| Structural highlights
Function
[LKHA4_YEAST] Aminopeptidase that preferentially cleaves tripeptides. Also has low epoxide hydrolase activity (in vitro). Can hydrolyze an epoxide moiety of LTA(4) to form LTB(4) (in vitro).[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Vertebrate leukotriene A(4) hydrolases are bifunctional zinc metalloenzymes with an epoxide hydrolase and an aminopeptidase activity. In contrast, highly homologous enzymes from lower organisms only have the aminopeptidase activity. From sequence comparisons, it is not clear why this difference occurs. In order to obtain more information on the evolutionary relationship between these enzymes and their activities, the structure of a closely related leucine aminopeptidase from Saccharomyces cerevisiae that only shows a very low epoxide hydrolase activity was determined. To investigate the molecular architecture of the active site, the structures of both the native protein and the protein in complex with the aminopeptidase inhibitor bestatin were solved. These structures show a more spacious active site, and the protected cavity in which the labile substrate leukotriene A(4) is bound in the human enzyme is partially obstructed and in other parts is more solvent accessible. Furthermore, the enzyme undergoes induced fit upon binding of the inhibitor bestatin, leading to a movement of the C-terminal domain. The main triggers for the domain movement are a conformational change of Tyr312 and a subtle change in backbone conformation of the PYGAMEN fingerprint region for peptide substrate recognition. This leads to a change in the hydrogen-bonding network pulling the C-terminal domain into a different position. Inasmuch as bestatin is a structural analogue of a leucyl dipeptide and may be regarded as a transition state mimic, our results imply that the enzyme undergoes induced fit during substrate binding and turnover.
A Leukotriene A(4) Hydrolase-Related Aminopeptidase from Yeast Undergoes Induced Fit upon Inhibitor Binding.,Helgstrand C, Hasan M, Uysal H, Haeggstrom JZ, Thunnissen MM J Mol Biol. 2010 Dec 10. PMID:21146536[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kull F, Ohlson E, Haeggstrom JZ. Cloning and characterization of a bifunctional leukotriene A(4) hydrolase from Saccharomyces cerevisiae. J Biol Chem. 1999 Dec 3;274(49):34683-90. PMID:10574934
- ↑ Kull F, Ohlson E, Lind B, Haeggstrom JZ. Saccharomyces cerevisiae leukotriene A4 hydrolase: formation of leukotriene B4 and identification of catalytic residues. Biochemistry. 2001 Oct 23;40(42):12695-703. PMID:11601994
- ↑ Tholander F, Kull F, Ohlson E, Shafqat J, Thunnissen MM, Haeggstrom JZ. Leukotriene A4 hydrolase, insights into the molecular evolution by homology modeling and mutational analysis of enzyme from Saccharomyces cerevisiae. J Biol Chem. 2005 Sep 30;280(39):33477-86. Epub 2005 Jul 15. PMID:16024909 doi:http://dx.doi.org/M506821200
- ↑ Thompson MW, Archer ED, Romer CE, Seipelt RL. A conserved tyrosine residue of Saccharomyces cerevisiae leukotriene A4 hydrolase stabilizes the transition state of the peptidase activity. Peptides. 2006 Jul;27(7):1701-9. Epub 2006 Apr 4. PMID:16597475 doi:http://dx.doi.org/10.1016/j.peptides.2006.02.006
- ↑ Helgstrand C, Hasan M, Uysal H, Haeggstrom JZ, Thunnissen MM. A Leukotriene A(4) Hydrolase-Related Aminopeptidase from Yeast Undergoes Induced Fit upon Inhibitor Binding. J Mol Biol. 2010 Dec 10. PMID:21146536 doi:10.1016/j.jmb.2010.11.059
- ↑ Helgstrand C, Hasan M, Uysal H, Haeggstrom JZ, Thunnissen MM. A Leukotriene A(4) Hydrolase-Related Aminopeptidase from Yeast Undergoes Induced Fit upon Inhibitor Binding. J Mol Biol. 2010 Dec 10. PMID:21146536 doi:10.1016/j.jmb.2010.11.059
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