5. Gliomas and glioblastomas are cancers that stem from glial cells in the brain

Question

5. Gliomas and glioblastomas are cancers that stem from glial cells in the brain such as astrocytes, oligodendrocytes, ependymal cells and microglia. Gliomas are given grades I-IV dependent upon their relative aggressive growth potential with grade IV being the "highest" grade. Upwards of eighty percent of gliomas contain heterozygous R132H mutations in cytosolic isocitrate dehydrogenase(IDH1) and many high grade glioblastomas that have progressed to "high" grade from "lower" grade have also been found to contain the same mutation. IDH1 catalyzes a reversible reaction: isocitrateNADPa-ketoglutarate+ NADPH. IDH2 mutations have also been found to be oncogenic in humans. IDH2 is located in the mitochondria and catalyzes the same reaction as IDH1. IDH3 is the isoform of isocitrate dehydrogenase discussed in class. IDH1 and IDH2 function as homodimers, while IDH3 is comprised of 2?, 1? and 1? subunits.

Explanation / Answer

Hi, the mutations in the enzyme IDH have been strongly linked to incidence of cancer. This enzyme converts the citrate into alpha-KG. The reaction ensures that the TCA cycle continues and oxidative phosphorylation takes place in the cell. However, as we see in the table, the mutant enzyme IDH1 has different kinetic parameters than the Wild-type. The Km for NADP+ and isocitrate has increased significantly , 49 to 84 and 65 to 370 respectively. This means affinity of the IDH1 has reduced towards these substrates. The forward reaction or formation KG needs more substrates and thus the overall rate of the reaction decreases. the TCA cycle slows down. The Km of KG has reduced from 1.9*1063 to 24, this means this reaction reaches 1/2Vmax very soon. The reverse reaction of formation of isocitrate from KG is favoured and TCA cycle reverses with net formation of isocitrate. this is also evident in the reduction of kcat, which is the net turnover number or net formation of product. kcat has reduced from 10^4 to just 37.5. The formation of KG is not favored by the mutant.
The mutations in IDH1 results in the abnormal production of 2KG. This causes widespread changes to DNA demethylases which depend on the activity of several enzymes which depend on KG for their activity. IDH1 normally mitigates the oxidative damage. the mutation in IDH1 increases the oxidative stress in the cell.
The IDh3 catalyse the reversible oxidative decarboxylation of isocitrate to form KG. This drives the TCA cycle forward to generate ATP. The energy status of the cell is coupled to the activity of IDH3 when energy is no longer needed the IDH3 is inhibited by ATP and NADH. A homozygous mutant for IDH3 will be severely affected by ATP synthesis, which might be lethal to cells. Hence such mutants are not found in IDH3.
2. The km of the idh1 mutant is high for kg and also the kcat is very high. the reaction towards formation of isocitrate is favoured and a reaction occurs in opposite direction. This is also evident from the graph 2, where the formation of NADPH is high in a mutant, and also in graph 3, the consumption of NADH is also very low. These results show that the TCA cycle does not proceed towards energy production, but rather build up of NADH and isocitrate.

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