Involvement of Arginine 120, Glutamate 524, and Tyrosine 355 in the Binding of Arachidonate and 2-Phenylpropionic Acid Inhibitors to the Cyclooxygenase Active Site of Ovine Prostaglandin Endoperoxide H Synthase-1 (∗)
Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 271, Issue: 4, Page: 2179-2184
1996
- 173Citations
- 46Captures
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Metrics Details
- Citations173
- Citation Indexes173
- 173
- CrossRef126
- Captures46
- Readers46
- 46
Article Description
Examination of the crystal structure of the ovine prostaglandin endoperoxide synthase-1 (PGHS-1)/ S -flurbiprofen complex (Picot, D., Loll, P. J., and Garavito, R. M.(1994) Nature 367, 243-2491) suggests ( a ) that the carboxyl group of arachidonic acid interacts with the arginino group of Arg 120 ; ( b ) that Arg 120 forms an important salt bridge with Glu 524 ; and ( c ) that Tyr 355, which is in close proximity to Arg 120, could determine the stereochemical specificity of PGHS-1 toward 2-phenylpropionic acid inhibitors. To test these concepts, we used site-directed mutagenesis to prepare ovine PGHS-1 mutants having modifications of Arg 120 (R120K, R120Q, R120E), Glu 524 (E524D, E524Q, E524K), and Tyr 355 (Y355F) and examined the properties of the mutant enzymes expressed in COS-1 cells. All of the mutants retained at least part of their cyclooxygenase and peroxidase activities except the R120E mutant, which had no detectable activity. The K m values of the R120K and R120Q mutants with arachidonic acid were 87 and 3300 μM, respectively, versus 4 μM for native PGHS-1. The R120Q mutant failed to undergo suicide inactivation during catalysis or time-dependent inhibition by flurbiprofen. These results are consistent with Arg 120 binding the carboxylate group of arachidonate and suggest that interaction of the carboxylate group of substrates and inhibitors with Arg 120 is necessary for suicide inactivation and time-dependent inhibition, respectively. The K m values for the E524D, E524Q, and E524K mutants were not significantly different from values obtained for the native PGHS-1, suggesting that this residue is not importantly involved in catalysis or substrate binding. The effect of modifications of Arg 120 and Tyr 355 on the stereospecificity of inhibitor binding were determined. Ratios of IC 50 values for cyclooxygenase inhibition by D- and L-ibuprofen, a competitive cyclooxygenase inhibitor, were 32, 67, and 7.1 for native PGHS-1, R120Q PGHS-1, and Y355F PGHS-1, respectively. The decreased stereochemical specificity observed with the Y355F PGHS-1 mutant suggests that Tyr 355 is a determinant of the stereospecificity of PGHS-1 toward inhibitors of the 2-phenylpropionic acid class.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0021925817461576; http://dx.doi.org/10.1074/jbc.271.4.2179; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0030068054&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/8567676; https://linkinghub.elsevier.com/retrieve/pii/S0021925817461576; https://dx.doi.org/10.1074/jbc.271.4.2179
Elsevier BV
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