Question

Mutations in citric acid cycle enzymes are rare, but devastating. For example, mutations in the fumarase enzyme that converts fumarate to malate causes symptoms including encephalopathy (a term for a wide range of brain development/function problems) and increased tumor risk.

a. Based on what you know about the citric acid cycle, why might mutations that reduce function of the fumerase enzyme result in these symptoms?

Answer 1

In cellular aerobic respiration, citric acid cycle plays the most important role. In this cycle the fumarase enzyme is involved in the conversion of fumarate to malate, thereby increasing the concentration of malate and decreasing the concentration of fumarate.

fumarase

Fumarate ------------------------------> Malate (reversible reaction)

This occurs inside the mitochondria, the power house of the cell. The gene responsible for the fumarase enzyme is fumarate hydratase(FH gene). This specific gene is located on chromosome 1 in the q arm of the chromosome. This gene is considered as tumor suppressor gene. As it keeps the tumor in check, any kind of natural or environmental factors causing mutation might change the amino acid sequence of the protein coding gene and it no longer serves the function of suppressing the tumor rather elevates the consequences of tumor causing actions. This can lead to deficiency of the protein leading to encephalopathy. In the course of evolution, this genetic mutation will be passed on to the next generation as a autosomal recessive disorder. When both the parents are carrier of the recessive gene, then the child receiving the carrier gene from both the parents is affected by the disease.