3. A class of mutations in TCA cycle enzymes result in a “hypermethylator phenotype” in a...

3. A class of mutations in TCA cycle enzymes result in a “hypermethylator phenotype” in a variety of human tumors. Briefly describe this phenomenon, including the enzymes and associated mutations, and how these epigenetic alterations can contribute to tumorigenesis.

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Expert Solution

A lot of reasons are there behind the occurrence of cancer. When normal cell undergo uncontrolled multiplication its status changes to cancerous cell.

In DNA , cytosine (N base of DNA) is methylated in the 5th position. Changes in the amount and distribution of 5-methyl cytosine leads to cancerous conditions. Cancers characteristically display extensive frequent focal DNA hypermethylation.

TCA cycle is needed to generate energy in human body. Large number of enzymes control this cycle. Increased number of cells (cancer) relies on an increased glycolytic flux and also it cause acquired alterations in some enzyme of TCA cycle. Major alterations happening in the enzymes are

1. Germ line defects in gene encoding subunits of Succinate dehydrogenase (SDH) and Fumarate hydratase(FH)

2. Somatic mutation in coding sequence of Isocitrate dehydrogenase(IDH)

MAJOR ENZYMES AND MUTATIONS

1. Succinate dehydrogenase(SDH)

Major function of this enzyme is the oxidation of Succinate to fumarate and reduction of ubiquinone to ubiquinol in ETC (electron transport chain).

SDH is a tumour suppressor contain 2 catalytic sub units A and B, which protrude in to the matrix of mitochondria. and two hydrophobic subunits C and D which anchor mitochondrial membrane and act as binding site for ubiquinone.

mutations - Gastro intestinal stromal tumors, renal cell cancers, thyroid tumors, neuroblastomas, and testicular seminoma.

2. Fumarate hydratse (FH)

Function of FH is to convert fumarate to L-Malate.

Mutations -

Homozygous FH deficiencies ; fumaric aciduria

Heterozygous FH deficiencies ; Hereditary leiomyomatosis, Kidney tumors

major effect of FH mutation is loss of wild type allele in the transformed cells.

3. Isocitrate dehydrogenase (IDH)

Function is to convert isocitrate to 2Oxo glutarare and also invoved in the production of CO2

Mutations - Acute myeloid leukemia

gladiator answered 1 year ago

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