Recent perspectives into biochemistry of decavanadate

Abstract

The number of papers about decavanadate has doubled in the past decade. In the present review, new insights into decavanadate biochemistry, cell biology, and antidiabetic and antitumor activities are described. Decameric vanadate species (V(10)) clearly differs from monomeric vanadate (V(1)), and affects differently calcium pumps, and structure and function of myosin and actin. Only decavanadate inhibits calcium accumulation by calcium pump ATPase, and strongly inhibits actomyosin ATPase activity (IC(50) = 1.4 μmol/L, V(10)), whereas no such effects are detected with V(1) up to 150 μmol/L; prevents actin polymerization (IC(50) of 68 μmol/L, whereas no effects detected with up to 2 mmol/L V(1)); and interacts with actin in a way that induces cysteine oxidation and vanadate reduction to vanadyl. Moreover, in vivo decavanadate toxicity studies have revealed that acute exposure to polyoxovanadate induces different changes in antioxidant enzymes and oxidative stress parameters, in comparison with vanadate. In vitro studies have clearly demonstrated that mitochondrial oxygen consumption is strongly affected by decavanadate (IC(50), 0.1 μmol/L); perhaps the most relevant biological effect. Finally, decavanadate (100 μmol/L) increases rat adipocyte glucose accumulation more potently than several vanadium complexes. Preliminary studies suggest that decavanadate does not have similar effects in human adipocytes. Although decavanadate can be a useful biochemical tool, further studies must be carried out before it can be confirmed that decavanadate and its complexes can be used as anticancer or antidiabetic agents.

Keywords: Actin; Actin polymerization; Antidiabetic agent; Antitumor agent; Calcium pump; Decavanadate; Insulin mimetic; Myosin; Vanadate.

Figure 1

Schematic structure of V₁₀ (V₁₀O₂₈^6-). Va, Vb and Vc represent the three different types of vanadium atoms described in the text.

Figure 2

Modes of calcium translocation by SR calcium pump as affected by different vanadate oligomers. V₁: Monomeric vanadate; V₄: Tetrameric vanadate; V₁₀: Decameric vanadate. Only V₁₀, and not V₁, was shown to inhibit calcium uptake in conditions 1 and 3, that is, when ATPase activity is coupled to calcium transport. V₁ only inhibits the ATPase in condition 2, where the calcium gradient is destroyed by oxalate or phosphate.

Figure 3

Relevant steps of ATP hydrolysis by actomyosin complex. The dominant process of ATP hydrolysis observed in vitro is indicated by the filled arrows. M: Myosin; Vi: Orthovanadate; V₁₀: Decavanadate. V₁₀, can blocked the process at two steps, without or with F-actin: before ATP hydrolysis and before product release, just before power stroke.

Figure 4

F-actin cysteine redox state, after 20 min exposure to decavanadate. Titration of cysteine was performed with 0.1 mmol/L 5,5’-ditiobis-(2-nitrobenzoic acid) and 2 μmol/L actin in 2 mmol/L Tris (pH 7.5), and 0.2 mmol/L CaCl₂. The increase in absorbance at 412 nm was continuously recorded over 10 min; To measure total cysteines the samples were treated afterwards with 1% SDS, and the absorbance was measured, over 15-30 min, until a steady value was reached. Titration with decavanadate produced a dose-dependent decrease in F-actin total cysteines, while Cys-374 (also named "fast cysteine") is reduced. The results shown are the average of triplicate experiments.

Figure 5

Exchange of bound ε-ATP of G-actin with ATP. Actin monomers (5 μmol/L) were incubated for 20 min with 0-200 μmol/L decavanadate, in 2 mmol/L Tris-HCl (pH 7.5), 0.2 mmol/L CaCl₂. The nucleotide exchange was monitored by the fluorescence decrease (λex = 350 nm; λem = 410 nm), as ε-ATP was replaced by ATP. Data are plotted as mean ± SD. The results shown are the average of triplicate experiments.

Figure 6

Scheme of proposed decavanadate (V₁₀) cellular targets. V₁₀ uptake through anionic channels (AC). Decavanadate might interact with membrane proteins. V₁₀ formation upon intracellular vanadium acidification in cytosol, but most probably in acidic organelles. Reduction of monomeric vanadate (V₁) by antioxidant agents. Binding of V₁₀ to target proteins; it is proposed that V₁₀ accumulates in subcellular organelles, such as mitochondria, affecting its function. Decavanadate also targets the contractile system, and its regulation, as well as calcium homeostasis (adapted from[14]).