title: Molecular recognition of peloruside A by microtubules. The C24 primary alcohol is essential for biological activity.
abstract: Peloruside is a microtubule-stabilizing agent that targets the same site as laulimalide. It binds to microtubules with a 1:1 stoichiometry and with a binding affinity in the low-muM range; thereby reducing the number of microtubular protofilaments in the same way as paclitaxel. Although the binding affinity of the compound is comparable to that of the low-affinity stabilizing agent sarcodictyin, peloruside is more active in inducing microtubule assembly and is more cytotoxic to tumor cells; this suggests that the peloruside site is a more effective site for stabilizing microtubules. Acetylation of the C24 hydroxyl group results in inactive compounds. According to molecular modeling, this substitution at the C24 hydroxyl group presumably disrupts the interaction of the side chain with Arg320 in the putative binding site on alpha-tubulin. The binding epitope of peloruside on microtubules has been studied by using NMR spectroscopic techniques, and is compatible with the same binding site.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Benet
authors.initials: B
authors.lastname: Pera
authors.forename: Mina
authors.initials: M
authors.lastname: Razzak
authors.forename: Chiara
authors.initials: C
authors.lastname: Trigili
authors.forename: Oriol
authors.initials: O
authors.lastname: Pineda
authors.forename: Angeles
authors.initials: A
authors.lastname: Canales
authors.forename: Rubén M
authors.initials: RM
authors.lastname: Buey
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.forename: Peter T
authors.initials: PT
authors.lastname: Northcote
authors.forename: Ian
authors.initials: I
authors.lastname: Paterson
authors.forename: Isabel
authors.initials: I
authors.lastname: Barasoain
authors.forename: José Fernando
authors.initials: JF
authors.lastname: Díaz
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008870:Microtubules / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007783:Lactones; D014404:Tubulin; C414085:peloruside A