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: isocitrate NADP* a-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. A. Wild type and mutant enzyme are transfected into two types of brain cell lines, LN-18 and U87MG. LC-MS-MS is used to quantify and identify relative kinds and amount of metabolite:s produced in the cells after they were transfected with either wild type or R132H enzyme. Only three metabolites were found to be present in higher amount in the cells that had received mutant isocitrate dehydrogenase. The primary metabolite, A in the figure below, was determined to be 2-hydroxyglutarate (2-HG), with the other two metabolites, B and C, being the sodium coordinated or dehydrated forms of 2-HG. How is 2-HG, depicted below, related to ?-ketoglutarate (a-KG)? The structure of A, 2-hydroxyglutarate (2-HG): ?? ?? ?? a-ketoglutarate is depicted below: B. What is the reaction performed by isocitrate dehydrogenase 3 (IDH3), which is the one you already know from this course? Is this reaction reversible? How do you describe this reaction? How does the IDH1 isozyme, the isozyme discussed here, differ from IDH3, the one we discussed in class?

Explanation / Answer

Ans: A. 2-HG is the hydroxyl form of ?-ketoglutarate. Mutations in IDH1&2 leads to 2-HG production from ?-ketoglutarate. After decarboxylation step instead of removing H+ ion (proton) H+ ion is added to produce 2-HG B. IDH3 is a citric acid cycle enzyme present in the mitochondria is a hetero tetramer consisting of 2 ?, 1?, 1? subunits. Whereas IDH1 and 2 are homodimers are present in the cytoplasm, mitochondria as well as the peroxisomes and do not participate in citric acid cycle. IDH3 catalyses the third step of the citric acid cycle and converts NAD+ to NADH. IDH1 and 2 use NADP+ as a cofactor instead of NAD+. IDH3 reaction is irreversible rate limiting reaction whereas IDH1 and 2 reversible reactions.

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