Enzymes groups lipoxygenases

The leukotrienes are implicated in various inflammatory conditions such as rheumatoid arthritis and inhibiting their biosynthesis is potentially a useful therapy. Some time ago ICI (AstraZeneca now) found that some THPs (TetraHydroPyrans) inhibited the enzyme 5-lipoxygenase in the pathway to leukotrienes and they concentrated on achiral compounds such as 85 (known as ICI D2138). However it soon became clear that an extra methyl group, as in 86, enhanced activity. This small change makes the molecule chiral by introducing two chiral centres. It was necessary to find which diastereoisomer (syn or anti) was more active and which enantiomer of that diastereoisomer was better.13... 

Mechanisms of lipid peroxidation that have been implicated in atherosclerosis may be pertinent to RA. Cellular lipoxygenase enzymes may promote LDL modification by inserting hydroperoxide groups into unsaturated fetty-acid side chains of the LDL complex (Yla-Herttuala etal., 1990). 15-Lipoxygenase has been implicated as an initiator of LDL oxidation (Cathcart etal., 1991) whilst 5-lipoxygenase does not appear to be involved (Jessup et al., 1991). Products of activated lipoxygenase enzymes within inflammatory synovial fluid surest that this pathway could be activated in RA (Costello etal., 1992). 

The acid-soluble SH-groups in platelets are mainly those of glutathione (GSH). GSH is a cofactor for enzymes such as peroxidase. If feverfew is able to interfere with this cofactor, enzyme function may be impaired. One pathway that may be affected in this way is the metabolism of arachidonic acid (Figure 6.1). In the presence of feverfew extract an increase was found in lipoxygenase product formation and impaired conversion of HPETE to HETE, for which GSH is a cofactor [52]. Inhibition of the liberation of [ " C]arachidonic acid from phospholipids was also found [53], which implies impairment of phospholipase A2 activity and for which SH-groups are thought to be important. 

Lipoxygenase (EC 1.13.11.12) is an enzyme that catalyzes the hydroperoxidation of polyunsaturated fatty acids and esters containing a cis-cis-l, 4-pentadiene system (Table 6). In 1947, Theorell et al. obtained the enzyme in a crystalline form from soybeans and reported that the enzyme neither contained nor required a metal cofactor192. Subsequent studies from three groups of investigators have demonstrated that the enzyme purified from soybeans in an iron-containing dioxygenase74-76 ... 

This group of compounds is formed from the lipid fraction of the juice, through the sequential action of several enzymes. In Fig. 4.2. the mechanism described by Crouzet (1986) for the formation of cis-3- and tran5 -2-hexanal and their corresponding alcohol is shown. Linolenic acid is a common constituent of grape juice. Through the action of a lipoxygenase enzyme, linolenic acid is transformed... 

Chemical and Physical Properties. Too little is known about the physical properties of pure lipoxygenases to permit their comparison. The separation of isoenzymes during their isolation and their diflFerential behavior in electrophoresis indicate the existence of different enzymes. However characterization of the enzymes through their enzymatic properties shows that the lipoxygenases comprise a large group of diverse enzymes. 

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