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Cyclooxygenase Pathway of the Arachidonate Cascade

  1. Francesca Seta,
  2. Markus Bachschmid

Published Online: 16 APR 2012

DOI: 10.1002/9780470015902.a0023401



How to Cite

Seta, F. and Bachschmid, M. 2012. Cyclooxygenase Pathway of the Arachidonate Cascade. eLS. .

Author Information

  1. Boston University School of Medicine, Boston, Massachusetts, USA

Publication History

  1. Published Online: 16 APR 2012


Prostanoids are potent lipid mediators produced from arachidonic acid by the action of prostaglandin endoperoxide H2 synthases (PGHS-1 and -2), also known as cyclooxygenases (COX-1 and -2). PGHS-1, by virtue of its constitutive expression, is associated with homeostatic functions, such as platelet aggregation and gastric cytoprotection, whereas PGHS-2, induced by a variety of inflammatory and mitogenic stimuli, is important in inflammation and cancer. However, this paradigm has been reevaluated over the years thanks to sophisticated genetic and pharmacological tools that have expanded tremendously our knowledge about the COX cascade. Despite identical structure and catalytic activities, subtle biochemical and metabolic differences account for a functional segregation of the two isoforms. Interestingly, in some biological processes, they seem not functionally interchangeable. Nonsteroidal anti-inflammatory drugs are popular anti-inflammatory, analgesic and antipyretic medications that block the formation of prostanoids. The search for specific inhibitors of the COX cascade, devoid of unwanted side effects, is still the subject of ongoing research.

Key Concepts:

  • Arachidonic acid (AA, 5,8,11,14-eicosatetraenoic acid), a 20-carbon, polyunsaturated fatty acid esterified into membrane phospholipids, can be metabolised via lipoxygenases, to produce leukotrienes; CYP450 monooxygenases to produce epoxyeicosatrienoic and hydroxyeicosatetraenoic acids (EETs and HETEs), and prostaglandin endoperoxide H2 synthase (PGHS) to produce prostanoids.

  • Prostanoids are a group of lipid autacoids including prostaglandins (PGD2, PGE2 and PGF2α), prostacyclin (PGI2) and thromboxanes (TXA2), that act through specific receptors (DP1−2, EP1−4, FPA−B, IP and TP) and, in some cases, nuclear receptors (PPAR), to elicit a variety of physiological and pathophysiological effects.

  • Prostaglandin H2 synthase (PGHS), commonly known as cyclooxygenase (COX), exists in two isoforms: PGHS-1 and -2, or COX-1 and -2 that catalyses the bis-oxygenation of AA into PGH2, further reduced by cell-specific downstream PGH2 reductases and isomerases (prostanoid synthases) into prostanoids.

  • PGHS-1 and PGHS-2 have identical catalytic activity that is best explained by a branched-chain reaction between the peroxidase site (POX) and the cyclooxygenase site (COX), both present in the catalytic active site of the enzyme.

  • PGHS-1 and PGHS-2 differ in peroxide requirement, substrate utilisation, subcellular localisation and translational and post-translational regulation, suggesting a segregated activity of the two isoforms when both are present.

  • PGHS-1, constitutively expressed in many cell types is associated with homeostatic functions, such as platelet aggregation and gastric cytoprotection and PGHS-2, mainly induced by inflammatory and mitogenic stimuli, is linked to inflammation and cancer. However, it is now clear that both isoforms are important for cardiovascular, renal and reproductive function and both play a role in inflammation and pain sensitisation.

  • PGHS-2, by virtue of a larger side pocket in the substrate-binding site, can metabolise polyunsaturated fatty acids other than AA with higher efficiency than PGHS-1, yielding lipid mediators different from prostanoids, such as glycerol-prostaglandins and aspirin-triggered lipoxins.

  • Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac and coxibs, are anti-inflammatory, analgesic and antipyretic drugs that block the formation of prostanoids by competitive or irreversible inhibition of AA binding to COX.

  • NSAIDs are a heterogeneous class of organic acids that differ considerably in pharmacokinetics and pharmacodynamics, including the selectivity for PGHS-1 and PGHS-2. Individual isoform selectivity attained in vivo is crucial for therapeutic and side effects, and this can vary among individuals and the drug used.


  • eicosanoids;
  • cyclooxygenase;
  • prostaglandin H2 endoperoxidase;
  • prostanoids;
  • peroxides;
  • tyrosyl radical;
  • arachidonic acid;
  • nonsteroideal anti-inflammatory drugs;
  • coxibs