Molecular and Cellular Biochemistry

, Volume 153, Issue 1–2, pp 17–24 | Cite as

Vanadium chemistry and biochemistry of relevance for use of vanadium compounds as antidiabetic agents

  • Debbie C. Crans
  • Mohammed Mahroof-Tahir
  • Anastasios D. Keramidas
Part I: Chemistry


The stability of 11 vanadium compounds is tested under physiological conditions and in administration fluids. Several compounds including those currently used as insulin-mimetic agents in animal and human studies are stable upon dissolution in distilled water but lack such stability in distilled water at pH7. Complex lability may result in decomposition at neutral pH and thus may compromise the effectiveness of these compounds as therapeutic agents; Even well characterized vanadium compounds are surprisingly labile. Sufficiently stable complexes such as the VEDTA complex will only slowly reduce, however, none of the vanadium compounds currently used as insulin-mimetic agents show the high stability of the VEDTA complex. Both the bis(maltolato)oxovanadium(IV) and peroxovanadium complexes extend the insulin-mimetic action of vanadate in reducing cellular environments probably by increased lifetimes under physiological conditions and/or by decomposing to other insulin mimetic compounds. For example, treatment with two equivalents of glutathione or other thiols the (dipicolinato)peroxovanadate(V) forms 9dipicolinato)oxovanadate(V) and vanadate, which are both insulin-mimetic vanadium(V) compounds and can continue to act. The reactivity of vanadate under physiological conditions effects a multitude of biological responses. Other vanadium complexes may mimic insulin but not induce similar responses if the vanadate formation is blocked or reduced. We conclude that three properties, stability, lability and redox chemistry are critical to prolong the half-life of the insulin-mimetic form of vanadium compounds under physiological conditions and should all be considered in development of vanadium-based oral insulin-mimetic agents.

Key words

vanadium chemistry vanadium biochemistry compound stability compound lability insulin-mimetic metabolic involvement 



adenosine 5′-diphosphate


adenosine 5′-triphosphate


adenosine 5′-diphosphate-vanadate




bis(peroxo)oxovanadium(V) dimer






ethylenediaminetetraacetic acid


electron paramagnetic resonance


exchange spectroscopy






β-nicotinamide adenine dinucleotide


β-nicotinamide adenine dinucleotide phosphate


β-nicotinamide adenine dinucleotide vanadate


nuclear magnetic resonance (also referred to as magnetic resonance imaging)














vanadate monomer


vanadate dimer


vanadate tetramer


vanadate pentamer

UV-vis spectroscopy

ultraviolet-visible spectroscopy


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  1. 1.
    Shechter Y: Insulin-mimetic effects of vanadate. Possible implications for future treatment of diabetes. Diabetes 39: 1–5, 1990Google Scholar
  2. 2.
    Posner BI; Shaver A, Fantus IG: Insulin mimetic agents: Vanadium and peroxovanadium compounds. In: C.J. Bailey, P.R. Flatt (ed.). New Antidiabetic Drugs, Smith, Gordon, 1990, pp. 107–118Google Scholar
  3. 3.
    Shechter Y, Shisheva A, Lazar R, Libman J, Shanzer A: Hydrophobic carriers of vanadyl ions augment the insulinomimetic actions of vanadyl ions in rat adipocytes. Biochem 31: 2063–2068, 1992Google Scholar
  4. 4.
    Orvig C, Thompson KH, Battell M, McNeill JH: Vanadium compounds as insulin mimics. In: H. Sigel, A. Sigel (ed.). Metal Ions in Biological Systems. Marcel Dekker Inc., New York, 1995, 31: 575–594Google Scholar
  5. 5.
    Posner BI, Faure R, Burgess JW, bevan AP, Lachance D, Zhang-Sun G, Fantus IG, Ng JB, Hall DA, Soo Lum B, Shaver A: Teroxovanadium compounds. A new class of potent phosphotyrosine phosphatase inhibitors which are insulin mimetics. J Biol Chem 269: 4596–4604, 1994Google Scholar
  6. 6.
    Crans DC: Enzyme interactions with labile oxovanadates and other oxometalates. Comments on Inorganic Chemistry 16: 35–76, 1994Google Scholar
  7. 7.
    Stankiewicz PJ, Tracey AS, Crans DC: Inhibition of phosphatemetabolizing enzymes by oxovanadium complexes. In: H. Sigel, A. Sigel (ed.). Metal Ions in Biological Systems. Marcel Dekker Inc., New York, 1995, 31: 287–324Google Scholar
  8. 8.
    Stankiewicz PJ, Tracey AS: Stimulation of enzyme activity by oxovanadium complexes. In: H. Sigel, A. Sigel (ed.). Metal Ions in Biological Systems. Marcel Dekker Inc., New York, 1995, 31: 249–286Google Scholar
  9. 9.
    Gresser MJ, Tracey AS, Stankiewicz PJ: The interaction of vanadate with tyrosine kinases and phosphatases. Adv Prot Phosphatases 4: 35–57, 1987Google Scholar
  10. 10.
    Nechay BR, Nanninga, LB, Nechay PSE, Post, RL, Grantham JJ, Macara IG, Kubena LF, Phillips TD, Nielsen FH: Role of vanadium in biology. FASEB 45: 123–132, 1986Google Scholar
  11. 11.
    Willsky GR: Vanadium in the biosphere. In: N.D. Chasteen (ed.). Vanadium in Biological Systems: Physiology and Biochemistry. Kluwer Academic Publishers: Boston, 1990, p. 1–24Google Scholar
  12. 12.
    Gresser MJ, Tracey AS: Vanadium(V) oxyanions: The esterification of ethanol with vanadate. J Am Chem Soc 107: 4215–4220, 1985Google Scholar
  13. 13.
    Gresser MJ, Tracey AS, Parkinson KM: Vanadium(V) oxyanions: The interaction of vanadate with pyrophosphate, phosphate, and arsenate. J Am Chem Soc 108: 6229–6234, 1986Google Scholar
  14. 14.
    Macara IG, Kustin K, Cantley LC, Jr.: Glutatione reduces cytoplasmic vanadate; mechanism and physiological implications. Biochim Biophys Acta 629: 95–106, 1980Google Scholar
  15. 15.
    Sakurai H, Shimomura S, Ishizu K: Reduction of vanadate(V) to oxovanadium(IV) by cysteine and mechanism and structure of the oxovanadium(IV)-cysteine complex subsequently formed. Inorg Chim Acta 55: L67-L69, 1981Google Scholar
  16. 16.
    Kustin K, McLeod GC, Gilbert TR, Briggs LBR 4th: Vanadium and other metal ions in the physiological ecology of marine orgarismus. Structure and Bonding 53: 139–161, 1983Google Scholar
  17. 17.
    Chasteen ND, Grady JK, Holloway CE: Characterization of the binding, kinetics, and redox stability of vanadium(IV) and vanadium(V) protein complexes in serum. Inorg Chem 25: 2754–2760, 1986Google Scholar
  18. 18.
    Willsky GR, White DA, McCabe BC: Metabolism of added orthovanadate to vanadyl and high-molecular-weight vanadates by Saccharomyces cerevisiae. J Biol Chem 259: 13273–13281, 1984Google Scholar
  19. 19.
    Cantley LC, Jr., Aisen P: The fate of cytoplasmic vanadium. J Biol Chem 254: 1781–1784, 1979Google Scholar
  20. 20.
    Crans DC, Cortizo AM, Etcheverry SB, Mahroof-Tahir M: Vanadate proliferation in osteoblast: Studies probing the active species, submitted, 1994Google Scholar
  21. 21.
    Chasteen ND: Vanadyl(IV) EPR spin probes inorganic and biochemical aspects. In: J. Reuben (ed.). Biological Magnetic Resonance. Plenum Press: New York, 1981, p. 53–119Google Scholar
  22. 22.
    Crans DC, Simone CM, Blanchard JS: Chemically induced modification of cofactor specificity of glucose-6-phosphate dehydrogenase. J Am Chem Soc 114: 4926–4928, 1992Google Scholar
  23. 23.
    Liochev SI, Fridovich I: Vanadate-stimulated oxidation of NAD(P)H in the presence of biological membranes and other sources of O2. Arch Biochem Biophys 279: 1–7, 1990Google Scholar
  24. 24.
    Nour-Eldeen AF, Craig MM, Gresser MJ: Interaction of inorganic vanadate with glucose-6-phosphate dehydrogenase. Nonenzymic formation of glucose-6-vanadate. J Biol Chem 260: 6836–6842, 1985Google Scholar
  25. 25.
    Drueckhammer DG, Durrwachter JR, Pederson RL, Crans DC, Daniels L, Wong C-H: Reversible and in situ formation of organic arsenates and vanadates as organic phosphate mimics in enzymatic reactions: Mechanistic investigation of aldol reactions and synthetic applications. J Org Chem 54: 70–77, 1989Google Scholar
  26. 26.
    Lindquist RN, Lynn JL, Jr., Lienhard GE: Possible transition-state analogs for ribonuclease. The complexes of uridine with oxovanadium(IV) ion and vanadium(V) ion. J Am Chem Soc 95: 8762–8768, 1973Google Scholar
  27. 27.
    Ray WJ, Jr., Puvathingal JM: Characterization of a vanadate-based transition-state-analogue complex of phosphoglucomutase by kinetic and equilibrium binding studies. Mechanistic implications. Biochem 29: 2790–2801, 1990Google Scholar
  28. 28.
    Percival MD, Doherty K, Gresser MJ: Inhibition of phosphoglucomutase by vanadate. Biochem 29: 2764–2769, 1990Google Scholar
  29. 29.
    Goodno CC: Inhibition of myosin ATPase by vanadate ion. Proc Natl Acad Sci USA 76: 2620–2624, 1979Google Scholar
  30. 30.
    Combest WL, Johnson RA: Detergent-induced distinctions between fluoride- and vanadate-stimulated adenylate cyclases and their responses to guanine nucleotides. Arch Biochem Biophys 225: 916–927, 1983Google Scholar
  31. 31.
    Lopez V, Stevens T, Lindquist RN: Vanadium ion inhibition of alkaline phosphatase-catalyzed phosphate ester hydrolysis. Arch Biochem Biophys 175: 31–38, 1976Google Scholar
  32. 32.
    Kadota S, Fantus IG, Deragon G, Guyda HJ, Hersh B, Posner BI: Peroxide(s) of vanadium: A novel and potent insulin-mimetic agent which activates the insulin receptor kinase. Biochem Biophys Res Commun 147: 259–266, 1987Google Scholar
  33. 33.
    Svensson IB, Stomberg R: Studies on peroxovanadates. I. The crystal structure of ammonium μoxo-bis(oxodiperoxovanadate(V)), (NH4)4[O(VO(O2)2)2]. Acta Chem Scand 25: 898–910, 1971Google Scholar
  34. 34.
    Shaver A, Ng JB, Hall DA, Lum BS, Posner BI: Insulin-mimetic peroxovanadium complexes: Preparation and structure of potassium oxodiperoxo(pyridine-2-carboxylato)vanadate(V), K2[VO(O2)2(C5H4NCOO)]·2H2O, and potassium oxodiperoxo(3-hydroxypyridine-2-carboxylato)vanadate(V), K2[VO(O2)2(OHC5H3NCOO)]·3H2O, and their reactions with cysteine. Inorg Chem 32: 3109–3113, 1993Google Scholar
  35. 35.
    Wieghardt K: Preparation and characterization of dipicolinatovanadium(V) complexes: Kinetics and mechanism of their reaction with hydrogen peroxide in acidic media. Inorg Chem 17: 57–64, 1978Google Scholar
  36. 36.
    McNeill JH, Yuen VG, Hoveyda HR, Orvig C: Bis(maltolato)-oxovanadium(IV) is a potent insulin mimic. J Med Chem 35: 1489–1491, 1992Google Scholar
  37. 37.
    Przyborowski L, Schwarzenbach G, Zimmerman T: Komplexe XXXVII. Die EDTA-komplexe des vanadiums(V). Helvectia Chimica Acta 48: 1556–1565, 1965Google Scholar
  38. 38.
    Djordjevic C, Lee M, Sinn E: Oxoperoxo(citrato)- and dioxo-(citrato)vanadates(V): Synthesis, spectra, and structure of a hydroxyl oxygen bridged dimer, K2[VO(O2)(C6H6O7)]2·2H2O. Inorg Chem 28: 719–723, 1989Google Scholar
  39. 39.
    Rieskamp H, Gietz P, Mattes R: Tetrameric dioxo(oxalato)-vanadates(V). The crystal structure of K[VO2(C2O4)2]2·H2O. Chem Ber 109: 2090–2096, 1976Google Scholar
  40. 40.
    Crans DC: Aqueous chemistry of labile oxovanadates: Of relevance to biological studies. Comments on Inorganic Chemistry 16: 1–33, 1994Google Scholar
  41. 41.
    Crans DC, Rithner CD, Theisen LA: Applicadon of dme-resolved51V 2D NMR for quantitation of kinede exchange pathways between vanadate monomer, dimer, tetramer, and pentamer. J Am Chem Soc 112: 2901–2908, 1990Google Scholar
  42. 42.
    Brichard SM, Bailey CJ, Henquin J-C: Marked improvement of glucose homeostasis in diabetic ob/ob mice given oral vanadate. Diabetes 39: 1326–1332, 1990Google Scholar
  43. 43.
    Arransio D, Suber L, Shul-pin GB: Photochemical oxidation of hydrocarbons by vanadium(v)peroxo complex. Izv Akad Nauk Ser Khim 8: 1918–1921, 1992Google Scholar
  44. 44.
    Bonchio M, Conte V, Di Furia F, Modena G, Moro S: Nature of the radical intermediates in the decomposition of peroxovanadium species in protic and aprotic media. Inorg Chem 33: 1631–1637, 1994Google Scholar
  45. 45.
    Crans DC, Ehde PM, Shin PK, Pettersson L: Structural and kinetic characterization of simple complexes as models for vanadate-protein interactions. J Am Chem Soc 113: 3728–3736, 1991Google Scholar
  46. 46.
    Crans DC, Shin PK, Armstrong KB: Application of NMR spectroscopy to studies of aqueous coordination chemistry of vanadium(V) complexes. In: H. Thorp, V. Pecoraro (ed.). Mechanistic Bioinorganic Chemistry. American Chemical Society: Washington, DC, 1995, in pressGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Debbie C. Crans
    • 1
  • Mohammed Mahroof-Tahir
    • 1
  • Anastasios D. Keramidas
    • 1
  1. 1.Department of Chemistry and Cell and Molecular Biology ProgramColorado State UniversityFort CollinsUSA

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