title: Mammalian MTHFD2L encodes a mitochondrial methylenetetrahydrofolate dehydrogenase isozyme expressed in adult tissues.
abstract: Previous studies in our laboratory showed that isolated, intact adult rat liver mitochondria are able to oxidize the 3-carbon of serine and the N-methyl carbon of sarcosine to formate without the addition of any other cofactors or substrates. Conversion of these 1-carbon units to formate requires several folate-interconverting enzymes in mitochondria. The enzyme(s) responsible for conversion of 5,10-methylene-tetrahydrofolate (CH(2)-THF) to 10-formyl-THF in adult mammalian mitochondria are currently unknown. A new mitochondrial CH(2)-THF dehydrogenase isozyme, encoded by the MTHFD2L gene, has now been identified. The recombinant protein exhibits robust NADP(+)-dependent CH(2)-THF dehydrogenase activity when expressed in yeast. The enzyme is localized to mitochondria when expressed in CHO cells and behaves as a peripheral membrane protein, tightly associated with the matrix side of the mitochondrial inner membrane. The MTHFD2L gene is subject to alternative splicing and is expressed in adult tissues in humans and rodents. This CH(2)-THF dehydrogenase isozyme thus fills the remaining gap in the pathway from CH(2)-THF to formate in adult mammalian mitochondria.
authors.affiliation: Department of Chemistry and Biochemistry and the Institute for Cellular and Molecular Biology, The University of Texas, Austin, Texas 78712, USA.
authors.forename: Swetha
authors.initials: S
authors.lastname: Bolusani
authors.forename: Blake A
authors.initials: BA
authors.lastname: Young
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Cole
authors.forename: Anne S
authors.initials: AS
authors.lastname: Tibbetts
authors.forename: Jessica
authors.initials: J
authors.lastname: Momb
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Bryant
authors.forename: Ashley
authors.initials: A
authors.lastname: Solmonson
authors.forename: Dean R
authors.initials: DR
authors.lastname: Appling
mesh_terms: D017398:Alternative Splicing / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000096:biosynthesis* / Q000235:genetics; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D009928:Organ Specificity / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013763:Tetrahydrofolates / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D024101:Mitochondrial Proteins; D013763:Tetrahydrofolates; C013123:5,10-methylenetetrahydrofolic acid; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP)