Catalytic activity and inhibition of human histone deacetylase 8 is dependent on the identity of the active site metal ion.
Article Details
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Gantt SL, Gattis SG, Fierke CA
Catalytic activity and inhibition of human histone deacetylase 8 is dependent on the identity of the active site metal ion.
Biochemistry. 2006 May 16;45(19):6170-8.
- PubMed ID
- 16681389 [ View in PubMed]
- Abstract
Histone deacetylases play a key role in regulating transcription and other cellular processes by catalyzing the hydrolysis of epsilon-acetyl-lysine residues. For this reason, inhibitors of histone deacetylases are potential targets for the treatment of cancer. A subset of these enzymes has previously been shown to require divalent metal ions for catalysis. Here we demonstrate that histone deacetylase 8 (HDAC8) is catalytically active with a number of divalent metal ions in a 1:1 stoichiometry with the following order of specific activity: Co(II) > Fe(II) > Zn(II) > Ni(II). The identity of the catalytic metal ion influences both the affinity of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and the Michaelis constant, with Fe(II)- and Co(II)-HDAC8 having K(M) values that are over 5-fold lower than that of Zn(II)-HDAC8. These data suggest that Fe(II), rather than Zn(II), may be the in vivo catalytic metal. In further support of this hypothesis, recombinant HDAC8 purified from E. coli contains 8-fold more iron than zinc before dialysis, and the HDAC8 activity in cell lysates is oxygen-sensitive. Identification of the in vivo metal ion of HDAC8 is essential for understanding the biological function and regulation of HDAC8 and for the development of improved inhibitors of this class of enzymes.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Ferrous ascorbate Histone deacetylase 8 Protein Humans UnknownNot Available Details Ferrous fumarate Histone deacetylase 8 Protein Humans UnknownNot Available Details Ferrous gluconate Histone deacetylase 8 Protein Humans UnknownNot Available Details Ferrous glycine sulfate Histone deacetylase 8 Protein Humans UnknownNot Available Details Ferrous succinate Histone deacetylase 8 Protein Humans UnknownNot Available Details Iron Histone deacetylase 8 Protein Humans UnknownCofactorDetails Zinc Histone deacetylase 8 Protein Humans UnknownCofactorDetails Zinc acetate Histone deacetylase 8 Protein Humans UnknownNot Available Details Zinc chloride Histone deacetylase 8 Protein Humans UnknownCofactorDetails Zinc sulfate, unspecified form Histone deacetylase 8 Protein Humans UnknownCofactorDetails