Substrate selectivity of 5-hydroxyeicosanoid dehydrogenase and its inhibition by 5-hydroxy-Delta6-long-chain fatty acids.
5-Oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) is a metabolite of the 5-lipoxygenase (5-LO) product 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE), formed by the microsomal enzyme 5-hydroxyeicosanoid dehydrogenase (5-HEDH). 5-oxo-ETE is a chemoattractant for neutrophils and eosinophils, both in vitro and in vivo. To examine the substrate selectivity of 5-HEDH and to search for potential inhibitors, we prepared a series of 5S-hydroxy fatty acids (C(12) to C(20) containing zero to four double bonds) by total chemical synthesis and examined their metabolism by microsomes from monocytic U937 cells. Although most of these fatty acids were oxidized to their 5-oxo metabolites by 5-HEDH, 5-HETE seemed to be the best substrate. However, substrates containing less than 16 carbons, a methylated alpha-carboxyl group, or a hydroxyl group at the omega-end of the molecule were not substantially metabolized. Some of the fatty acids tested were fairly potent inhibitors of the formation of 5-oxo-ETE by 5-HEDH, in particular 5-hydroxy-6-octadecenoic acid and 5-hydroxy-6-eicosenoic acid. Both substances selectively inhibited 5-oxo-ETE formation by human peripheral blood mononuclear cells incubated with arachidonic acid and calcium ionophore without affecting the formation of leukotriene B(4), 12-HETE, or 12-hydroxy-5,8,10-heptadecatrienoic acid. We conclude that the requirements for appreciable metabolism by 5-HEDH include a chain length of at least 16 carbons, a free alpha-carboxyl group, and a hydrophobic group at the omega-end of the molecule. 5-Hydroxy-Delta(6) C(18) and C(20) fatty acids selectively inhibit 5-HEDH without inhibiting 5-LO, leukotriene A(4) hydrolase, 12-lipoxygenase, or cyclooxygenase. Such compounds may be useful in defining the role of 5-oxo-ETE and its mechanism of synthesis.
Patel
Pranav
P
Claude Pepper Institute, Department of Chemistry, Florida Institute of Technology, Melbourne, Florida, USA.
Cossette
Chantal
C
Anumolu
Jaganmohan R
JR
Erlemann
Karl-Rudolf
KR
Grant
Gail E
GE
Rokach
Joshua
J
Powell
William S
WS
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D020298:U937 Cells
D005229:Fatty Acids, Monounsaturated; D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D000429:Alcohol Oxidoreductases; C099244:5-hydroxyeicosanoid dehydrogenase