2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling.

Cell metabolism (2015-07-21)
Xudong Fu, Randall M Chin, Laurent Vergnes, Heejun Hwang, Gang Deng, Yanpeng Xing, Melody Y Pai, Sichen Li, Lisa Ta, Farbod Fazlollahi, Chuo Chen, Robert M Prins, Michael A Teitell, David A Nathanson, Albert Lai, Kym F Faull, Meisheng Jiang, Steven G Clarke, Timothy F Cloughesy, Thomas G Graeber, Daniel Braas, Heather R Christofk, Michael E Jung, Karen Reue, Jing Huang

We discovered recently that the central metabolite α-ketoglutarate (α-KG) extends the lifespan of C. elegans through inhibition of ATP synthase and TOR signaling. Here we find, unexpectedly, that (R)-2-hydroxyglutarate ((R)-2HG), an oncometabolite that interferes with various α-KG-mediated processes, similarly extends worm lifespan. (R)-2HG accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. We show that, like α-KG, both (R)-2HG and (S)-2HG bind and inhibit ATP synthase and inhibit mTOR signaling. These effects are mirrored in IDH1 mutant cells, suggesting a growth-suppressive function of (R)-2HG. Consistently, inhibition of ATP synthase by 2-HG or α-KG in glioblastoma cells is sufficient for growth arrest and tumor cell killing under conditions of glucose limitation, e.g., when ketone bodies (instead of glucose) are supplied for energy. These findings inform therapeutic strategies and open avenues for investigating the roles of 2-HG and metabolites in biology and disease.

Product Number
Product Description

Octyl-(R)-2HG, ≥98% (HPLC)
L-α-Hydroxyglutaric acid disodium salt, ≥98.0% (GC)

Social Media

LinkedIn icon
Twitter icon
Facebook Icon
Instagram Icon


Research. Development. Production.

We are a leading supplier to the global Life Science industry with solutions and services for research, biotechnology development and production, and pharmaceutical drug therapy development and production.

© 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

Reproduction of any materials from the site is strictly forbidden without permission.