α-Amanitin is a fungal toxin which inhibits eukaryotic RNA polymerases. The three eukaryotic RNA polymerases show differential sensitivity to this toxin. Which one of the following order (higher to lower) is correct in respect of sensitivity towards α-amanitin ?
(1) RNA POL III > RNA POL II > RNA POL I
(2) RNA POL II > RNA POL III > RNA POL I
(3) RNA POL I > RNA POL III > RNA POL II
(4) RNA POL II > RNA POL I > RNA POL III

Differential Sensitivity of Eukaryotic RNA Polymerases to α-Amanitin: Detailed Explanation

Slug: differential-sensitivity-rna-polymerases-alpha-amanitin

Understanding α-Amanitin and Its Target

α-Amanitin is a potent cyclic peptide toxin derived from certain poisonous mushrooms, notably the death cap (Amanita phalloides). Its biological significance stems from its ability to selectively inhibit eukaryotic RNA polymerases, the enzymes responsible for transcribing DNA into RNA. However, not all RNA polymerases are equally affected—each shows a distinct sensitivity profile to α-amanitin, which is crucial for both research and clinical toxicology.

Sensitivity Order of Eukaryotic RNA Polymerases

There are three main types of eukaryotic nuclear RNA polymerases:

• RNA Polymerase I: Synthesizes ribosomal RNA (rRNA), except 5S rRNA.

• RNA Polymerase II: Synthesizes messenger RNA (mRNA) and some small nuclear RNAs (snRNAs).

• RNA Polymerase III: Synthesizes transfer RNA (tRNA), 5S rRNA, and other small RNAs.

When exposed to α-amanitin, these polymerases exhibit the following sensitivity (from highest to lowest):

Correct order of sensitivity (higher to lower):
RNA Polymerase II > RNA Polymerase III > RNA Polymerase I

So, the correct answer is Option (2): RNA POL II > RNA POL III > RNA POL I.

Mechanism Behind Differential Sensitivity

• RNA Polymerase II: α-Amanitin binds tightly to the largest subunit of RNA polymerase II, blocking the enzyme’s translocation along the DNA template and effectively halting mRNA synthesis. This high affinity explains its extreme sensitivity.

• RNA Polymerase III: While also inhibited by α-amanitin, polymerase III requires a much higher concentration for inhibition, reflecting a lower binding affinity.
  RNA Polymerase I: This enzyme is structurally distinct in the region where α-amanitin binds, making it essentially resistant to the toxin at concentrations that inhibit the other two polymerases.

Why Is This Important?

Understanding the differential sensitivity of RNA polymerases to α-amanitin is vital for:

• Research: α-Amanitin is used experimentally to distinguish between the activities of different RNA polymerases in eukaryotic cells.

• Toxicology: Explains the molecular basis for the deadly effects of certain mushroom poisonings, which primarily disrupt mRNA synthesis in the liver and other organs.

Conclusion

α-Amanitin is a powerful tool and a deadly toxin, with its effects on eukaryotic RNA polymerases following a clear order of sensitivity:
RNA Polymerase II (most sensitive) > RNA Polymerase III > RNA Polymerase I (resistant).
This knowledge is not only key for exam preparation but also for understanding fundamental molecular biology and the dangers of natural toxins