DCBB, FCT, University of Algarve, 8005-139 Faro, Portugal.
Dalton Trans. 2013 Sep 7;42(33):11770-7. doi: 10.1039/c3dt50462j.
The putative applications of poly-, oligo- and mono-oxometalates in biochemistry, biology, pharmacology and medicine are rapidly attracting interest. In particular, these compounds may act as potent ion pump inhibitors and have the potential to play a role in the treatment of e.g. ulcers, cancer and ischemic heart disease. However, the mechanism of action is not completely understood in most cases, and even remains largely unknown in other cases. In the present review we discuss the most recent insights into the interaction between mono- and polyoxometalate ions with ion pumps, with particular focus on the interaction of decavanadate with Ca(2+)-ATPase. We also compare the proposed mode of action with those of established ion pump inhibitors which are currently in therapeutic use. Of the 18 classes of compounds which are known to act as ion pump inhibitors, the complete mechanism of inhibition is only known for a handful. It has, however, been established that most ion pump inhibitors bind mainly to the E2 ion pump conformation within the membrane domain from the extracellular side and block the cation release. Polyoxometalates such as decavanadate, in contrast, interact with Ca(2+)-ATPase near the nucleotide binding site domain or at a pocket involving several cytoplasmic domains, and therefore need to cross through the membrane bilayer. In contrast to monomeric vanadate, which only binds to the E2 conformation, decavanadate binds to all protein conformations, i.e. E1, E1P, E2 and E2P. Moreover, the specific interaction of decavanadate with sarcoplasmic reticulum Ca(2+)-ATPase has been shown to be non-competitive with respect to ATP and induces protein cysteine oxidation with concomitant vanadium reduction which might explain the high inhibitory capacity of V10 (IC50 = 15 μM) which is quite similar to the majority of the established therapeutic drugs.
多金属氧酸盐、寡金属氧酸盐和单金属氧酸盐在生物化学、生物学、药理学和医学中的潜在应用正在迅速引起人们的兴趣。特别是，这些化合物可能作为有效的离子泵抑制剂，并有可能在治疗溃疡、癌症和缺血性心脏病等疾病方面发挥作用。然而，在大多数情况下，其作用机制尚不完全清楚，在其他情况下甚至仍然知之甚少。在本综述中，我们讨论了关于单金属氧酸盐和多金属氧酸盐离子与离子泵相互作用的最新见解，特别关注了十钒酸盐与 Ca(2+)-ATP 酶的相互作用。我们还将提出的作用模式与目前在治疗中使用的已确立的离子泵抑制剂的作用模式进行了比较。在已知的 18 类作为离子泵抑制剂的化合物中，只有少数几种的完全抑制机制是已知的。然而，已经确定大多数离子泵抑制剂主要从细胞外侧的膜结构域结合到 E2 离子泵构象，并阻止阳离子释放。相比之下，多金属氧酸盐如十钒酸盐与 Ca(2+)-ATP 酶在核苷酸结合位点结构域附近或涉及几个细胞质结构域的口袋中相互作用，因此需要穿过膜双层。与仅结合到 E2 构象的单体钒酸盐不同，十钒酸盐结合到所有蛋白质构象，即 E1、E1P、E2 和 E2P。此外，已经表明十钒酸盐与肌浆网 Ca(2+)-ATP 酶的特异性相互作用对 ATP 是非竞争性的，并诱导蛋白质半胱氨酸氧化，同时钒还原，这可能解释了 V10 的高抑制能力（IC50=15 μM），这与大多数已确立的治疗药物相当相似。
