2-Oxoglutarate-dependent dioxygenases (2OGDDs) are a superfamily of enzymes that play diverse roles in many biological processes, including regulation of hypoxia-inducible factor-mediated adaptation to hypoxia, extracellular matrix formation, epigenetic regulation of gene transcription and the reprogramming of cellular metabolism. 2OGDDs all require oxygen, reduced iron and 2-oxoglutarate (also known as α-ketoglutarate) to function, although their affinities for each of these co-substrates, and hence their sensitivity to depletion of specific co-substrates, varies widely. Numerous 2OGDDs are recurrently dysregulated in cancer. Moreover, cancer-specific metabolic changes, such as those that occur subsequent to mutations in the genes encoding succinate dehydrogenase, fumarate hydratase or isocitrate dehydrogenase, can dysregulate specific 2OGDDs. This latter observation suggests that the role of 2OGDDs in cancer extends beyond cancers that harbour mutations in the genes encoding members of the 2OGDD superfamily. Herein, we review the regulation of 2OGDDs in normal cells and how that regulation is corrupted in cancer.
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This work was supported by Academy of Finland grants 266719 and 308009 and grants from the S. Jusélius Foundation, the Finnish Cancer Organization and the Jane and Aatos Erkko Foundation to P.K. J.-A.L. is supported by the NIH. W.G.K. is a Howard Hughes Medical Investigator and supported by the NIH.
W.G.K. Jr. declares the following competing interests: Lilly Pharmaceuticals (board of directors), Agios Pharmaceuticals (scientific advisory board), Cedilla Therapeutics (founder), Fibrogen (scientific advisory board, royalties), Nextech Invest (scientific advisory board, carried interest) and Tango Therapeutics (founder). J.-A.L. and P.K. declare no competing interests.
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NCBI protein database: https://www.ncbi.nlm.nih.gov/protein
RCSB protein databank: https://www.rcsb.org/
One of two molecules that have the same atomic formula and the same sequence of atomic bonds but that differ in their 3D orientations insofar as they are mirror images of each other.
A deficiency in the amount of oxygen being supplied to body tissues.
Intermediates of metabolism that abnormally accumulate in cancer cells and that promote tumorigenesis.
A bidentate ligand is a base that donates two pairs of electrons to a metal atom.
A state in which the level of oxygen in the blood is lower than normal.
- K m
(Michaelis constant). The substrate concentration required for an enzymatic reaction to achieve one-half of its maximum velocity in vitro; a high Km value indicates low affinity and a low Km value indicates high affinity.
(Half-maximal inhibitory concentration). The concentration at which an inhibitor half-maximally inhibits a biochemical reaction in vitro.
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Losman, JA., Koivunen, P. & Kaelin, W.G. 2-Oxoglutarate-dependent dioxygenases in cancer. Nat Rev Cancer 20, 710–726 (2020). https://doi.org/10.1038/s41568-020-00303-3