Question

EpothiloneB: binds to b-tubulin and prevents depolymerization

Many chemotherapeutic drugs target microtubules and microfilaments. Two drugs are listed below. One affects microtubules and one affects microfilaments. These drugs ACT ON THE NORMAL PROCESSES of cytoskeletal dynamics. Use your understanding of these processes to postulate on how the drug achieves its effect!

Given the effect of the drug what stage or stages of the cell cycle might be affected by this drug? Explain your reasoning

Answer 1

Microtubules are an important component of the cytoskeleton and is made up of alpha beta heterodimer. Protofilaments are formed when the alpha and beta subunits polymerize. These protofilaments will associate in an GTP dependent fashion to form hollow cylinders. Polymerization occurs at plus end of the microtubule. At the minus end (other end), microtubules under go depolymerization. Thus, microtubules grow at plus end, while the depolymerize (shorten) at minus end.

Epothilone B is a drug isolated from Myxobacteria. It stabilizes microtubules, and also induces apoptosis. This drug, bind to specific loci on microtubule. Epothilone binds to the beta tubulin. Beta tubulin has the GTP binding site. GTP bound to this site can be hydrolyzed to GDP. The other GTP bound to alpha subunit is not hydrolyzed to GDP. Thus, epothilone B promotes polymerization of microtubules. This results in a stabilized microtubule which will pack tightly. Such microtubules have 12 protofilaments.

Epothilone B also prevents calcium induced depolymerization of microtubules. As a result, there is formation of hyperstable microtubules. Microtubules are involved in mitosis stage of cell cycle, where they are involved in mitotic spindle formation and separation of chromosome. The hyperstable microtubules will inhibit mitosis stage of cell cycle and the cell remain halted in the G2/ M stage. The drug will also trigger apoptosis in the cell.