Biosynthesis of prostaglandins

Much of our present knowledge of the biosynthesis of the PG s stems from the very elegant and extensive investigations of the groups of van Dorp in Holland and of Samuelsson in Sweden. Both these leading groups - and also others, have published review articles on PG biosynthesis during the period under review. 

Reports on the inhibition of PG biosynthesis by several agents have appeared and Lee and Lands have reported that Cu + added to enzyme preparations stimulates PGF production. The comparative aspects of PG biosynthesis in animal tissues have been examined by Christ and van Dorp.  

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Covalent bond (Section 1 3) Chemical bond between two atoms that results from their shanng of two electrons COX 2 (Section 26 6) Cyclooxygenase 2 an enzyme that cat alyzes the biosynthesis of prostaglandins COX 2 inhibitors reduce pain and inflammation by blocking the activity of this enzyme... 

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. 

In biological reactions, the situation is different from that in the laboratory. Only one substrate molecule at a time is present in the active site of the enzyme where reaction takes place, and that molecule is held in a precise position, with coenzymes and other necessary reacting groups nearby. As a result, biological radical reactions are both more controlled and more common than laboratory or industrial radical reactions. A particularly impressive example occurs in the biosynthesis of prostaglandins from arachiclonic acid, where a sequence of four radical additions take place. The reaction mechanism was discussed briefly in Section 5.3. 

Figure 7.9 Pathway for the biosynthesis of prostaglandins from arachidonic acid. Steps 2 and 5 are radical addition reactions to 02 steps 3 and 4 are radical additions to carbon-carbon double bonds.

Salicylic acid analogues are often active as nonsteroidal antiinflammatory agents because they interfere with biosynthesis of prostaglandins. Diflunisal (3) appears to be such an agent. It is synthesized from the nitrobiphenyl 1 by catalytic reduction to... 

The stimulus for the recent surge of activity in this previously dormant area of organic chemistry can be traced to the prostaglandin connection . That is to the discovery that saturated bicyclic peroxides are key intermediates in the biosynthesis of prostaglandins and other physiologically active substances by the enzymatic oxygenation of polyunsaturated fatty acids. 

Studies on the biosynthesis of prostaglandins revealed that a strained bicyclic bis(secondary-alkyl) peroxide was not only a key intermediate, but could survive the biological conditions long enough to be isolated, albeit in minute amounts. This was a startling discovery in that no simple bicyclic peroxides of the same type were known, clearly for reasons of preparative difficulty. The prostaglandin connection focused attention upon this missing class of peroxides and stimulated... 

The dose of aciclovir in patients with renal impairment should be reduced as aciclovir is eliminated by the renal system. Most penicillins are eliminated by the renal system and hence dose reduction of amoxicillin is required in cases of renal impairment. Non-steroidal anti-inflammatory drugs cause the inhibition of the biosynthesis of prostaglandins involved in the maintenance of renal blood flow. This may precipitate acute renal insufficiency in patients with renal impairment. Furthermore non-steroidal anti-inflammatory drugs tend to cause water and sodium retention and hence aggrevate renal impairment. 

Fig. 6.11. Formation and function of diacylglycerol. The figure schematically shows two main pathways for formation of diacylglycerol (DAG). DAG can be formed from PtdInsP2 by the action of phospholipase C (PL-C). Another pathway starts from phosphatidyl chohne. Phospholipase D (PL-D) converts phosphatidyl choline to phosphatidic add (Ptd), and the action of phosphatases results in DAG. Arachidonic add, the starting point of biosynthesis of prostaglandins and other intracellular and extracellular messenger substances, can be cleaved from DAG. PKC protein kinase C Ptdins phosphatidyl inositol.

Increased biosynthesis of prostaglandins has been associated with one form of Bartter s syndrome. This is a rare disease characterized by low-to-normal blood pressure, decreased sensitivity to angiotensin, hyperreninemia, hyperaldosteronism, and... 

The anti-inflammatory activity of the NSAIDs is mediated chiefly through inhibition of biosynthesis of prostaglandins (Figure 36-2). Various NSAIDs have additional possible mechanisms of action, including inhibition of chemotaxis, down-regulation of interleukin-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events. Aspirin irreversibly acetylates and blocks platelet cyclooxygenase, while most non-COX-selective NSAIDs are reversible inhibitors. 

Acetylsalicyclic acid, aspirin, inhibits the cyclooxygenase-catalyzed first step in the biosynthesis of prostaglandins, prostacyclins and thromboxanes. These latter substances are responsible for the inflammatory and pyretic effects of infection. It is believed that the chemical inhibition reaction involves the acetylation of the enzyme by the aspirin. 

Figure 3 Simple schema of the biosynthesis of prostaglandins (PG), thromboxanes (TX), and leukotrienes from arachidonic acid consequent to cell injury (modified after Bonica, 1990).

Carboxylic acids, compounds of the type RCOH, constitute one of the most frequently encountered classes of organic compounds. Countless natural products are carboxylic acids or are derived from them. Some carboxylic acids, such as acetic acid, have been known for centuries. Others, such as the prostaglandins, which are powerful regulators of numerous biological processes, remained unknown until relatively recently. Still others, aspirin for example, are the products of chemical synthesis. The therapeutic effects of aspirin, welcomed long before the discovery of prostaglandins, are now understood to result from aspirin s ability to inhibit the biosynthesis of prostaglandins. 

A number of brilliant total syntheses of natural prostaglandins have been developed and these also have provided a number of interesting prostaglandin analogs (see Exercise 30-24). The biosynthesis of prostaglandins proceeds by oxygenation at Cl l of unsaturated fatty acids. This is followed by... 

Vane discovered that aspirin blocks the biosynthesis of prostaglandins. 

The anti-inflammatory activity of the NSAIDs is mediated chiefly through inhibition of biosynthesis of prostaglandins. Various NSAIDs have additional possible mechanisms of action,... 

Figure 2. Biosynthesis of prostaglandins, thromboxanes, prostacyclins, and leukotrienes.

Arachidonic acid (5 ,8 , HE, 14 -eicosatetraenoic acid) is a precursor for the biosynthesis of prostaglandins. Apply torsion angle rotations involving bond C9-C10 and C10-C11 to search for the prostaglandin-like conformation. 

The biosynthesis of prostaglandins from unsaturated fatty acids involves the successive participation of both a dioxygenase and a monooxygenase 649,6SOa,b The mechanism shown in Scheme 4 has been suggested649,650a,b... 

Prostaglandins are cyclopentane derivatives of unsaturated C20-fatty acids. They display hormonal as well as regulatory activities and were detected for the first time in spermatic fluid. They are obviously widely spread in animal tissue. Biosynthesis of prostaglandins involves cyclization of polyunsaturated carboxylic acids, e.g. arachidonic acid [(5Z,8Z,llZ,14Z)-5,8,ll,14-eicosatetraenoic acid] is enzymatically converted directly into prostaglandin PGE2. Prostaglandins stimulate and contract certain smooth muscles. At very low concentrations they lower the blood pressure and influence the heart frequency. Some of them can release labour and... 

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