MCT2 mediates concentration-dependent inhibition of glutamine metabolism by MOG

Louise Fets, Paul C. Driscoll, Fiona Grimm, Aakriti Jain, Patrícia M. Nunes, Michalis Gounis, Ginevra Doglioni, George Papageorgiou, Timothy J. Ragan, Sebastien Campos, Mariana Silva dos Santos, James I. MacRae, Nicola O’Reilly, Alan J. Wright, Cyril H. Benes, Kevin D. Courtney, David House, Dimitrios Anastasiou

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

α-Ketoglutarate (αKG) is a key node in many important metabolic pathways. The αKG analog N-oxalylglycine (NOG) and its cell-permeable prodrug dimethyloxalylglycine (DMOG) are extensively used to inhibit αKG-dependent dioxygenases. However, whether NOG interference with other αKG-dependent processes contributes to its mode of action remains poorly understood. Here we show that, in aqueous solutions, DMOG is rapidly hydrolyzed, yielding methyloxalylglycine (MOG). MOG elicits cytotoxicity in a manner that depends on its transport by monocarboxylate transporter 2 (MCT2) and is associated with decreased glutamine-derived tricarboxylic acid–cycle flux, suppressed mitochondrial respiration and decreased ATP production. MCT2-facilitated entry of MOG into cells leads to sufficiently high concentrations of NOG to inhibit multiple enzymes in glutamine metabolism, including glutamate dehydrogenase. These findings reveal that MCT2 dictates the mode of action of NOG by determining its intracellular concentration and have important implications for the use of (D)MOG in studying αKG-dependent signaling and metabolism.

Original languageEnglish (US)
Pages (from-to)1032-1042
Number of pages11
JournalNature Chemical Biology
Volume14
Issue number11
DOIs
StatePublished - Nov 1 2018

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Glutamine
Dioxygenases
Glutamate Dehydrogenase
Prodrugs
Metabolic Networks and Pathways
oxalylglycine
Respiration
Adenosine Triphosphate
Enzymes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Fets, L., Driscoll, P. C., Grimm, F., Jain, A., Nunes, P. M., Gounis, M., ... Anastasiou, D. (2018). MCT2 mediates concentration-dependent inhibition of glutamine metabolism by MOG. Nature Chemical Biology, 14(11), 1032-1042. https://doi.org/10.1038/s41589-018-0136-y

MCT2 mediates concentration-dependent inhibition of glutamine metabolism by MOG. / Fets, Louise; Driscoll, Paul C.; Grimm, Fiona; Jain, Aakriti; Nunes, Patrícia M.; Gounis, Michalis; Doglioni, Ginevra; Papageorgiou, George; Ragan, Timothy J.; Campos, Sebastien; Silva dos Santos, Mariana; MacRae, James I.; O’Reilly, Nicola; Wright, Alan J.; Benes, Cyril H.; Courtney, Kevin D.; House, David; Anastasiou, Dimitrios.

In: Nature Chemical Biology, Vol. 14, No. 11, 01.11.2018, p. 1032-1042.

Research output: Contribution to journalArticle

Fets, L, Driscoll, PC, Grimm, F, Jain, A, Nunes, PM, Gounis, M, Doglioni, G, Papageorgiou, G, Ragan, TJ, Campos, S, Silva dos Santos, M, MacRae, JI, O’Reilly, N, Wright, AJ, Benes, CH, Courtney, KD, House, D & Anastasiou, D 2018, 'MCT2 mediates concentration-dependent inhibition of glutamine metabolism by MOG', Nature Chemical Biology, vol. 14, no. 11, pp. 1032-1042. https://doi.org/10.1038/s41589-018-0136-y
Fets L, Driscoll PC, Grimm F, Jain A, Nunes PM, Gounis M et al. MCT2 mediates concentration-dependent inhibition of glutamine metabolism by MOG. Nature Chemical Biology. 2018 Nov 1;14(11):1032-1042. https://doi.org/10.1038/s41589-018-0136-y
Fets, Louise ; Driscoll, Paul C. ; Grimm, Fiona ; Jain, Aakriti ; Nunes, Patrícia M. ; Gounis, Michalis ; Doglioni, Ginevra ; Papageorgiou, George ; Ragan, Timothy J. ; Campos, Sebastien ; Silva dos Santos, Mariana ; MacRae, James I. ; O’Reilly, Nicola ; Wright, Alan J. ; Benes, Cyril H. ; Courtney, Kevin D. ; House, David ; Anastasiou, Dimitrios. / MCT2 mediates concentration-dependent inhibition of glutamine metabolism by MOG. In: Nature Chemical Biology. 2018 ; Vol. 14, No. 11. pp. 1032-1042.
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