CYCLOOXYGENASE

Cyclooxygenase

Cyclooxygenase

Cyclooxygenase, abbreviated as (COX), and also known as prostaglandin-endoperoxide synthase (PTGS), fatty acid COX, PGH synthase, and EC 1.14.99.1.  Cyclooxygenase is a key regulatory enzyme in the synthetic pathway of eicosanoid production.  Eicosanoids are responsible for multiple inflammatory, mitogenic, and angiogenic activities in various tissue and organ systems.  Therefore, cyclooxygenase is implicated in the production of fever, inflammation, and pain.

Regardless of the etiology, a deficiency of cyclooxygenase results in both beneficial and detrimental physiological conditions relative to imbalances of the eicosanoids.  Thus, tracing research of the cyclooxygenase pathway is essential to an understanding of cyclooxygenase deficiency and examining the variable effects of cyclooxygenase inhibition are advantageous.

By 1964, after recognition of this basic structure, Bergstrom and colleagues successfully synthesized series 2 prostaglandins from arachidonic acid using sheep seminal fluid. However, the physiologic significance of prostaglandin production did not unfold until 1971 when Vane, Smith, and Willis discovered that aspirin and indomethacin inhibited prostaglandin biosynthesis. Further investigations by Smith concluded that aspirin and indomethacin inhibited synthesis by specifically blocking oxygenation of arachidonic acid. Collectively, these landmark discoveries have provided initial insight into the cyclooxygenase pathway of arachidonate metabolism.

Recent advances in genomic analysis have led to a clearer understanding of the cyclooxygenase pathway. Initial investigations by Miyamoto in 1976 and Simmons in 1989 have demonstrated that 2 isoforms exist: cyclooxygenase-1 (PTGS-1) and cyclooxygenase-2 (PTGS-2) respectively. The transcription of cyclooxygenase-1 yields a 2.7-kilobase (kb) mRNA that encodes a 576-residue, 65-kd protein. Conversely, the transcription of cyclooxygenase-2 yields a 4.5-kb mRNA that encodes a 70-kd protein with roughly 70-75% homology to the cyclooxygenase-1 protein. By 1991, Funk and colleagues localized cyclooxygenase-1 to 9q32-q33.3 via somatic hybrid DNA analysis. Three years later, Tay and colleagues localized cyclooxygenase-2 to 1q25.2-q25.3 via fluorescein in situ hybridization. Furthermore, using sequence analysis of human genomic DNA, researchers have concluded that the amino acids important for catalysis by cyclooxygenase-1 are conserved and equally important for catalysis by cyclooxygenase-2.

Evidence suggests that cyclooxygenase-1 and cyclooxygenase-2 are similar in structure and function but exist as 2 distinct enzymatic entities. They have been defined as monotropic integral membrane proteins located primarily in the endoplasmic reticulum (COX-1) and perinuclear envelope (COX-2). Their distinct biosynthetic activity includes an endoperoxidase synthase reaction that oxygenates and cyclizes polyunsaturated fatty acid precursors (eg, arachidonic acid) to form prostaglandin G2 (PGG2) and a peroxidase reaction that converts PGG2 to prostaglandin H2 ([PGH2].  In turn, PGH2 is converted to biologically active products (ie, prostaglandin E2 [PGE2]) by individual synthase and reductase reactions.

Recent studies have demonstrated that the eicosanoids produced by cytosolic cyclooxygenase-1 participate in autocrine and paracrine activities, while those produced by perinuclear cyclooxygenase-2 result in intracrine activity. This subcellular localization of the cyclooxygenase enzyme using new microscopy techniques has helped to explain why 2 isoforms exist. Furthermore, researchers have proposed that cyclooxygenase-1 and cyclooxygenase-2 acquire arachidonic acid from different phospholipases, suggesting participation through separate pathways.

Cyclooxygenase-1 is expressed constitutively and isolated throughout most cell lines in almost all mammalian ...