[HTML][HTML] Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase

M Shin, J Momb, DR Appling - Cancer & metabolism, 2017 - Springer
Cancer & metabolism, 2017Springer
Background Folate-dependent one-carbon metabolism provides one-carbon units for
several biological processes. This pathway is highly compartmentalized in eukaryotes, with
the mitochondrial pathway producing formate for use in cytoplasmic processes. The
mitochondrial enzyme MTHFD2 has been reported to use NAD+ as a cofactor while the
isozyme MTHFD2L utilizes NAD+ or NADP+ at physiologically relevant conditions. Because
MTHFD2 is highly expressed in many cancer types, we sought to determine the cofactor …
Background
Folate-dependent one-carbon metabolism provides one-carbon units for several biological processes. This pathway is highly compartmentalized in eukaryotes, with the mitochondrial pathway producing formate for use in cytoplasmic processes. The mitochondrial enzyme MTHFD2 has been reported to use NAD+ as a cofactor while the isozyme MTHFD2L utilizes NAD+ or NADP+ at physiologically relevant conditions. Because MTHFD2 is highly expressed in many cancer types, we sought to determine the cofactor preference of this enzyme.
Results
Kinetic analysis shows that purified human MTHFD2 exhibits dual redox cofactor specificity, utilizing either NADP+ or NAD+ with the more physiologically relevant pentaglutamate folate substrate.
Conclusion
These results show that the mitochondrial folate pathway isozymes MTHFD2 and MTHFD2L both exhibit dual redox cofactor specificity. Our kinetic analysis clearly supports a role for MTHFD2 in mitochondrial NADPH production, indicating that this enzyme is likely responsible for mitochondrial production of both NADH and NADPH in rapidly proliferating cells.
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