학술논문
MCT2 mediates concentration-dependent inhibition of glutamine metabolism by MOG
Document Type
Article
Author
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
Source
Nature Chemical Biology; November 2018, Vol. 14 Issue: 11 p1032-1042, 11p
Subject
Language
ISSN
15524450; 15524469
Abstract
a-Ketoglutarate (aKG) is a key node in many important metabolic pathways. The aKG analog N-oxalylglycine (NOG) and its cell-permeable prodrug dimethyloxalylglycine (DMOG) are extensively used to inhibit aKG-dependent dioxygenases. However, whether NOG interference with other aKG-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 aKG-dependent signaling and metabolism.