Sarcoplasmic Reticulum Calcium ATPase Is Inhibited by Organic Vanadium Coordination Compounds: Pyridine-2,6-dicarboxylatodioxovanadium(V), BMOV, and an Amavadine Analogue

Abstract

The general affinity of the sarcoplasmic reticulum (SR) Ca 2+ -ATPase was examined for three different classes of vanadium coordination complexes including a vanadium(V) compound, pyridine-2,6-dicarboxylatodioxovanadium(V) (PDC-V(V)), and two vanadium(IV) compounds, bis(maltolato)oxovanadium(IV) (BMOV), and an analogue of amavadine, bis(N-hydroxylamidoiminodiacetato)vanadium(IV) (HAIDA-V(IV)). The ability of vanadate to act either as a phosphate analogue or as a transition-state analogue with enzymes' catalysis phosphoryl group transfer suggests that vanadium coordination compounds may reveal mechanistic preferences in these classes of enzymes. Two of these compounds investigated, PDC-V(V) and BMOV, were hydrolytically and oxidatively reactive at neutral pH, and one, HAIDA-V(IV), does not hydrolyze, oxidize, or otherwise decompose to a measurable extent during the enzyme assay. The SR Ca 2+ -ATPase was inhibited by all three of these complexes. The relative order of inhibition was PDC-V(V) > BMOV > vanadate > HAIDA-V(IV), and the IC 50 values were 25, 40, 80, and 325 µM, respectively. Because the observed inhibition is more potent for PDC-V(V) and BMOV than that of oxovanadates, the inhibition cannot be explained by oxovanadate formation during enzyme assays. Furthermore, the hydrolytically and redox stable amavadine analogue HAIDA-V(IV) inhibited the Ca 2+ -ATPase less than oxovanadates. To gauge the importance of the lipid environment, studies of oxidized BMOV in microemulsions were performed and showed that this system remained in the aqueous pool even though PDC-V(V) is able to penetrate lipid interfaces. These findings suggest that the hydrolytic properties of these complexes may be important in the inhibition of the calcium pump. Our results show that two simple coordination complexes with known insulin enhancing effects can invoke a response in calcium homeostasis and the regulation of muscle contraction through the SR Ca 2+ -ATPase.

Recent advances into vanadyl, vanadate and decavanadate interactions with actin

“…15,16 The broadening of NMR vanadate signals upon interaction with proteins has also been previously reported for several vanadate complexes. [17][18][19][20] As observed by SDS-PAGE gel electrophoresis, the isolation of actin, according to Pardee and Spudich, 21 produced a G-actin (42.3 kDa) with 99% purity (not shown), which allows concluding that the NMR observations described above are due to the interaction of the monomeric state of actin, G-actin, with decavanadate. On the other hand, the addition of actin in its polymerized form, F-actin, up to 50 mM, induces a much smaller broadening of V 10 signals (1.5-fold), in comparison with G-actin, suggesting that decavanadate protein binding sites are encrusted upon actin polymerization.…”

“…Taken together, the presence of ATP promotes the broadening of monomeric NMR vanadate signal but it prevents the broadening of decavanadate signals, suggesting that this nucleotide promotes monomeric vanadate interaction with actin but on contrary blocks decavanadate interaction. 15 The broadening of 20) and has served on the Editorial Boards of scientific journals. To date, he has supervised and/or co-supervised more than 80 post-doc, PhD, MSc and undergraduate students, and has published about 60 peer-reviewed journal articles, reviews and book chapters.…”

“…It was recently described that other vanadium species than the ones that are being studied can be observed under the experimental conditions. 20 In fact, even for vanadium complexes, known to induce several insulin-like effects, it was verified that other species can be formed, with vanadium oxidation states other than the original one. 20 Therefore, besides the factors known to describe the vanadium complex chemistry, namely, several oxidation states, similarity between phosphate and vanadate, the occurrence of several vanadate oligomers in solution and the formation of vanadium complexes with many molecules of biological interest, we may add the importance to address the stability of the vanadium complexes or species and to certify the presence of decameric vanadate species (responsible for the yellow colour of vanadate solutions), before to attempt to attribute a certain biological activity or effect to a vanadium complex or species.…”

Effects of decavanadate and insulin enhancing vanadium compounds on glucose uptake in isolated rat adipocytes

“…Mitochondria, for instance, a potential producer of reactive oxygen species, has been recently suggested to be a potential target of decavanadate [17], being suggested that mitochondrial membrane depolarization is a key event in vanadate-induced necrotic cell death of cardiomyocytes [18]. Studies have been done to learn more about the contribution of decameric vanadate species and also about the same vanadium complexes used in the present study, on Ca 2+ -ATPase from sarcoplasmatic reticulum, a transmembrane transport system that is involved in the regulation of muscle contraction [19]. Also, in skeletal muscle cells, it has been demonstrated that decameric vanadate also modulate myosin and actomyosin ATPase activities, responsible for the energy transduction that occurs during the process of muscle contraction [20,21].…”

Ion pumps as biological targets for decavanadate

“…8 SR Ca 2+ -ATPase activity is also inhibited by vanadium complexes such as vanadium-citrate and bis(maltolato)oxovanadium(IV) (BMOV) ( Table 1). 47,48 These and other vanadium compounds have been described in the treatment of diabetes mellitus. 49 Furthermore, decavanadate, 50 and compounds containing decavanadate 51 have been reported to lower glycemic levels, 50,51 and to normalize plasma lipid profiles.…”