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Structure-Based Dissection of the Active Site Chemistry of Leukotriene A4 Hydrolase: Implications for M1 Aminopeptidases and Inhibitor Design

Tholander, Fredrik; Muroya, Ayumu LU ; Roques, Bernard-Pierre; Fournie-Zaluski, Marie-Claude; Thunnissen, Marjolein LU and Haeggstrom, Jesper Z. (2008) In Chemistry and Biology 15(9). p.920-929
Abstract
M1 aminopeptidases comprise a large family of biologically important zinc enzymes. We show that peptide turnover by the M1 prototype, leukotriene A4 hydrolase/aminopeptidase, involves a shift in substrate position associated with exchange of zinc coordinating groups, while maintaining the overall coordination geometry. The transition state is stabilized by residues conserved among M1 members and in the final reaction step, Glu-296 of the canonical zinc binding HEXXH motif shuffles a proton from the hydrolytic water to the leaving group. Tripeptide substrates bind along the conserved GXMEN motif, precisely occupying the distance between Glu-271 and Arg-563, whereas the Arg specificity is governed by a narrow S1 pocket capped with Asp-375.... (More)
M1 aminopeptidases comprise a large family of biologically important zinc enzymes. We show that peptide turnover by the M1 prototype, leukotriene A4 hydrolase/aminopeptidase, involves a shift in substrate position associated with exchange of zinc coordinating groups, while maintaining the overall coordination geometry. The transition state is stabilized by residues conserved among M1 members and in the final reaction step, Glu-296 of the canonical zinc binding HEXXH motif shuffles a proton from the hydrolytic water to the leaving group. Tripeptide substrates bind along the conserved GXMEN motif, precisely occupying the distance between Glu-271 and Arg-563, whereas the Arg specificity is governed by a narrow S1 pocket capped with Asp-375. Our data provide detailed insights to the active site chemistry of M1 aminopeptidases and will aid in the development of novel enzyme inhibitors. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Chemistry and Biology
volume
15
issue
9
pages
920 - 929
publisher
Cell Press
external identifiers
  • wos:000259918200007
  • scopus:51849151991
ISSN
1879-1301
DOI
10.1016/j.chembiol.2008.07.018
language
English
LU publication?
yes
id
aaf516df-0527-4354-af52-d13d35798e77 (old id 1285842)
date added to LUP
2009-02-06 08:58:41
date last changed
2017-10-29 03:30:51
@article{aaf516df-0527-4354-af52-d13d35798e77,
  abstract     = {M1 aminopeptidases comprise a large family of biologically important zinc enzymes. We show that peptide turnover by the M1 prototype, leukotriene A4 hydrolase/aminopeptidase, involves a shift in substrate position associated with exchange of zinc coordinating groups, while maintaining the overall coordination geometry. The transition state is stabilized by residues conserved among M1 members and in the final reaction step, Glu-296 of the canonical zinc binding HEXXH motif shuffles a proton from the hydrolytic water to the leaving group. Tripeptide substrates bind along the conserved GXMEN motif, precisely occupying the distance between Glu-271 and Arg-563, whereas the Arg specificity is governed by a narrow S1 pocket capped with Asp-375. Our data provide detailed insights to the active site chemistry of M1 aminopeptidases and will aid in the development of novel enzyme inhibitors.},
  author       = {Tholander, Fredrik and Muroya, Ayumu and Roques, Bernard-Pierre and Fournie-Zaluski, Marie-Claude and Thunnissen, Marjolein and Haeggstrom, Jesper Z.},
  issn         = {1879-1301},
  language     = {eng},
  number       = {9},
  pages        = {920--929},
  publisher    = {Cell Press},
  series       = {Chemistry and Biology},
  title        = {Structure-Based Dissection of the Active Site Chemistry of Leukotriene A4 Hydrolase: Implications for M1 Aminopeptidases and Inhibitor Design},
  url          = {http://dx.doi.org/10.1016/j.chembiol.2008.07.018},
  volume       = {15},
  year         = {2008},
}