The step that commits arachidonic and other poly unsaturated 20-carbon fatty acids to prostanoid synthesis is catalyzed by one of two enzymes: prostaglandin endoperoxide synthase-1 or -2 (PGHS-1 and -2), also known as cyclooxygenase-1 or -2 (COX-1 and COX-2). The two forms catalyze the same two reactions at two different sites on the protein: the insertion of two O2 molecules into the fatty acid chain called the cyclooxygenase reaction to form PGG2, followed by the peroxidase reaction at carbon 15 to form PGH2 (see Figure 1). In vivo, other peroxidases may also carry out this second step to convert PGG2 to PGH2.

Fig1. Eicosanoid biosynthesis. The pathway of the biosynthesis of the main prostanoids from the most abundant substrate, arachidonic acid, is shown. The 5-lipoxygenase (5-LOX) pathway leads to the leukotrienes (LT) through HpETE (hydroxyperoxytetraenoic acid). The action of 12-lipoxygenase on LTA4 leads to lipoxin A4. Arachidonic acid can also be converted directly to LXA4 through the 15-lipoxygenase pathway. The cyclooxygenase (COX-1 and COX-2) pathway gives rise, through the COX product PGH2, to the prostanoids, prostaglandins, and thromboxanes. Each biologically active prostanoid is produced from PGH2 by a specific synthase. The synthase(s) expressed by a given cell determine which prostanoid(s) the cell will make. TXA2 has a particularly short half-life and its inactive breakdown product, TXB2, is shown.

COX-1 and COX-2 are encoded by separate genes; the two isoforms from the same species share about 65% amino acid identity. Each isoform shares about 85% identity with its counterpart from another species. Both isoforms are synthesized with a signal peptide to direct it to the endoplasmic reticulum where it is bound to a single face of the phospholipid bilayer. The mature forms of COX-1 and COX-2 are 576 and 587 amino acids long, respectively.

Recent evidence indicates that both COX-1 and COX-2 exist as homodimers in the cell, the two identical monomers binding to one another over a large shared interface of the proteins. When one monomer binds a ligand, either a substrate molecule (i.e., fatty acid) or a regulatory molecule, it is not catalytically active, but its dimer partner becomes catalytically active. The activity of the catalytic partner can be affected by the molecule bound by the first, or allosteric, monomer. Thus, the homodimer actually functions as a heterodimer. These details of structure and function of COX-1 and COX-2 are important in the development of specific inhibitors of the isoforms, particularly COX-2.

One structural and therefore functional difference between COX-1 and COX-2 lies in the catalytic sites where the cyclooxygenase reaction takes place. Crucial differences in the amino acids within and around this site result in a more capacious site in COX-2 than in COX-1. This difference, determined by x-ray crystal lographic studies, is important to the effort discussed below, to develop drugs which are specific for COX-2, since most cyclooxygenase inhibitors function by pre venting access of arachidonic acid to the active site of the enzyme.

The primary physiological difference between COX-1 and COX-2 lies in their regulation. COX-1 is generally considered to be expressed constituitively, with possible increases of 2–4 fold in response to stimuli such as hormones or growth factors. On the other hand, in many tissues and cell types there is little or no expression of COX-2 under basal conditions but it is inducible by agents signaling such events as inflammation, including lipopolysaccharides, cytokines, and certain growth factors. The concept of COX-1 as the constituitive “housekeeping” form and COX-2 as the inducible one is not absolute: in some cells, for example in brain and kidney, COX-2 is present at low levels all the time (“constituitive”) and has “housekeeping” functions of its own such as in the maintenance of cardiovascular homeostasis and of uterine contractions during labor.

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مواضيع ذات صلة

Examples of Biological Actions of Prostaglandins

Cyclooxygenase Inhibitors

Phospholipase A2

Overview of Eicosanoid Synthesis

Structure and Nomenclature of Eicosanoids

Water is an Excellent Nucleophile

Interaction with Water Influences the Structure of Biomolecules

Fibrin Clots Are Dissolved by Plasmin

The Activity of Antithrombin, an Inhibitor of Thrombin, Is Increased by Heparin

Conversion of Fibrinogen to Fibrin Is Catalyzed by Thrombin

Factor Xa Leads to Activation of Prothrombin to Thrombin

Most Transmembrane Proteins Have Membrane Spanning α Helices