Question

Ubiquitination relies on 3 enzymes E1, which activate ubiquitin; E2, which are the conjugating enzymes, and E3 enzymes, which help guide the E2 enzymes to specific substrates. In any given cell there are just a couple types of E1 enzymes, several types of E2 enzymes that partner with small subsets of E3 enzymes, and even more types of E3 enzymes, which bind with small subsets of specific protein substrates. Given this information, which of these mutations would you hypothesize to be the most harmful to a cell?"

	a.	a mutation in one type of E1 enzyme
	b.	a mutation in one type of E2 enzyme
	c.	a mutation in one type of E3 enzyme
	d.	all of these mutations would be equally harmful

Answer 1

Answer- a) Mutation in one type of E1 enzyme.

Explanation :- In the process of Ubiquitination a protein is inactivated by attaching Ubiquitin to it. Ubiquitin is a small molecule,it acts like a tag which signals the protein transport mechanism, It indicates to take the protein to the proteosome for degradation.

Proteosome are the protein complexes where degradation of unrequired and damaged proteins occur by the process of proteolysis. it is a chemical reaction which breaks the peptide bonds.

Ubiqitination process depends on three enzymes E1, E2 & E3.

E1 is known as ubiquiton activating enzyme, ubiquitin is activated by getting attached to the ubiquitin-activating enzyme (E1), it is then transferred to a second enzyme, called ubiquitin-conjugating enzyme (E2). The final transfer of ubiquitin to the target protein is mediated by a third enzyme (E3), or ubiquitin ligase. E3 is responsible for the selective recognition of suitable substrate proteins.

In some cases, the ubiquitin is first transferred from E2 to E3 and then to the target protein . In other cases, the ubiquitin is transferred directly from E2 to the target protein in a complex with E3.

Most cells contain a single E1, but have many E2s and multiple families of E3 enzymes. Different members of the E2 and E3 families recognize different substrate proteins, and the specificity of these enzymes are they targets cellular proteins for degradation by the ubiquitin-proteasome pathway.

E1 is the enzyme found in the upper strata or at the starting of the pathway and plays a significant role in activating the C-terminus of ubiquitin, it has no specificity for downstream targets. So loss of E1 affects all the downward steps.

In Drosophila it is seen that mutations in the Drosophila Ubiquitin Activating Enzyme, Uba1 or E1,that is loss of only one functional copy of E1 drastically reduces the adult lifespan. Rare homozygous hypomorphic E1 mutants reaches adulthood. These mutants shows reduced life span and inappropriate Ras activation in the brain. Removing a single functional copy of Ras, restores the lifespan of heterozygous E1 mutants to that of wild-type flies and increased the survival of homozygous E1 mutants.

E1 homozygous mutants, also shows severe motor impairment. Reduced lifespan and motor impairment is also found in case of human disease in X-linked Infantile Spinal Muscular Atrophy, it occurs due to mutation in E1.

so it is hypothesized that mutation in one of the enzyme of E1 is most harmful to the cell.