Correia J J
Department of Biochemistry, University of Mississippi Medical Center, Jackson 39216.
Pharmacol Ther. 1991 Nov;52(2):127-47. doi: 10.1016/0163-7258(91)90004-6.
The interaction of antimitotic drugs with guanine nucleotides in the tubulin-microtubule system is reviewed. Antimitotic agent-tubulin interactions can be covalent, entropic, allosteric or coupled to other equilibria (such as divalent cation binding, alternate polymer formation, or the stabilization of native tubulin structure). Antimitotics bind to tubulin at a few common sites and alter the ability of tubulin to form microtubules. Colchicine and podophyllotoxin compete for a common overlapping binding site but only colchicine induces GTPase activity and large conformational changes in the tubulin heterodimer. The vinca alkaloids, vinblastine and vincristine, the macrocyclic ansa macrolides, maytansine and ansamitocin P-3, and the fungal antimitotic, rhizoxin, share and compete for a different binding site near the exchangeable nucleotide binding site. The macrocyclic heptapeptide, phomopsin A, and the depsipeptide, dolastatin 10, bind to a site adjacent to the vinca alkaloid and nucleotide sites. Colchicine, vinca alkaloids, dolastatin 10 and phomopsin A induce alternate polymer formation (sheets for colchicine, spirals for vinblastine and vincristine and rings for dolastatin 10 and phomopsin A). Maytansine, ansamitocin P-3 and rhizoxin inhibit vinblastine-induced spiral formation. Taxol stoichiometrically induces microtubule formation and, in the presence of GTP, assembly-associated GTP hydrolysis. Analogs of guanine nucleotides also alter polymer morphology. Thus, sites on tubulin for drugs and nucleotides communicate allosterically with the interfaces that form longitudinal and lateral contacts within a microtubule. Microtubule associated proteins (MAPs), divalent cations, and buffer components can alter the surface interactions of tubulin and thus modulate the interactions between antimitotic drugs and guanine nucleotides.
本文综述了抗有丝分裂药物与微管蛋白 - 微管系统中鸟嘌呤核苷酸的相互作用。抗有丝分裂剂与微管蛋白的相互作用可以是共价的、熵的、别构的或与其他平衡偶联（如二价阳离子结合、交替聚合物形成或天然微管蛋白结构的稳定）。抗有丝分裂剂在一些常见位点与微管蛋白结合，并改变微管蛋白形成微管的能力。秋水仙碱和鬼臼毒素竞争一个共同的重叠结合位点，但只有秋水仙碱能诱导GTP酶活性以及微管蛋白异二聚体的大的构象变化。长春花生物碱、长春碱和长春新碱、大环安莎大环内酯类、美登素和安丝菌素P - 3，以及真菌抗有丝分裂剂根霉素，共享并竞争可交换核苷酸结合位点附近的一个不同结合位点。大环七肽腐草霉素A和环肽多拉司他汀10结合到长春花生物碱和核苷酸位点相邻的一个位点。秋水仙碱、长春花生物碱、多拉司他汀10和腐草霉素A诱导交替聚合物形成（秋水仙碱形成片层，长春碱和长春新碱形成螺旋，多拉司他汀10和腐草霉素A形成环）。美登素、安丝菌素P - 3和根霉素抑制长春碱诱导的螺旋形成。紫杉醇按化学计量诱导微管形成，并且在GTP存在下，诱导与组装相关联的GTP水解。鸟嘌呤核苷酸类似物也改变聚合物形态。因此，微管蛋白上药物和核苷酸的位点与微管内形成纵向和横向接触的界面进行别构通讯。微管相关蛋白（MAPs）、二价阳离子和缓冲成分可以改变微管蛋白的表面相互作用，从而调节抗有丝分裂药物与鸟嘌呤核苷酸之间的相互作用。
