Exp Mol Med.  2003 Apr;35(2):61-66.

Gold compound auranofin inhibits I kappaB kinase (IKK) by modifying Cys-179 of IKK beta subunit

• Jeon KI
• Byun MS
• Jue DM

Abstract

Antirheumatic gold compounds have been shown to inhibit NF-kB activation by blocking IkB kinase (IKK) activity. To examine the possible inhibitory mechanism of gold compounds, we expressed wild type and mutant forms of IKk alpha and beta subunits in COS-7 cells and determined the effect of gold on the activity of these enzymes both in vivo and in vitro. Substitution of Cys-179 of IKK beta with alanine (C179A) rendered the enzyme to become resistant to inhibition by a gold compound auranofin, however, similar protective effect was not observed with an equivalent level of IKK alpha (C178A) mutant expressed in the cells. Auranofin inhibited constitutively active IKK alpha and beta and variants; IKK alpha (S176E, S180E) or IKK beta (S177E, S181E), suggesting that gold directly cause inhibition of activated enzyme. The different inhibitory effect of auranofin on IKK alpha (C178A) and IKK beta (C179A) mutants indicates that gold could inhibit the two subunits of IKK in a different mode, and the inhibition of NF- kB and IKK activation induced by inflammatory signals in gold-treated cells appears through its interaction with Cys-179 of IKK beta.

Keyword

antirheumatic agent gold; auranofin; cys-teine; mutagenesis; NF-kappaB; protein-serine-threonine ki-nases

MeSH Terms

Amino Acid Substitution
Animals
Auranofin/*pharmacology
COS Cells
Cysteine/genetics/*metabolism
Enzyme Activation/drug effects
Gold Compounds/*pharmacology
Protein Subunits/chemistry
Protein-Serine-Threonine Kinases/*antagonists & inhibitors/chemistry/genetics/*metabolism
Sulfhydryl Compounds/pharmacology