Lactonization of the oncometabolite d-2-hydroxyglutarate produces a novel endogenous metabolite

Berger RS, Wachsmuth CJ, Waldhier MC, Renner-Sattler K, Thomas S, Chaturvedi A, Niller HH, Bumes E, Hau P, Proescholdt M, Gronwald W, Heuser M, Kreutz M, Oefner PJ, Dettmer K (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Cancers MDPI

Book Volume: 13

Article Number: 1756

Journal Issue: 8

DOI: 10.3390/cancers13081756

Abstract

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. Using13C5-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.

Involved external institutions

Universität Regensburg DE Germany (DE) Universitätsklinikum Regensburg DE Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE)

How to cite

APA:

Berger, R.S., Wachsmuth, C.J., Waldhier, M.C., Renner-Sattler, K., Thomas, S., Chaturvedi, A.,... Dettmer, K. (2021). Lactonization of the oncometabolite d-2-hydroxyglutarate produces a novel endogenous metabolite. Cancers, 13(8). https://doi.org/10.3390/cancers13081756

MLA:

Berger, Raffaela S., et al. "Lactonization of the oncometabolite d-2-hydroxyglutarate produces a novel endogenous metabolite." Cancers 13.8 (2021).

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