Action at a Distance

• DOI: 10.1074/jbc.m114.635987
• Publication Date: 2015-04-01T09:35:14Z
• Authors: Anna L. Blobaum; Shu Xu; Scott W. Rowlinson; Kelsey C. Duggan; Surajit Banerjee; Shalley N. Kudalkar; William R. Birmin...; Kebreab Ghebresel...; Lawrence J. Marnett
• Keywords: Mefenamic acid; Flurbiprofen; Ibuprofen; Prostaglandin H2

Cyclooxygenase enzymes (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin G2. The inhibitory activity rapid, reversible COX inhibitors (ibuprofen, naproxen, mefenamic acid, lumiracoxib) demonstrated a significant increase in potency time dependence inhibition against double tryptophan murine COX-2 mutants at 89/90 89/119 positions. In contrast, slow, time-dependent (diclofenac, indomethacin, flurbiprofen) were unaffected by those mutations. Further mutagenesis studies suggested that mutation position 89 was principally responsible for changes inhibitors, whereas 90 may exert some effect on COX-2-selective diarylheterocycle inhibitors; no observed with 119. Several crystal structures or without NSAIDs indicated placement bulky residue caused closure gap lobby, alteration histidine changed electrostatic profile side pocket COX-2. Thus, these two residues, especially Val-89 lobby region, are crucial entrance exit from active site.