L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH
Andrew M Intlekofer1,2, Bo Wang1, Hui Liu3
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Nature Chemical Biology
|March 7, 2017
Summary
Lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) can produce L-2-hydroxyglutarate (L-2HG) from alpha-ketoglutarate (αKG). Acidic conditions boost L-2HG production, stabilizing HIF-1α in normoxia.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolomics
Background:
- 2-hydroxyglutarate (2HG) exists as D- and L-enantiomers, inhibiting α-ketoglutarate (αKG)-dependent enzymes.
- Oncogenic IDH mutations produce D-2HG, blocking cell differentiation.
- L-2HG accumulates under hypoxia, aiding physiologic adaptation.
Purpose of the Study:
- Investigate stereospecific L-2HG production by LDH and MDH.
- Determine the role of acidic pH in L-2HG generation.
- Elucidate the link between L-2HG and HIF-1α stabilization.
Main Methods:
- Enzymatic assays using purified LDH and MDH.
- Analysis of αKG reduction and L-2HG production.
- Assessment of HIF-1α stabilization under varying pH conditions.
Main Results:
- LDH and MDH stereospecifically produce L-2HG from αKG.
- Acidic pH enhances L-2HG production by promoting αKG binding to LDHA.
- Acid-enhanced L-2HG stabilizes HIF-1α in normoxia.
Conclusions:
- LDH and MDH exhibit promiscuous activity toward αKG, generating L-2HG.
- Microenvironmental acidity influences L-2HG production and cellular responses.
- Metabolite production by enzymes can be modulated by pH, impacting cell fate.
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