Inhibition of tubulin polymerization with ribose-modified analogs of GDP and GTP reduced inhibition with microtubule-associated proteins and magnesium |
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| Authors: | Ernest Hamel Chii M. Lin |
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| Affiliation: | Laboratory of Medicinal Chemistry and Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20205 U.S.A. |
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| Abstract: | Inhibitory effects of ribose-modified GDP and GTP analogs on tubulin polymerization were examined to explore nucleotide structural requirements at the exchangeable GTP binding site. With microtubule-associated proteins and Mg2+, GTP-supported polymerization was only modestly inhibited by GDP, and still weaker inhibitory activity was found with two analogs, dGDP and 9-β-D-arabinofuranosylguanine-5′-diphosphate (araGDP). Omission of Mg2+ significantly enhanced the inhibitory effects of GDP, dGDP and araGDP and resulted in weak inhibition of the reaction by several other GDP analogs. The relative inhibitory activity of the GDP analogs had no discernable relationship to the relative activity of cognate GTP analogs in supporting microtubule-associated protein-dependent polymerization. One GTP analog, 2′,3′-dideoxyguanosine 5′-triphosphate (ddGTP), supports polymerization both with and without microtubule-associated proteins. The inhibitory activity of GDP and GDP analogs in ddGTP-supported polymerization was much greater in the absence of microtubule-associated proteins than in their presence; and both reactions were more readily inhibited than was microtubule-associated protein-dependent, GTP-supported polymerization. Microtubule-associated protein-independent, ddGTP-supported polymerization was also potently inhibited by GTP and a number of GTP analogs. GTP was in fact twice as inhibitory as GDP. The relative inhibitory activity of the GTP analogs was comparable to the relative inhibitory activity of the cognate GDP analogs and very different from their relative activity in supporting polymerization. |
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| Keywords: | Tubulin polymerization Guanine nucleotide analog Microtubule-associated protein acycloGDP and acycloGTP the di- and triphosphate derivatives at the side-chain hydroxyl of 9-(2-hydroxyethoxymethyl)guanine(acycloguanosine) ox-red GDP the dialcohol derivatives of GDP ox-redGTP GTP obtained by periodate oxidation and borohydride reduction araGDP araGTP triphosphate ddGDP 2′,3′-dideoxyguanosine 5′-di- ddGTP triphosphate 3′dGDP 3′-deoxyguanosine 5′-di- 3′dGTP triphosphate 2′OMeGDP 2′OMeGTP triphosphate 3′OMeGDP 3′OMeGTP triphosphate 2′OMeGDP guanosine 2′-monophosphate 5′-di 2′OMeGTP triphosphate 3′PGDP guanosine 3′-monophosphate 5′-di 3′PGTP triphosphate Mes 4-morpholineethane-sulfonate |
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