Ion pumps as biological targets for decavanadate

Abstract

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 V 10 (IC 50 = 15 μM) which is quite similar to the majority of the established therapeutic drugs.

Intracellular Ca2+ release from endoplasmic reticulum regulates slow wave currents and pacemaker activity of interstitial cells of Cajal

“…IC50 concentrations for these drugs on this transporter have been reported to be 0.2-3 M and 0.03 M, respectively (1,18). Ryanodine and tetracaine were used to block ryanodine receptor ER Ca 2ϩ channels.…”

Understanding the Regioselective Hydrolysis of Human Serum Albumin by Zr(IV)-Substituted Polyoxotungstates Using Tryptophan Fluorescence Spectroscopy

“…Metal-substituted POMs have been used as catalysts in several catalytic reactions, ranging from the epoxidation of olefins and alkanes to the splitting of water [26][27][28][29]. Additionally, POMs exhibit biological activity, which includes in vitro and in vivo anticancer, antiviral, antibiotic, antiprotozoal and antidiabetic activity [23,24,30]. Furthermore, inhibition of enzymes can be achieved as a result of the interaction of POMs with proteins [24,31], making POMs potential drugs for Alzheimer's disease [31].…”

“…These molecules are an assemblage of oxo-bridged early transition metals (mostly Mo, W, and V) in their highest oxidation state [13,14]. Their chemical and physical properties can be tuned, giving rise to a large number of possible applications in the fields of catalysis [15][16][17], material science [18][19][20] and medicine [21][22][23][24]. Moreover, the removal of one or more of the addenda atoms from the POM framework results in the formation of a lacunary species, which can coordinate different metal ions, resulting in the formation of metal-substituted POMs [11,25].…”

Characterization of decavanadate and decaniobate solutions by Raman spectroscopy

“…[1][2][3][4] Decavanadate is a homoleptic isopolyoxovanadate that interacts with high affinity with several proteins such as myosin, actin, and Ca 2+ -ATPase, thus affecting a range of cellular processes, including calcium homeostasis, muscle contraction, cytoskeleton dynamics and mitochondrial oxygen consumption. [4][5][6][7][8][9][10][11] Furthermore, the antidiabetic, anti-virus, anti-bacterial and anti-tumor activities of V 10 and vanadate compounds are attracting increasing interest. [12][13][14][15][16][17][18] Decavanadate also exhibits insulin-mimetic behavior, and it was shown that, upon incubation with decavanadate, rat adipocytes accumulate much more glucose than with well-established mimetic agents such as BMOV.…”