What is cyclooxygenase (COX) deficiency?

Updated: Feb 19, 2019
  • Author: George T Griffing, MD; Chief Editor: George T Griffing, MD  more...
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Answer

Regardless of the etiology, a deficiency of cyclooxygenase (COX), a key regulatory enzyme in the synthetic pathway of eicosanoid production, results in beneficial and detrimental physiologic conditions relative to imbalances of the eicosanoids. [1] Thus, tracing research of the COX pathway is essential to an understanding of COX deficiency, and examining the variable effects of COX inhibition are advantageous.

Eicosanoids, which include prostaglandins, leukotrienes, thromboxanes, and lipoxins, are responsible for multiple inflammatory, mitogenic, and angiogenic activities in various tissue and organ systems. Therefore, COX — also known as prostaglandin-endoperoxide synthase (PTGS), fatty acid COX, prostaglandin H (PGH) synthase, and EC 1.14.99.1 — is implicated in the production of fever, inflammation, and pain.

In 1930, American gynecologists Kurzok and Lieb first described the stimulatory effects of seminal fluid on human uterine muscle tissue. A few years later, von Euler of Sweden independently discovered similar effects of human seminal fluid on smooth muscle tissue. He localized the biologic activity to a fraction of lipid soluble acids that he termed "prostaglandin," hypothesizing that these substances originate in the prostate gland. Two decades later, the prostaglandins were deduced to be a family of related compounds that contain 20-carbon polyunsaturated fatty acids with a cyclopentane ring, as depicted below.

Twenty-carbon polyunsaturated fatty acid with cycl Twenty-carbon polyunsaturated fatty acid with cyclopentane ring.

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 provided initial insight into the COX pathway of arachidonate metabolism.

Advances in genomic analysis have led to a clearer understanding of the COX pathway. Initial investigations by Miyamoto and Simmons demonstrated that 2 isoforms exist: COX-1 (PTGS-1) and COX-2 (PTGS-2), respectively. The transcription of COX-1 yields a 2.7-kilobase (kb) messenger ribonucleic acid (mRNA) that encodes a 576-residue, 65-kd protein. Conversely, the transcription of COX-2 yields a 4.5-kb mRNA that encodes a 70-kd protein with roughly 70-75% homology to the COX-1 protein.

Funk and co-investigators localized COX-1 to 9q32-q33.3 via somatic hybrid deoxyribonucleic acid (DNA) analysis. Tay and colleagues then localized COX-2 to 1q25.2-q25.3 via fluorescein in situ hybridization. Furthermore, using sequence analysis of human genomic DNA, researchers concluded that the amino acids important for catalysis by COX-1 are conserved and are equally important for catalysis by COX-2.


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