Cyclooxygenase-derived prostaglandins

Nakatani K, Norimichi N, Tsutomu A, Hideyuki Y, Yasushi O. Inhibition of cyclooxygenase and prostaglandin E2 synthesis by -y-mangostin, a xanthone derivative in man-gosteen, in C6 rat glioma cells. Biochem Pharmacol 2002 63 73-79. 

A. 17,20 lyase is required for androgen synthesis, cyclooxygenase for prostaglandin production, 11- 3-hydroxysteroid dehydrogenase-2 acts as a reductase-converting cortisol to its inactive 11-keto derivative cortisone, whereas 18-hydroxylase is required for aldosterone production. 

Bandeira-Melo C, Serra ME, Diaz BL, Cordeiro RSB, Silva PMR, Lenzi HL, Bakhle YS, Serhan CN, Martins MA Cyclooxygenase-2-derived prostaglandin Ej and lipoxin A4 accelerate resolution of allergic edema in Angiostrongylus costaricensis-infected rats Relationship with concurrent eosinophilia. J Immunol 2000 164 1029-1036. 

Klementiev B, Novikova T, Korshunova I, Berezin V, Bock E (2008) The NCAM-derived P2 peptide facilitates recovery of cognitive and motor function and ameliorates neuropathology following traumatic brain injury. Eur J Neurosci 27 2885-2896 Kunz T, Marklund N, Hillered L, Oliw EH (2002) Cyclooxygenase-2, prostaglandin synthases, and prostaglandin H2 metabolism in traumatic brain injury in the rat. J Neurotrauma 19 1051-1064... 

The enzyme system responsible for the biosynthesis of PGs is widely distributed in mammalian tissues and has been extensively studied (2). It is referred to as prostaglandin H synthase (PGHS) and exhibits both cyclooxygenase and peroxidase activity. In addition to the classical PGs two other prostanoid products, thromboxane [57576-52-0] (TxA ) (3) and prostacyclin [35121 -78-9] (PGI2) (4) are also derived from the action of the enzyme system on arachidonic acid (Fig. 1). 

All prostaglandins are cyclopentanoic acids derived from arachidonic acid. The biosynthesis of prostaglandins is initiated by an enzyme associated with the endoplasmic reticulum, called prostaglandin endoperoxide synthase, also known as cyclooxygenase. The enzyme catalyzes simultaneous oxidation and cyclization of arachidonic acid. The enzyme is viewed as having two distinct activities, cyclooxygenase and peroxidase, as shown in Figure 25.28. 

Fig. 3. Mechanisms of vasocontraction and vasorelaxation in endothelial and smooth muscle cells. COX cyclooxygenase, eNOS endothelial nitric oxide synthase, HO-1 heme oxygenase-1, EET epoxyeicosatrienoic acid, EDHF endothelium-derived hyperpolariz-ing factor, PGI2 prostaglandin I2, NO nitric oxide, CO carbon monoxide, PLC phospholipase C, IP3 inositol 1,4,5-trisphosphate, DAG diacylglycerol, ER/SR endo-plasmic/sarcoplasmic reticulum, AC adenylyl cyclase, cAMP cyclic adenosine monophosphate, sGC soluble guanylyl cyclase, cGMP cyclic guanosine monophosphate.

The eicosanoids, so called because of their derivation from a 20-carbon unsaturated fatty acid, arachidonic acid (eicosatetraenoic acid), are obtained from membrane phospholipids and synthesized de novo at the time of cellular stimulation. Arachidonic acid is cleaved from membrane-bound phosphatidylcholine by the enzyme phospholipase A2. Alternatively, arachidonic acid may be derived by the sequential actions of phospholipase C and diacylglyceryl lipase. Arachidonic acid can then follow either of two enzymatic pathways that result in the production of inflammatory mediators. The pathway initiated by cyclooxygenase (COX) produces prostaglandins the lipoxygenase pathway generates leukotrienes (Fig. 36.2). 

Prostaglandin (PC). Components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. 

Figure 8.9 Prostaglandins and leukotrienes are potent eicosanoid lipid mediators, derived from phospholipase-released arachidonic acids, that are involved in numerous homeostatic biological functions and inflammation. They are generated by cyclooxygenase isozymes and 5-lipoxygenase, respectively, and their biosynthesis and pharmacological actions are inhibited by clinically relevant nonsteroidal anti-inflammatory drugs.

Cyclooxygenase (COX), one of the two activities of prostaglandin endoperoxide synthase (PGHS), is the key enzyme in the conversion of arachidonic acid derived from lipids of the cell membrane to prostaglandins and other eicosanoids (Fig. 3). 

---