Microtubule Targeting Drugs

Microtubules are integral components of the mitotic spindle apparatus during metaphase in dividing cells. They are also involved in many nonmitotic functions such as intracellular scaffolding, locomotion and chemotaxis, secretory processes, anchorage of subcellular organelles, and neurotransmission. They are composed of tubulin heterodimers that assemble into 13 protofilaments aligned side by side around a hollow central core. Posttranslation modification after tubulin polymerization accounts for the functional diversity of microtubules in various tissues.

There is a constant flux between the microtubule and the intracellular pool of tubulin. Each tubulin molecule is associated with two molecules of guanosine triphosphate (GTP). GTP is found only at the rapidly growing, or plus end, of the microtubule. Its hydrolysis after tubulin polymerization is not essential for microtubule growth at the plus end; however, hydrolysis of GTP does lower the concentration of the free tubulin subunit required for net polymerization at the plus end. The plus end switches spontaneously and rapidly between slow growth and rapidly shrinking states.97 This "dynamic instability" occurs once the GTP "cap" is lost from the end of microtubule upon hydrolysis and depoly-merization occurs. In contrast, the "minus end" is where net disassociation occurs because protofilaments align slowly at this end.

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