Novel structural and functional properties of leukotriene A4 hydrolase. Implications for the development of enzyme inhibitors.
Recent work in our laboratory, some of which is described in this report, has established that LTA4 hydrolase is a bifunctional metalloenzyme that contains one zinc atom, essential for both catalytic activities. The well-characterized epoxide hydrolase activity, i.e., the conversion of LTA4 into LTB4 is inhibited by exposure to LTA4, and this irreversible enzyme inactivation also affects the peptidase activity. In contrast, the peptide hydrolysis proceeds without any signs of enzyme inactivation, can be stimulated by physiologic concentrations of chloride ions, and is critically dependent on the presence of a Glu residue in position 296 of the protein. A model of the active center, which summarizes these novel structural and functional properties of LTA4 hydrolase, is presented in Fig. 6.
Haeggström
J Z
JZ
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Wetterholm
A
A
Medina
J F
JF
Samuelsson
B
B
D000595:Amino Acid Sequence; D001665:Binding Sites; D002712:Chlorides / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism
D002712:Chlorides; D018698:Glutamic Acid; D004851:Epoxide Hydrolases; D015032:Zinc; C043134:leukotriene A4 hydrolase