Enzyme inhibitor
This novel marine metabolite and microtubule-stabilizing agent (FW = 548.67 g/mol; IUPAC: (1S,3S,4R,7R,9R,11R,13S,14S,15S)-4,11,13,14- tetrahydroxy-7-[(2Z,4S)-4-(hydroxymethyl)hex-2-en-2-yl]-3,9,15- trimethoxy-12,12-dimethyl-6,17-dioxabicyclo[11.3.1]heptadecan-5-one) from the New Zealand sponge Mycale hentscheli has potent paclitaxel-like activity and is cytotoxic at low-nM concentrations. Its 16-membered macrolide ring resembles that found in the anticancer agent epothilone. Peloruside A arrests cells in the G2-M phase of the cell cycle and induces apoptosis. The peloruside A site on the a,b-tubulin heterodimer is topologically distinct from the taxoid site (which is used by paclitaxel, docetaxel, epothilone A, and discodermolide) and synergizes with these agents, enhancing their antimitotic action. Based on an earlier model for peloruside A binding to β-tubulin, a later and more persuasive model shows more extensive desolvation and a greater array of favorable hydrophobic and electrostatic interactions for peloruside A binding. The latter model is also suitable for laulimalide binding. Peloruside A-resistant lines contain single-base mutations in β-tubulin that result in the following substitutions: Arg-306-His, Tyr-340-Ser, Asn-337-Asp, and Ala-296-Ser in various combinations. These mutations are localized to peptides previously identified by Hydrogen-Deuterium exchange mapping, and center on a cleft in which the drug side chain appears to dock. Significantly, βII-tubulin and βIII-tubulin mediate sensitivity to peloruside A and laulimalide, but not paclitaxel or vinblastine, in human ovariancarcinoma cells. Analysis of microtubule (MT) growth times supports the view that catastrophic MT disassembly depends on the age of MTs. Colchicine and vinblastine accelerate aging in a manner that depends on the presence of end-binding proteins. On the other hand, while Paclitaxel and Peloruside A induce catastrophes, they compensate by promoting MT rescues and reversing the MT aging
