1 gene reveals a monofunctional 10-formyltetrahydrofolate synthetase in mammalian mitochondria . J. Biol. Chem. . 280 . 9 . 7597–602 . March 2005 . 15611115 . 10.1074/jbc.M409380200 . free .
5. Parle-McDermott A, Pangilinan F, O'Brien KK, Mills JL, Magee AM, Troendle J, Sutton M, Scott JM, Kirke PN, Molloy AM, Brody LC . A common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency . Hum. Mutat. . 30 . 12 . 1650–6 . December 2009 . 19777576 . 10.1002/humu.21109 . 2787683.
6. 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. 10.1002/humu.22459. 24123340. 6583361. 1059-7794.