Mammalian MTHFD2L Encodes a Mitochondrial Methylenetetrahydrofolate Dehydrogenase Isozyme Expressed in Adult Tissues

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 se...

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Published in:The Journal of biological chemistry 2011-02, Vol.286 (7), p.5166-5174
Main Authors: Bolusani, Swetha, Young, Blake A., Cole, Nicola A., Tibbetts, Anne S., Momb, Jessica, Bryant, Joshua D., Solmonson, Ashley, Appling, Dean R.
Format: Article
Language:English
Subjects:
Alternative Splicing - physiology
Animals
Cell Metabolism
CHO Cells
Cricetinae
Cricetulus
Folate Metabolism
Gene Expression Regulation, Enzymologic - physiology
Gene Structure
Humans
Isoenzymes - biosynthesis
Isoenzymes - genetics
Membrane Enzymes
Metabolism
Methylenetetrahydrofolate Dehydrogenase (NADP) - biosynthesis
Methylenetetrahydrofolate Dehydrogenase (NADP) - genetics
Mitochondria - enzymology
Mitochondria - genetics
Mitochondrial Metabolism
Mitochondrial Proteins - biosynthesis
Mitochondrial Proteins - genetics
One-carbon Metabolism
Organ Specificity - physiology
Rats
Rats, Sprague-Dawley
Tetrahydrofolates - metabolism
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Summary: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 (CH2-THF) to 10-formyl-THF in adult mammalian mitochondria are currently unknown. A new mitochondrial CH2-THF dehydrogenase isozyme, encoded by the MTHFD2L gene, has now been identified. The recombinant protein exhibits robust NADP+-dependent CH2-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 CH2-THF dehydrogenase isozyme thus fills the remaining gap in the pathway from CH2-THF to formate in adult mammalian mitochondria.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.196840