Vanadium is widely distributed, the twenty-first most abundant element in the Earth's crust, with an average content of 135 ppm. In sea water, vanadium ranks thirty-fourth in abundance, with an average concentration of only 2 ppb. Because it evolved as an essential element for certain forms of life and also because of its wide industrial use, the biological actions of vanadium are of interest to scientists. Excellent accounts of the history and previous know ledge of vanadium are available. (1-7). The chemistry of vanadium is complex because the metal can exist in oxidation states from -1 to +5 and forms polymers frequently (8). Recently Rubinson (9) reviewed the material concerning the form of biochemically active vanadium. The following generalizations appear justified. At low­ normal concentrations in mammals and birds, any free vanadium will be in hydrated, monomeric form. In the body fluids at pH 4-8, the predominant species will be VOi ( + 5 oxidation state), vanadate (metavanadate). VOi may enter certain cells by an anion transport system and be reduced by glutathione to VOH (+4 oxidation state), vanadyl. By way of speculation, the oxidation­ reduction reactions may be as follows: H+ + VOi + 2GSH � Y02+ + G2S2 + OH+ e + H20. Extensive binding to extraand intracellular ligands may be expected. Since phosphate and Mg2+ are ubiquitous in biological processes, YOi as the analogue of phosphate and Y02+, which resembles the size of Mg2+ (respective ionic radii: 0.60 and 0.65 ft.), potentially have many bio­ chemical and cellular sites of action. For example, vanadium compounds in­ hibit ATP phosphohydrolases, ribonuclease, adenylate kinase, phosphofructo­ kinase, squalene synthetase, glyceraldehyde-3-phosphate dehydrogenase (10),

Mechanisms of Action of Vanadium

Vanadate--a new tool for biologists.

Calcium transport mechanisms in membrane vesicles from guinea pig brain synaptosomes.

The oxyanions of vanadium, chromium, molybdenum, arsenic, and selenium are stable forms of these elements in high oxidation states which cross cell membranes using the normal phosphate and/or sulfate transport systems of the cell. Once inside the cell, these oxyanions may sulfuryl transfer reactions. Often the oxyanions serve as alternate enzyme substrates but form ester products which are hydrolytically unstable compared with the sulfate and phosphate esters and, therefore, decompose readily in aqueous solution. Arsenite and selenite are capable of reacting with sulfhydryl groups in proteins. Some cells are able to metabolize redox active oxyanions to forms of the elements in other stable oxidation states. Specific enzymes may be involved in the metabolic processes. The metabolites of these elements may form complexes with small molecules, proteins and nucleic acids which inhibit their ability to function properly. The divalent ions of beryllium, manganese, cobalt, nickel, cadmium, mercury, and lead are stable forms of these elements which may mimic essential divalent ions such as magnesium, calcium, iron, copper, or zinc. These ions may complex small molecules, enzymes, and nucleic acids in such a way that the normal activity of these species is altered. Free radicals may be produced in the presence of these metal ions which damage critical cellular molecules.

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The role of metals in carcinogenesis: biochemistry and metabolism.

Publisher Summary This chapter highlights physiological and metabolic effects on enzyme activities. Vanadium, a group V element, belongs to the first transition series and can form compounds mainly in valence states 3+, 4+, and 5+, both anionic and cationic species. Several criteria of essentiality of an element are satisfied by the properties of vanadium such as low molecular weight, excellent catalytic activity, appropriate atomic structure, its position as a transition metal, ability to form chelates potentially with biologically active compounds, ubiquity in the geosphere and possibly in the biosphere, homeostatic regulation by controlled accumulation and rapid excretion, deficiency in animals and plants showing characteristic symptoms, and low toxicity on oral intake. At least three significant enzymes of the plasma membrane are affected by vanadate—Na, K-ATPase is inhibited in nanomolar concentrations and adenylate cyclase and NADH oxidase are activated in micro-molar to milli-molar concentrations. These enzymes are interrelated. ATP is the substrate for the first two, and both substrates are nucleotides. Vanadate, affecting the transition state of phosphate, seems to have an affinity for the binding sites on these enzymes.

Does vanadium play a role in cellular regulation

Nerve cells can maintain a very low intracellular calcium concentration ([Ca2+]i) against large Ca2+ electrochemical gradients (see ref. 1 for review). The properties of the calcium efflux from these cells depend on [Ca2+]i (ref. 2), and within the physiological range, most Ca efflux depends on ATP (which stimulates with high affinity) and is insensitive to Nai, Na0 and Ca0 (uncoupled Ca efflux). When the [Ca2+]i is well above the physiological range, Ca efflux becomes only partially dependent on ATP (acting now with low affinity), is inhibited by Nai and is stimulated by Na0 and Ca0 (Na–Ca exchange). Orthovanadate, a powerful inhibitor of the (Na++K+) ATPase and the Na pump3,4, also inhibits the Ca-stimulated ATPase activity, which is the enzymatic basis for the uncoupled Ca pump, in human red cells5. The experiments reported here show that in squid axons the ATP-dependent uncoupled Ca efflux can be fully and reversibly inhibited by vanadate, whereas concentrations of vanadate 10 times higher have no effect on the Na–Ca exchange. This is another indication that the uncoupled Ca efflux represents an ATP-driven Ca pump, and supports the suggestion that the uncoupled Ca efflux and Na–Ca exchange are mediated by different mechanisms2.

Vanadate inhibits uncoupled Ca efflux but not Na--Ca exchange in squid axons.

The introduction of the squid giant axon preparation to studies on Ca homeostasis has proven very useful in laying the foundations in the study of Ca regulation. In particular the Na/Ca exchange mechanism has been characterized in terms of its regulatory processes using the well define technique of intracellular dialysis and membrane potential control. The Na/Ca exchange countertransport system plays a critical role in physiological processes including cardiac contractility and photoreception. It has also been implicate in the etiology of essential hypertension, cardiac arrhythmias and cell death. The ability of the Na/Ca exchanger to regulate the intracellular ionized Ca concentration ([Ca2+i]) under physiological conditions, is determined by the direction (net Ca efflux or Ca influx), and magnitude of transport. The direction of Ca transport is decided by the chemical gradient of sodium and calcium. The magnitude of the exchange is regulated by kinetic factors. This kinetic factors are critical since they decide whether the exchanger will mediate a net Ca movement under certain conditions. Recently, a large effort has been put together to characterize the secondary modulation of the Na/Ca exchanger. In particular modulation by MgATP and intracellular Ca2+. In nerve cells we have discover that MgATP regulates the exchanger through as phosphorylation-dephosphorylation processes most probably relate to the action of a kinase-phosphatase system. The other important ligand that regulates the exchange activity is the level of [Ca2+i]. We have found the presence of a regulatory site in the cytoplasmic face of the exchanger different from the transport site and probably responsible for turning the carrier "on" or "off". In this article we will depict some of the processes involved in the metabolic and ionic regulation of the Na/Ca exchanger.

H. R. Rojas

Papers

Vanadate inhibits uncoupled Ca efflux but not Na--Ca exchange in squid axons.

[Regulation of the Na/Ca exchanger].