Lactonization of the Oncometabolite D-2-Hydroxyglutarate Produces a Novel Endogenous Metabolite.

Raffaela S Berger,Magdalena C Waldhier,Wolfram Gronwald,Marina Kreutz,Christian J Wachsmuth,Anuhar Chaturvedi,Katja Dettmer,Simone Thomas,Peter Hau,Martin Proescholdt,Michael Heuser,Peter J Oefner,Hans-Helmut Niller,Elisabeth Bumes,Kathrin Renner-Sattler

doi:10.3390/cancers13081756

Abstract

Simple SummarySomatic mutations in isocitrate dehydrogenase give rise to the excessive production and accumulation of D-2-hydroxyglutarate in certain malignancies. In addition to this well-described oncometabolite, we discovered a chemically related metabolite, namely 2-hydroxyglutarate-γ-lactone, which is derived directly from 2-hydroxyglutarate. This novel metabolite may impact the anti-tumor immune response.In recent years, onco-metabolites like D-2-hydroxyglutarate, which is produced in isocitrate dehydrogenase-mutated tumors, have gained increasing interest. Here, we report a metabolite in human specimens that is closely related to 2-hydroxyglutarate: the intramolecular ester of 2-hydroxyglutarate, 2-hydroxyglutarate-γ-lactone. Using 13C5-L-glutamine tracer analysis, we showed that 2-hydroxyglutarate is the endogenous precursor of 2-hydroxyglutarate-lactone and that there is a high exchange between these two metabolites. Lactone formation does not depend on mutated isocitrate dehydrogenase, but its formation is most probably linked to transport processes across the cell membrane and favored at low environmental pH. Furthermore, human macrophages showed not only striking differences in uptake of 2-hydroxyglutarate and its lactone but also in the enantiospecific hydrolysis of the latter. Consequently, 2-hydroxyglutarate-lactone may play a critical role in the modulation of the tumor microenvironment.

Highlights

The deregulation of cellular energetics and metabolism is an important hallmark of cancer
In some serum samples of patients with a IDH1/2 mutation, the intensity of the D-2-HG-lactone derivative was increased in comparison to the D-2-HG derivative (Figure 2), while both L-enantiomers were hardly observable
We studied the varying ability of cells to catalyze the lactonization of D2-HG

Summary

Introduction

The deregulation of cellular energetics and metabolism is an important hallmark of cancer. Several mutations that affect cellular metabolism were identified including the TCA cycle [3,4] and, in particular, the function of isocitrate dehydrogenase (IDH) [5,6]. IDH is a homodimeric enzyme with three different isoforms with distinct subcellular compartmentalization. IDH1, the cytosolic isoform, and IDH2, the mitochondrial isoform, are both NADP+ -dependent, whereas mitochondrial IDH3 is. NAD+ -dependent and a core component of the TCA cycle. All isoforms catalyze the reversible oxidative decarboxylation of isocitrate to α-ketoglutarate [7]. For IDH1 and IDH2, single base substitutions have been identified that result in a neo-enzymatic activity, i.e., the production of D-2-hydroxyglutarate (D-2-HG) from α-ketoglutarate [8].

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