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Photoactivation of an Inhibitor of the 12/15‐Lipoxygenase Pathway
Author(s) -
Herre Stephan,
Schadendorf Torsten,
Ivanov Igor,
Herrberger Christian,
Steinle Wencke,
RückBraun Karola,
Preissner Robert,
Kuhn Hartmut
Publication year - 2006
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200600082
Subject(s) - lipoxygenase , isomerization , chemistry , enzyme , stereochemistry , arachidonate 5 lipoxygenase , biochemistry , double bond , recombinant dna , intracellular , arachidonic acid , catalysis , organic chemistry , gene
Lipoxygenases are lipid‐peroxidizing enzymes that have been implicated in the pathogenesis of inflammatory diseases and lipoxygenase inhibitors may be developed as anti‐inflammatory drugs. Structure comparison with known lipoxygenase inhibitors has suggested that (2 Z )‐2‐(3‐benzylidene)‐3‐oxo‐2,3‐dihydrobenzo[b]thiophene‐7‐carboxylic acid methyl ester might inhibit the lipoxygenase pathway but we found that it exhibited only a low inhibitory potency for the pure 12/15‐lipoxygenase (IC 50 =0.7 m M ). However, photoactivation, which induces a Z ‐to‐ E isomerization of the double bond, strongly augmented the inhibitory potency and an IC 50 value of 0.021 m M was determined for the pure E isomer. Similar isomer‐specific differences were observed with the recombinant enzyme and its 12‐lipoxygenating Ile418Ala mutant, as well as in intracellular lipoxygenase activity. Structure modeling of the enzyme/inhibitor complex suggested the molecular reasons for this isomer specificity. Since light‐induced isomerization may proceed in the skin, such photoreactive compounds might be developed as potential drugs for inflammatory skin diseases.