Arachidonic acid, prostaglandins from structure

Prostaglandins are a group of C20 lipids found in all human tissues and fluids. They are derived biosynthetically from all-cis eicosa-5,8,11,14-tetraenoic acid, known commonly as arachidonic acid. Prostaglandin El is an example. Draw arachidonic acid in such a way that it is structurally similar to PGEi in geometry, and identify the two carbons that must form a bond. 

Eicosanoids and terpenoids are still other classes of lipids. Eicosanoids, of which prostaglandins are the most abundant kind, are derived biosynthetically from arachidonic acid, are found in all body tissues, and have a wide range of physiological activity. Terpenoids are often isolated from the essential oils of plants, have an immense diversity of structure, and are produced biosynthetically from the five-carbon precursor isopentenyl diphosphate (IPP). lsopentenyl diphosphate is itself biosynthesized from 3 equivalents of acetate in the mevalonate pathway. 

Pairs of spin labels were introduced in human prostaglandin endoperoxide H2 synthase-2 (PGHS-2) at locations where significant structural changes had been observed in X-ray crystal structures of holoenzyme and protein bound to NSAID s.75 Interspin distances were obtained by Fourier deconvolution of spectra recorded at 183 K for 10 doubly spin-labelled mutants. Interspin distances for complexes with arachidonic acid, flurbiprofen, and SC-58125 agree well with values predicted from X-ray crystal structures, but do not agree well for the holoenzyme. It is proposed that the predominant conformation of the holoenzyme in solution is different from the structure in the crystal. 

The structures and biosynthetic pathways of several of the prostaglandins are indicated in Fig. 21-7. Prostaglandins are usually abbreviated PG with an additional letter and numerical subscript added to indicate the type. The E type are (3-hydroxyketones, the F type 1,3-diols, and the A type a, (3-unsatur-ated ketones. Series 2 prostaglandins arise from arachidonic acid, while series 1 and 3 arise from fatty acids containing one fewer or one more double bond, respectively (Fig. 21-7). Additional forms are known.257 259... 

Lipids play a number of important biological roles. Phospholipids are triesters of glycerol in which one ester is derived from a phosphatidylamine. They are important structural units in cell membranes. Prostaglandins are 20-carbon cyclopentane derivatives of arachidonic acid that have profound biological effects, even in minute quantities. Waxes are monoesters of long-chain acids and alcohols. 

Figure 8 (a) Putative reaction scheme of prostaglandin endoperoxide H2 synthases (PGHS). (b) Structure of PGHS-1 with key residues in catalysis in complex with substrate arachidonic acid (AA). (This figure was generated from coordinates of IDIY deposited in the Protein Data Bank)... 

A relatively simple thiazole has been shown to be a quite potent antiinfla-matory agent. Darbufelone (143), which is quite different in structure from all preceding NSAIDs inhibits both arms of the arachidonic acid cascade at the very inception of the process. This in effect shuts off production of both prostaglandins and leukotrienes. This agent is prepared in a single step by condensation of substituted benzaldehyde 141 with the enolate from thiazolone (142). ... 

The family of compounds referred to as eicosanoids, which includes the prostaglandins (PCs), leukotrienes (LTs) and thromboxanes (TXs), have been shown to play key roles in the inflammatory process (Flower et al 1985). Eicosanoids are derived from 20-carbon essential fatty acids, with arachidonic acid being the most common precursor. Perturbations of cell membranes, whether chemical, physical or immune-mediated, release phospholipids, which are rapidly converted to arachidonic acid by phospholipase A2 and other acylhydrolases. Once released, arachidonic acid and its congeners form the substrates for a number of enzyme systems (Fig. 14.1). Products that contain ring structures (PCs and TXs) are the result of metabolism by the cyclooxygenase (COX) enzymes, while the hydroxylated derivatives of straight-chain fatty acids (LTs) result from the action of various lipoxygenases (Flower et al 1985). 

Flg 2 (a) Hypothetical receptor map of the active site of prostaglandin cyclooxygenase, showing points of binding or reactivity with the enzyme substrate, arachidonic acid (b) The anti-inflammatory aryl-acetlc acids - here, Indomethacln - which inhibit this enzyme, can fit the same receptor map in a way which explains their structure-activity relationships (from Ref 13 with permission) ... 

Some of the unsaturated fatty acids containing more than one double bond cannot be synthesized by the body For many years it has been known that linolenic acid and linoleic acid, called the essential fatty acids, are necessary for specific biochemical functions and must be supplied in the diet (see Table 18.1). The fimction of linoleic acid became clear in the 1960s when it was discovered that linoleic acid is required for the bios)mthesis of arachidonic acid, the precursor of a class of hormonelike molecules known as eicosanoids. The name is derived from the Greek word eikos, meaning "twenty," because they are all derivatives of twenty-carbon fatty acids. The eicosanoids include three groups of structurally related compounds the prostaglandins, the leukotrienes, and the thromboxanes. 

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