-transparent.png){kind=logo}
Leukotriene A4 (LTA4) hydrolase [7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9 ,11,14-tetraenoate hydrolase; EC 3.3.2.6] is a bifunctional zinc metalloenzyme which converts LTA4 into the chemotactic agent leukotriene B4 (LTB4). Suicide inactivation, a typical feature of LTA4 hydrolase/aminopeptidase, occurs via an irreversible, apparently mechanism-based, covalent binding of LTA4 to the protein in a 1:1 stoichiometry. Differential lysine-specific peptide mapping of unmodified and suicide-inactivated LTA4 hydrolase has been used to identify a henicosapeptide, encompassing the amino acid residues 365-385 of human LTA4 hydrolase, which is involved in the binding of LTA4, LTA4 methyl ester, and LTA4 ethyl ester to the native enzyme. A modified form of this peptide, generated by lysine-specific digestion of LTA4 hydrolase inactivated by LTA4 ethyl ester, could be isolated for complete Edman degradation. The sequence analysis revealed a gap at position 14, which shows that binding of the leukotriene epoxide had occurred via Tyr-378 in LTA4 hydrolase. Inactivation of the epoxide hydrolase and the aminopeptidase activity was accompanied by a proportionate modification of the peptide. Furthermore, both enzyme inactivation and peptide modification could be prevented by preincubation of LTA4 hydrolase with the competitive inhibitor bestatin, which demonstrates that the henicosapeptide contains functional elements of the active site(s). It may now be possible to clarify the molecular mechanisms underlying suicide inactivation and epoxide hydrolysis by site-directed mutagenesis combined with structural analysis of the lipid molecule, covalently bound to the peptide.
M J Mueller, and
A Wetterholm, and
M Blomster, and
H Jörnvall, and
B Samuelsson, and
J Z Haeggström
November 1992,
The Journal of biological chemistry,
M J Mueller, and
A Wetterholm, and
M Blomster, and
H Jörnvall, and
B Samuelsson, and
J Z Haeggström
September 1990,
The Journal of biological chemistry,
M J Mueller, and
A Wetterholm, and
M Blomster, and
H Jörnvall, and
B Samuelsson, and
J Z Haeggström
June 1996,
Proceedings of the National Academy of Sciences of the United States of America,
M J Mueller, and
A Wetterholm, and
M Blomster, and
H Jörnvall, and
B Samuelsson, and
J Z Haeggström
November 1994,
Annals of the New York Academy of Sciences,
M J Mueller, and
A Wetterholm, and
M Blomster, and
H Jörnvall, and
B Samuelsson, and
J Z Haeggström
July 1987,
The Journal of biological chemistry,
M J Mueller, and
A Wetterholm, and
M Blomster, and
H Jörnvall, and
B Samuelsson, and
J Z Haeggström
May 1998,
The Journal of biological chemistry,
M J Mueller, and
A Wetterholm, and
M Blomster, and
H Jörnvall, and
B Samuelsson, and
J Z Haeggström
August 2002,
Prostaglandins & other lipid mediators,
M J Mueller, and
A Wetterholm, and
M Blomster, and
H Jörnvall, and
B Samuelsson, and
J Z Haeggström
January 1990,
Advances in prostaglandin, thromboxane, and leukotriene research,
M J Mueller, and
A Wetterholm, and
M Blomster, and
H Jörnvall, and
B Samuelsson, and
J Z Haeggström
November 1990,
Biochemical and biophysical research communications,
M J Mueller, and
A Wetterholm, and
M Blomster, and
H Jörnvall, and
B Samuelsson, and
J Z Haeggström
October 1995,
Journal of lipid mediators and cell signalling,
