Leukotriene A4 hydrolase: a critical role of glutamic acid-296 for the binding of bestatin.
Leukotriene A(4) hydrolase is a bifunctional Zn(2+)-containing enzyme catalysing the formation of the potent chemotaxin leukotriene B(4). From an analysis 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 IC(50) values for inhibition of the epoxide hydrolase activity decreased in the mutants to 0.7-0.003% of the control. Hence Glu-296 is an important structural determinant for binding of bestatin to leukotriene A(4) hydrolase; this conclusion might also apply to other members of the M1 family of metallopeptidases.
Andberg
M
M
Department of Medical Biochemistry and Biophysics, Division of Chemistry II, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Wetterholm
A
A
Medina
J F
JF
Haeggström
J Z
JZ
D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid; D020128:Inhibitory Concentration 50; D007930:Leucine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009154:Mutation; D011480:Protease Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D011480:Protease Inhibitors; D011994:Recombinant Proteins; D018698:Glutamic Acid; D004851:Epoxide Hydrolases; D000626:Aminopeptidases; D007930:Leucine; C012211:ubenimex; C043134:leukotriene A4 hydrolase