Abstract

Leukotriene A4 Hydrolase (LTA4H) is a bifunctional zinc metalloenzyme that comprises both epoxide hydrolase and aminopeptidase activity, exerted by two overlapping catalytic sites. The epoxide hydrolase function of the enzyme catalyzes the biosynthesis of the pro-inflammatory lipid mediator leukotriene (LT) B4. Recent literature suggests that the aminopeptidase function of LTA4H is responsible for degradation of the tripeptide Pro-Gly-Pro (PGP) for which neutrophil chemotactic activity has been postulated. It has been speculated that the design of epoxide hydrolase selective LTA4H inhibitors that spare the aminopeptidase pocket may therefore lead to more efficacious anti-inflammatory drugs. In this study, we conducted a high throughput screen (HTS) for LTA4H inhibitors and attempted to rationally design compounds that would spare the PGP degrading function. While we were able to identify compounds with preference for the epoxide hydrolase function, absolute selectivity was not achievable for highly potent compounds. In order to assess the relevance of designing such aminopeptidase-sparing LTA4H inhibitors, we studied the role of PGP in inducing inflammation in different settings in wild type and LTA4H deficient (LTA4H KO) animals but could not confirm its chemotactic potential. Attempting to design highly potent epoxide hydrolase selective LTA4H inhibitors, therefore seems to be neither feasible nor relevant.

Highlights

  • Leukotriene A4 Hydrolase (LTA4H) is a bifunctional zinc metalloenzyme that comprises both epoxide hydrolase and aminopeptidase activity, exerted by two overlapping catalytic sites

  • These data suggest that LTA4H may have two opposing roles in the regulation of inflammation: on the one hand, LTA4H is responsible for biosynthesis of the pro-inflammatory, neutrophil chemotactic lipid mediator LTB4 and on the other hand, it degrades and inactivates the chemotactic tripeptide PGP9,11

  • We found that close and even smaller analogues of ARM1 and 4-MDM failed to show any selectivity for the epoxide hydrolase function of the enzyme (Table 1)

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Summary

Introduction

Leukotriene A4 Hydrolase (LTA4H) is a bifunctional zinc metalloenzyme that comprises both epoxide hydrolase and aminopeptidase activity, exerted by two overlapping catalytic sites. While less is known about the physiological relevance of the aminopeptidase activity of LTA4H, Snelgrove and co-workers suggested that it can degrade the tripeptide PGP which has been reported to be a collagen-derived matrikine and neutrophil chemoattractant[8,9,10] These data suggest that LTA4H may have two opposing roles in the regulation of inflammation: on the one hand, LTA4H is responsible for biosynthesis of the pro-inflammatory, neutrophil chemotactic lipid mediator LTB4 and on the other hand, it degrades and inactivates the chemotactic tripeptide PGP9,11. The authors of this study proposed that epoxide hydrolase specific LTA4H inhibitors sparing the aminopeptidase function may have superior anti-inflammatory activity because they would not interfere with the degradation of PGP while inhibiting LTB4 biosynthesis

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