Prostaglandin H2 Synthase

Picot, D., Loll, P.J., Garavito, R.M. The x-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 367 243-249, 1994. 

Fu JY, Masferrer JL, Seibert K et al (1990) The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem 265 16737-16740... 

Loll P. J., Picot D., Garavito M. The structured basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nature Struct Biol 1995 2,637-43. 

The enzyme prostaglandin H2 synthase-1 (PGHS-1) manufactures prostaglandin H2, which is converted to prostaglandin E2 and causes fever and inflammation. PGHS-1 contains two protein subunits with long channels. 

The thromboxanes have a six-membered ring containing an ether. They are produced by platelets (also called thrombocytes) and act in the formation of blood clots and the reduction of blood flow to the site of a clot. The nonsteroidal antiinflammatory drugs (NSAIDs)— aspirin, ibuprofen, and meclofenamate, for example— were shown by John Vane to inhibit the enzyme prostaglandin H2 synthase (also called cyclooxygenase or COX), which catalyzes an early step in the pathway from arachidonate to prostaglandins and thromboxanes (Fig. 10-18 see also Box 21-2). 

FIGURE 21-15 The "cyclic" pathway from arachidonate to prostaglandins and thromboxanes, (a) After arachidonate is released from phospholipids by the action of phospholipase A2/ the cyclooxygenase and peroxidase activities of COX (also called prostaglandin H2 synthase) catalyze the production of PGH2/ the precursor of other... 

Mammals have two isozymes of prostaglandin H2 synthase, COX-1 and COX-2. These have different functions but closely similar amino acid sequences (60% to 65% sequence identity) and similar reaction mechanisms at both of their catalytic centers. COX-1 is responsible for the synthesis of the prostaglandins that regulate the secretion of gastric mucin, and COX-2 for the prostaglandins that mediate inflammation, pain, and fever. Aspirin inhibits both isozymes about equally, so a dose sufficient to reduce inflammation also risks stomach irritation. Much research is aimed at developing new NSAIDs that inhibit COX-2 specifically, and several such drugs have become available. 

Aronoff DM, Boutaud O, Marnett LJ, Oates JA. Inhibition of prostaglandin H2 synthases by salicylate is dependent on the oxidative state of the enzymes. J. Pharmacol. Exp. Ther. 2003 304 589-595. 

Capdevila JH, Morrow JD, Belosludtev YY, Beauchamp DR, DuBois RN, Falck Jr. The catalytic outcomes of the constitutive and the mitogen inducible isoforms of prostaglandin H2 synthase are markedly affected by glutathione and glutathione per-oxidase(s). Biochemistry 1995 34 3325-3337. 

Figure 17.32. (a) Inactivation of prostaglandin H2 synthase by aspirin, and (b) inhibitors cocrystallized with prostaglandin synthase. 

The localization of prostaglandin H2 synthase-1 in the membrane is crucial to its function. The substrate for this enzyme, arachidonic acid, is a hydrophobic molecule generated by the hydrolysis of membrane lipids. 

Figure 12.22. Formation of Prostaglandin H2. Prostaglandin H2 synthase-1 catalyzes the formation of prostaglandin H2 from arachidonic acid in two steps.

Figure 12.23. Attachment of Prostaglandin H2 Synthase-1 to the Membrane. Prostaglandin H2 synthase-1 is held in the membrane by a set of a helices coated with hydrophobic side chains. One monomer of the dimeric enzyme is shown.

Figure 12.24. HYdrophobic Channel of Prostaglandin H2 Synthase. A view of prostaglandin H2 synthase from the membrane, showing the hydrophobic channel that leads to the active site. The membrane-anchoring helices are shown in orange.

Figure 12.25. Aspirin s Effects On Prostaglandin H2 Synthase-1. Aspirin acts by transferring an acetyl group to a serine residue in prostaglandin H2 synthase-1.

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