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Stereoselective hydrolysis of epoxy‐eicosanoids by mammalian soluble epoxide hydrolases
Author(s) -
Schmidt Cosima,
Fischer Robert,
Markovic Marija,
Morisseau Christophe,
Hammock Bruce D.,
Schunck WolfHagen
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.479.32
Subject(s) - epoxide hydrolase 2 , chemistry , stereoselectivity , arachidonic acid , epoxide , enzyme , enantiomer , eicosanoid , stereochemistry , stereospecificity , biochemistry , hydrolysis , catalysis
Various signalling pathways are stereoselectively modulated by epoxy‐eicosanoids which are themselves produced and degraded in a stereoselective manner by CYP enzymes and soluble epoxide hydrolases (sEH). We observed that the contractility of cardiomyocytes and their response to calcium‐overload is decreased by 11(S),12(R)‐epoxyeicosatrienoic acid (EET) and 17(R),18(S)‐epoxyeicosatetraenoic acid (EETeTr). 11(R),12(S)‐EET showed the opposite effect, the corresponding diols were inactive. Cardiac CYP enzymes equally produced both enantiomers of 11,12‐EET from arachidonic acid but converted eicosapentaenoic acid preferentially to 17(R),18(S)‐EETeTr. Purified recombinant sEH enzymes from human, rat and mouse unisonously showed a high stereoselectivity in terms of preferentially hydrolysing the S,R‐enatiomer of 11,12‐EET but the R,S‐enatiomer of 17,18‐EETeTr, e.g. the catalytic efficiency of mouse sEH was 7‐fold higher towards the R,S‐compared to the S,R‐enantiomer of 17,18‐EETeTr. The sEH enzymes also displayed moderate to strict stereoselectivities when hydrolyzing omega‐3 epoxy‐docosahexaenoic acid as well as other regioisomeric EETs. These data suggest that sEH enzymes do not simply reduce the total epoxy‐eicosanoid level but rather play an important role in adjusting the balance between active and inactive enantiomers and those with opposite biological activities.