Cyclooxygenase (COX; prostaglandin G/H synthase, EC 1.14.99.1) catalyzes the first two steps in the biosynthesis of prostaglandins (PGs). The two COX isoforms COX-1 and COX-2 are the targets of the widely used nonsteroidal anti-inflammatory drugs, indicating a role for these enzymes in pain, fever, inflammation, and tumorigenesis. The ubiquitous constitutive expression of COX-1 and inducible expression of COX-2 have led to the widely held belief that COX-1 produces homeostatic PGs, while PGs produced by COX-2 are primarily pathophysiological. However, recent discoveries call this paradigm into question and reveal as yet underappreciated functions for both enzymes. This review focuses on some of these new insights.-Rouzer, C. A., and L. J. Marnett. Cyclooxygenases: structural and functional insights. J. Lipid Res. 2009. 50: S29-S34.
Supplementary key words prostaglandinThe cyclooxygenase isoforms (COX-1 and COX-2) are among the most thoroughly studied and best understood mammalian oxygenases. Possessing two separate but linked active sites, the COXs catalyze the bis-dioxygenation and subsequent reduction of arachidonic acid (AA) to prostaglandin (PG)G 2 and PGH 2 (Fig. 1A). The mechanism of oxygenation has been well characterized through kinetics, mutagenesis, and X-ray crystallography (1-3). PGH 2 is subject to metabolism by downstream enzymes yielding the family of PGs, each member of which exerts a range of physiologic effects through specific G-protein-coupled receptors (Fig. 1B) (4, 5). The discovery that the COXs are the target of the nonsteroidal anti-inflammatory drugs (NSAIDs), which play a primary therapeutic role in the treatment of pain, fever, and inflammation (6), promulgated the first wave of experimentation on the constitutively expressed COX-1 during the 1970s and 1980s. Then, just as interest began to wane, the discovery of the inducible isoform, COX-2, rekindled a massive new effort that ultimately led to new insights about both isoforms. A search of PubMed over the past 2 years indicates that there have been over 70 review articles containing "cyclooxygenase" in their title, leading one to question the need for yet another. However, despite the overwhelming mass of data available on these enzymes, recent discoveries suggest that some original assumptions concerning their roles in physiology and pathophysiology require reexamination. This review will emphasize these issues.
STRUCTURE OF THE COX ENZYMESHuman COX-1 and COX-2 are homodimers of 576 and 581 amino acids, respectively. Both enzymes contain three high mannose oligosaccharides, one of which facilitates protein folding. A fourth oligosaccharide, present only in COX-2, regulates its degradation. Considering the 60% identity in sequence between COX-1 and COX-2, it is not surprising that their three-dimensional structures are nearly superimposable. Each subunit of the dimer consists of three domains, the epidermal growth factor domain (residues 34-72), the membrane binding domain (residues 73-116), and the catalytic domain comprisi...
