Crystal structure of human leukotriene A(4) hydrolase, a bifunctional enzyme in inflammation

Leukotriene (LT) A(4) hydrolase/aminopeptidase (LTA4H) is a bifunctional zi nc enzyme that catalyzes the biosynthesis of LTB4, a potent lipid chemoattr actant involved in inflammation, Immune responses, host defense against inf ection, and PAF-induced shock. The high resolution crystal structure of LTA 4H in complex with the competitive inhibitor bestatin reveals a protein fol ded into three domains that together create a deep cleft harboring the cata lytic Zn2+ site. A bent and narrow pocket, shaped to accommodate the substr ate LTA(4), constitutes a highly confined binding region that can be target ed in the design of specific antiinflammatory agents. Moreover, the structu re of the catalytic domain is very similar to that of thermolysin and provi des detailed insight into mechanisms of catalysis, in particular the chemic al strategy for the unique epoxide hydrolase reaction that generates LTB4.