Modifications in FLAP's second cytosolic loop influence 5-LOX interaction, inhibitor binding, and leukotriene formation

Document Type

Article

Publication Date

1-1-2025

Abstract

Leukotrienes, synthesized via the 5-lipoxygenase (5-LOX) pathway in the arachidonic acid cascade, are critical in inflammation. Effective leukotriene production requires interaction between 5-LOX and 5-LOX-activating protein (FLAP) at the nuclear membrane. This study used site-directed mutagenesis to explore amino acid residues in FLAP's inhibitor binding pocket and cytosolic loops, assessing their impact on 5-LOX product formation, the FLAP inhibitor MK886's efficacy, 5-LOX translocation, and 5-LOX/FLAP complex formation. Mutations in the second cytosolic loop, especially at residue S108, reduced MK886 potency and disrupted 5-LOX/FLAP complex formation. These results highlight the second cytosolic loop of FLAP in the 5-LOX/FLAP interaction and proper leukotriene formation and suggest that targeting this region could aid in the development of new FLAP inhibitors with improved pharmacokinetics.

Publication Source (Journal or Book title)

FEBS Letters

This document is currently not available here.

Share

COinS