Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations.

The most frequently mutated metabolic genes in human cancer are those encoding the enzymes isocitrate dehydrogenase 1 (IDH1) and IDH2; these mutations have so far been identified in more than 20 tumor types. Since mutations were first reported in glioma over a decade ago, extensive research has revealed their association with altered cellular processes. Mutations in lead to a change in enzyme function, enabling efficient conversion of 2-oxoglutarate to 2-hydroxyglutarate (2-HG).

Isocitrate dehydrogenase gene variants in cancer and their clinical significance.

Human isocitrate dehydrogenase (IDH) genes encode for the IDH1, 2 & 3 isoenzymes which catalyse the formation of 2-oxoglutarate from isocitrate and are essential for normal mammalian metabolism. Although mutations in these genes in cancer were long thought to lead to a 'loss of function', combined genomic and metabolomic studies led to the discovery that a common IDH 1 mutation, present in low-grade glioma and acute myeloid leukaemia (AML), yields a variant (R132H) with a striking change of function leading to the production of (2R)-hydroxyglutarate (2HG) which consequently accumulates in large quantities both within and outside cells. Elevated 2HG is proposed to promote tumorigenesis, although the precise mechanism by which it does this remains uncertain.

Roles of metal ions in the selective inhibition of oncogenic variants of isocitrate dehydrogenase 1.

Cancer linked isocitrate dehydrogenase (IDH) 1 variants, notably R132H IDH1, manifest a 'gain-of-function' to reduce 2-oxoglutarate to 2-hydroxyglutarate. High-throughput screens have enabled clinically useful R132H IDH1 inhibitors, mostly allosteric binders at the dimer interface. We report investigations on roles of divalent metal ions in IDH substrate and inhibitor binding that rationalise this observation.

Isocitrate dehydrogenase variants in cancer - Cellular consequences and therapeutic opportunities.

Abnormal metabolism is common in cancer cells and often correlates with mutations in genes encoding for enzymes involved in small-molecule metabolism. Isocitrate dehydrogenase 1 (IDH1) is the most frequently mutated metabolic gene in cancer. Cancer-associated substitutions in IDH1 and IDH2 impair wild-type production of 2-oxoglutarate and reduced nicotinamide adenine dinucleotide phosphate (NADPH) from isocitrate and oxidised nicotinamide adenine dinucleotide phosphate (NADP ), and substantially promote the IDH variant catalysed conversion of 2-oxoglutarate to d-2-hydroxyglutarate (d-2HG).

Anion-exchange chromatography mass spectrometry provides extensive coverage of primary metabolic pathways revealing altered metabolism in IDH1 mutant cells.

Altered central carbon metabolism is a hallmark of many diseases including diabetes, obesity, heart disease and cancer. Identifying metabolic changes will open opportunities for better understanding aetiological processes and identifying new diagnostic, prognostic, and therapeutic targets. Comprehensive and robust analysis of primary metabolic pathways in cells, tissues and bio-fluids, remains technically challenging.