Enzyme redesign guided by cancer-derived IDH1 mutations

Reitman, Zachary J.; Choi, Bryan D.; Spasojević, Ivan; Bigner, Darell D.; Sampson, John H.; Yan, Hai

doi:10.1038/nchembio.1065

Cited by 22 publications

(16 citation statements)

References 22 publications

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“…Indeed, mammalian carboxylation needs ATP and biotin for the CO 2 activation, and carboxylation of 2-oxoglutarate by the recombinant tumor mutants of isocitrate dehydrogenase has never been observed, even if the mutants do reduce 2-oxoglutarate to 2-hydroxyglutarate [ 26 ]. Analogous mutants of the isocitrate dehydrogenase homolog oxidizing homoisocitrate did not catalyze the carboxylation reaction either [ 64 ]. Our findings provide experimental evidence for the functional importance of the OGDH-dependent turnover of the TCA cycle in cancer cells, clearly showing that homeostasis of different types of tumor cells, including the most malignant glioblastoma cells, is significantly perturbed upon inhibition of oxidative decarboxylation of 2-oxoglutarate.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of mitochondrial 2-oxoglutarate dehydrogenase impairs viability of cancer cells in a cell-specific metabolism-dependent manner

et al. 2016

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2-Oxoglutarate dehydrogenase (OGDH) of the tricarboxylic acid (TCA) cycle is often implied to be inactive in cancer, but this was not experimentally tested. We addressed the question through specific inhibition of OGDH by succinyl phosphonate (SP). SP action on different cancer cells was investigated using indicators of cellular viability and reactive oxygen species (ROS), metabolic profiling and transcriptomics. Relative sensitivity of various cancer cells to SP changed with increasing SP exposure and could differ in the ATP- and NAD(P)H-based assays. Glioblastoma responses to SP revealed metabolic sub-types increasing or decreasing cellular ATP/NAD(P)H ratio under OGDH inhibition. Cancer cell homeostasis was perturbed also when viability indicators were SP-resistant, e.g. in U87 and N2A cells. The transcriptomics database analysis showed that the SP-sensitive cells, such as A549 and T98G, exhibit the lowest expression of OGDH compared to other TCA cycle enzymes, associated with higher expression of affiliated pathways utilizing 2-oxoglutarate. Metabolic profiling confirmed the dependence of cellular SP reactivity on cell-specific expression of the pathways. Thus, oxidative decarboxylation of 2-oxoglutarate is significant for the interdependent homeostasis of NAD(P)H, ATP, ROS and key metabolites in various cancer cells. Assessment of cell-specific responses to OGDH inhibition is of diagnostic value for anticancer strategies.

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Section: Discussionmentioning

confidence: 99%

Inhibition of mitochondrial 2-oxoglutarate dehydrogenase impairs viability of cancer cells in a cell-specific metabolism-dependent manner

et al. 2016

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“…170 However, several enzymatic transformations are currently being developed that could pave the way towards a completely biological synthesis method. [171][172][173] A consideration of the biotechnological production of AA, as well as the metabolic pathways leading to its precursors, has recently been reviewed by Polen et al 174…”

Section: Conversion Of D-glucosementioning

confidence: 99%

Emerging catalytic processes for the production of adipic acid

Vyver

Román‐Leshkov

2013

Catal. Sci. Technol.

293

216

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Research efforts to find more sustainable pathways for the synthesis of adipic acid have led to the introduction of new catalytic processes for producing this commodity chemical from alternative resources. With a focus on the performance of oxygen and hydrogen peroxide as preferred oxidants, this minireview summarizes recent advances made in the selective oxidation of cyclohexene, cyclohexane, cyclohexanone and n-hexane to adipic acid. Special attention is paid to the exploration of catalytic pathways involving lignocellulosic biomass-derived chemicals such as 5-hydroxymethylfurfural, D-glucose, g-valerolactone and compounds representative of lignin and lignin-derived bio-oils.Scheme 1 Simplified reaction scheme of the current industrial process for AA production by catalytic oxidation of KA oil with nitric acid. Scheme 6 Proposed mechanism for the transformation of cyclohexanone to e-caprolactone over HMSnP-1 in the presence of O 2 . 96 Scheme 7 Baeyer-Villiger oxidation of cyclohexanone with H 2 O 2 . Scheme 8 Hydrogenation of 5-hydroxymethylfurfural to 2,5-di-hydroxymethyltetrahydrofuran with RANEY s -Ni catalysts. 150 Scheme 10 Schematic illustration of the active sites on rhodium-rhenium catalysts for the hydrogenolysis of 2-THPM. Adapted from ref. 152.Scheme 9 Consecutive reaction pathway for the conversion of 2,5-di-hydroxymethyltetrahydrofuran to tetrahydro-2H-pyran-2-ylmethanol via 1,2,6-hexanetriol. 150

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“…However, the effi cient production of a key enzyme activity, 2-hydroxyadipate dehydrogenase, required for this process has been lacking. By translating the cancer-associated gain-of-function mutations in the IDH enzymes to the related Saccharomyces cerevisiae homoisocitrate dehydrogenase enzyme, investigators were able to reengineer this protein to catalyze the required reaction and produce chirally pure (R)-2-hydroxyadipic acid ( 15 ). It remains to be seen whether this approach will enable the cost-effective and scalable fossil fuel-independent production of this key chemical.…”

Section: Idh Mutations In Protein Engineeringmentioning

confidence: 99%

Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities

2013

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Heterozygous mutations in catalytic arginine residues of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are common in glioma, acute myeloid leukemia, chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. The mutant enzymes acquire a neomorphic activity that converts α-ketoglutarate (α-KG) to D-2-hydroxyglutarate (D2HG), a rare metabolite. In cells and tissues expressing mutant IDH, D2HG concentrations are highly elevated. D2HG may act as an "oncometabolite" by inhibiting a class of α-KG-dependent enzymes involved in epigenetic regulation, collagen synthesis, and cell signaling. Knock-in mouse models of IDH1 mutations have shed light on these mechanisms and will provide valuable animal models for further investigation.Signifi cance: Mutations in IDH1 and IDH2 promote the development of a number of malignancies. These active site mutations cause a gain-of-function leading to the accumulation of the rare metabolite D2HG. Mouse models of these mutations should provide insights into the mechanisms driving tumorigenesis and facilitate evaluation of new treatments. Cancer Discov; 3(7); 730-41.

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Enzyme redesign guided by cancer-derived IDH1 mutations

Cited by 22 publications

References 22 publications

Inhibition of mitochondrial 2-oxoglutarate dehydrogenase impairs viability of cancer cells in a cell-specific metabolism-dependent manner

Inhibition of mitochondrial 2-oxoglutarate dehydrogenase impairs viability of cancer cells in a cell-specific metabolism-dependent manner

Emerging catalytic processes for the production of adipic acid

Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities

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