Introduction
The enzyme prostaglandin H2 synthase-1 (PGHS-1) is a bifunctional heme protein that catalyzes both the cyclooxygenase and peroxidase reactions needed to produce prostaglandins G2 and H2 from arachidonic acid [2]. Prostaglandins initiate and modulate cell and tissue responses involved in many physiological processes such as platelet aggregation and inflammation. Non-steroidal anti-inflammatory drugs like aspirin, ibuprofen, and indomethacin directly target PGHS-1, and inhibit the conversion of AA [3].
Fig.1 The conversion of Arachidonic acid to Prostaglandins, prostacyclin and thromboxaneA2. The cyclooxygenase (COX) reaction converts AA and two molecules of O2 to the hydroperoxide prostaglandin G2 (PGG2), which in turn undergoes a two electron reduction to the alcohol PGH2 via the peroxidase (POX) reaction. PGH2 is the essential precursor of prostaglandins, prostacyclin, and thromboxane A2. Aspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs inhibit the production of PGH2 by competing with AA for binding to the cyclooxygenase site. (4)
PGHS-1 is an integral membrane protein located primarily in the endoplasmatic reticulum [2]. This bifunctional enzyme comprises three independent folding units: an epidermal growth factor domain, a membrane-binding motif and an enzymatic domain. Two adjacent but spatially distinct active sites were found for its haem-dependent peroxidase and cyclooxygenase activities. The cyclooxygenase active site is created by a long, hydrophobic channel that is the site of non-steroidal anti-inflammatory drug binding. The conformation of the membrane-binding motif strongly suggests that the enzyme integrates into only one leaflet of the lipid bilayer and is thus a monotopic membrane protein [5].
Fig.2 PGHS-1 dimer showing the membrane interaction surface, how the epidermal growth factor-like (EGF) domain (green) and the membrane binding domain (brown) form the membrane interaction surface. (6)
Fig.3 PGHS-1 dimer surface showing how the epidermal growth factor-like (EGF) domain (blue) and the membrane binding domain (brown) form the membrane interaction surface. (6)