title: Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues.
abstract: Mammalian mitochondria are able to produce formate from one-carbon donors such as serine, glycine, and sarcosine. This pathway relies on the mitochondrial pool of tetrahydrofolate (THF) and several folate-interconverting enzymes in the mitochondrial matrix. We recently identified MTHFD2L as the enzyme that catalyzes the oxidation of 5,10-methylenetetrahydrofolate (CH2-THF) in adult mammalian mitochondria. We show here that the MTHFD2L enzyme is bifunctional, possessing both CH2-THF dehydrogenase and 5,10-methenyl-THF cyclohydrolase activities. The dehydrogenase activity can use either NAD(+) or NADP(+) but requires both phosphate and Mg(2+) when using NAD(+). The NADP(+)-dependent dehydrogenase activity is inhibited by inorganic phosphate. MTHFD2L uses the mono- and polyglutamylated forms of CH2-THF with similar catalytic efficiencies. Expression of the MTHFD2L transcript is low in early mouse embryos but begins to increase at embryonic day 10.5 and remains elevated through birth. In adults, MTHFD2L is expressed in all tissues examined, with the highest levels observed in brain and lung.
authors.affiliation: From the Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712.
authors.forename: Minhye
authors.initials: M
authors.lastname: Shin
authors.affiliation: From the Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Bryant
authors.affiliation: From the Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712.
authors.forename: Jessica
authors.initials: J
authors.lastname: Momb
authors.affiliation: From the Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712 dappling@austin.utexas.edu.
authors.forename: Dean R
authors.initials: DR
authors.lastname: Appling
mesh_terms: D000367:Age Factors; D017398:Alternative Splicing / Q000502:physiology; D000619:Aminohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005574:Formate-Tetrahydrofolate Ligase / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology*; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D054259:Neural Tube / Q000196:embryology / Q000201:enzymology*; D010084:Oxidation-Reduction; D011247:Pregnancy; D051381:Rats; D013379:Substrate Specificity
chemical_list: D007527:Isoenzymes; D009097:Multienzyme Complexes; C055342:methylene tetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase; D009243:NAD; D009249:NADP; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D005492:Folic Acid; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases; D005574:Formate-Tetrahydrofolate Ligase
keywords: Folate Metabolism; Mitochondrial Metabolism; Multifunctional Enzymes; NAD; Neurodevelopment
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