Leukotriene A(4) hydrolase: a critical role of glutamic acid-296 for the binding of bestatin

Leukotriene A(4) hydrolase is a bifunctional Zn2+-containing enzyme catalys ing the formation of the potent chemotaxin leukotriene B-4. From an analysi s of three mutants of Glu-296 we have found that this catalytic residue is critical for the binding of bestatin, a classical aminopeptidase inhibitor. For bestatin, but not for three other tight-binding inhibitors, the IC50 v alues for inhibition of the epoxide hydrolase activity decreased in the mut ants to 0.7-0.003 % of the control. Hence Glu-296 is an important structura l determinant for binding of bestatin to leukotriene A(4) hydrolase; this c onclusion might also apply to other members of the M1 family of metallopept idases.