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Inhibition of cyclic AMP dependent protein kinase by vanadyl sulfate

Kioumars A Jelveh1, Rachel Zhande, Roger W Brownsey

  • 1Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada, V6T 1Z3.

Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry
|March 1, 2006
PubMed

Insights

Vanadium compounds may treat diabetes by inhibiting protein kinase A (PKA). This study found vanadyl sulfate inhibits PKA, especially when vanadyl ions are not sequestered, offering new insights into vanadium

Area of Science:

  • Biochemistry
  • Enzymology
  • Pharmacology

Background:

  • Vanadium salts impact mammalian enzyme activity in vitro.
  • The in vivo mechanisms of vanadium in ameliorating diabetes are not well understood.
  • Vanadium's inhibition of protein tyrosine phosphatases is a leading hypothesis.

Purpose of the Study:

  • To investigate if vanadyl sulfate trihydrate (VS) inhibits 3',5'-cyclic adenosine monophosphate (cAMP) dependent protein kinase (PKA).
  • To explore the conditions under which VS inhibits PKA.
  • To elucidate the role of vanadyl ions in PKA inhibition.

Main Methods:

  • Enzyme inhibition assays were performed using vanadyl sulfate trihydrate (VS).
  • PKA activity was measured under conventional and modified conditions to minimize vanadyl ion sequestration.
  • The effects of sodium orthovanadate and chelating agents (EDTA, glycyl peptides) were assessed.

Main Results:

  • VS inhibited PKA at high concentrations (>400 microM) under standard conditions.
  • Significant PKA inhibition (IC50<10 microM) was observed when vanadyl ion sequestration was minimized.
  • Vanadyl ions, not orthovanadate, were identified as the active PKA inhibitor.
  • Inhibition was abolished by chelators, suggesting a role for free vanadyl.
  • Vanadyl inhibition of PKA exhibited mixed kinetics and may mimic Mg2+ effects.

Conclusions:

  • Vanadyl sulfate can inhibit PKA, particularly under conditions that preserve free vanadyl ions.
  • This PKA inhibition provides a potential mechanism for vanadium's effects on lipolysis and energy metabolism regulated by cAMP.
  • Given conserved kinase active sites, vanadyl may affect other protein kinases.

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