Identification of a new chondropsin class of antitumor compound that selectively inhibits V-ATPases
Identification of a new chondropsin class of antitumor compound that selectively inhibits V-ATPases
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DOI：
10.1074/jbc.m306595200
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发表时间：
2003-11-07
影响因子：
4.8
通讯作者：
Boyd, MR
中科院分区：
文献类型：
--
作者：
Bowman, EJ;Gustafson, KR;Boyd, MR
我们确定了一个新的天然存在的类液泡H+-ATP酶（V-ATP酶）的抑制剂分离的液泡膜粗糙脉孢菌和嗜铬颗粒膜的牛。到目前为止，新的类别包括六个chondropsins和poecillastrin A，具有33 - 37元环的大聚酮衍生的大环内酯内酰胺。在国家癌症研究所的60细胞筛选中，软骨素类显示出与已确立的V-ATP酶抑制剂的巴弗洛霉素/康卡那霉素和水杨卤酰胺/洛巴他胺类基本上无法区分的肿瘤细胞生长抑制指纹。在离体条件下，真菌液泡V-ATP酶活性在0.04 - 0.7 μ M范围内受到抑制，嗜铬颗粒V-ATP酶活性在0.4-> 10 μ M范围内受到抑制。因此，新抑制剂的效力略低于其他两类抑制剂，这两类抑制剂通常对V-ATP酶具有< 10 nM的Ki值，并且新抑制剂在其特异性方面不同于其他两类抑制剂。巴夫洛霉素类抑制所有真核V-ATP酶，水杨卤酰胺类抑制哺乳动物V-ATP酶但不抑制真菌V-ATP酶，新的chondropsin类抑制N. crassa V-ATPase优于嗜铬颗粒V-ATPase。在N. crassa V-ATP酶影响巴弗洛霉素的结合有小的，但可重复的影响的亲和力的软骨脱落蛋白的V-ATP酶，这表明一个类似的抑制机制的可能性。
We identify a new naturally occurring class of inhibitor of vacuolar H+-ATPases (V-ATPases) isolated from vacuolar membranes of Neurospora crassa and from chromaffin granule membranes of Bos taurus. To date, the new class includes six chondropsins and poecillastrin A, large polyketide-derived macrolide lactams with 33 - 37 membered rings. In the National Cancer Institute's 60-cell screen the chondropsin class showed a tumor cell growth inhibitory fingerprint essentially indistinguishable from that of the bafilomycin/concanamycin and the salicylihalamide/lobatamide classes of well-established V-ATPase inhibitors. Half-maximal inhibition of V-ATPase activity in vitro occurred at 0.04 - 0.7 muM for the fungal vacuolar V-ATPase and at 0.4 to > 10 muM for the chromaffin granule V-ATPase. Thus, the new inhibitors are somewhat less potent than the other two classes, which typically have K-i values of < 10 nM for V-ATPases, and the new inhibitors differ from the other two classes in their specificity. The bafilomycin class inhibits all eucaryotic V-ATPases, the salicylihalamide class inhibits mammalian V-ATPases but not fungal V-ATPases, and the new chondropsin class inhibits the N. crassa V-ATPase better than the chromaffin granule V-ATPase. Two mutations in the N. crassa V-ATPase that affect the binding of bafilomycin had small but reproducible effects on the affinity of chondropsins for the V-ATPase, suggesting the possibility of a similar mechanism of inhibition.