Arachidonic acid, prostaglandins from radical reaction

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.

The unique characteristic of free peroxyl radicals formed from unsaturated fatty acids is their ability to transform into cyclic radicals. This reaction is of utmost importance because it leads to highly biologically active compounds. Enzymatic oxidation of arachidonic acid catalyzed by COX results in the formation of prostaglandins having various physiopathological... 

Figure 12.6. Catalytic mechanism of the cyclooxygenase reaction, leading from arachidonic acid (top left) to prostaglandin G2 (top right). Y and YH represent Tyr 3 85. Molecular oxygen reacts in its jT-radical form. Note that this is only the first one of the two reactions catalyzed by cyclooxygenase.

Figure 12.7. Overview of the peroxidase reaction of cyclooxygenase. a Prostaglandin G2 enters the peroxidase active site after leaving the cyclooxygenase site. It is reduced by heme, which thereby is converted into the cation radical form (red). The heme is reduced in turn by glutathion (GSH) in a stepwise fashiom b Priming of the cyclooxygenase site. The heme cation radical abstracts a hydrogen atom from Tyr 385, which thereby replaces one glutathione. The prostaglandin G (PGG) that is required to form the heme cation radical in the first place must be provided by another enzyme molecule. (AA-H arachidonic acid...

Prostaglandin biosynthesis is initiated by abstraction of a hydrogen atom from arachidonic acid by an iron-oxygen radical, thereby generating a new, carbon radical in a substitution reaction. Don t be intimidated bv the size of the... 

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 arachidonic acid, where a sequence of four radical additions take place. The reaction mechanism was discussed briefly in Section 5.3. 

The essential individual steps are the following First, arachidonic acid bonds ionically to arginine-120 of prostaglandin-H2-synthase. The oxoiron(IV)-por-phyrin complex abstracts a hydrogen radical from tyrosine-385. This then cleaves off, regio- and stereo-selectively, the allylic (13-pro-S)-hydrogen atom of arachidonic acid, and thereby initiates the cycloaddition with oxygen. In the reaction centre of the hydroperoxidase, the hydroperoxide is then reduced to the alcohol in a second step (Fig. 5.97). [216]... 

---