1gw6
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Leukotriene A4 (LTA4, 5S-trans-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid) hydrolase | + | Leukotriene A4 (LTA4, 5S-trans-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid) hydrolase (LTA4H)/aminopeptidase is a bifunctional zinc metalloenzyme that catalyzes the final and rate-limiting step in the biosynthesis of leukotriene B4 (LTB4, 5S,12R-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid), a classical chemoattractant and immune modulating lipid mediator. Two chemical features are key to the bioactivity of LTB4, namely, the chirality of the 12R-hydroxyl group and the cis-trans-trans geometry of the conjugated triene structure. From the crystal structure of LTA4H, a hydrophilic patch composed of Gln-134, Tyr-267, and Asp-375 was identified in a narrow and otherwise hydrophobic pocket, believed to bind LTA4. In addition, Asp-375 belongs to peptide K21, a previously characterized 21-residue active site-peptide to which LTA4 binds during suicide inactivation. In the present report we used site-directed mutagenesis and x-ray crystallography to show that Asp-375, but none of the other candidate residues, is specifically required for the epoxide hydrolase activity of LTA4H. Thus, mutation of Asp-375 leads to a selective loss of the enzyme's ability to generate LTB4 whereas the aminopeptidase activity is preserved. We propose that Asp-375, possibly assisted by Gln-134, acts as a critical determinant for the stereoselective introduction of the 12R-hydroxyl group and thus the biological activity of LTB4. |
==About this Structure== | ==About this Structure== | ||
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[[Category: Leukotriene-A(4) hydrolase]] | [[Category: Leukotriene-A(4) hydrolase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Haeggstrom, J | + | [[Category: Haeggstrom, J Z.]] |
| - | [[Category: Rudberg, P | + | [[Category: Rudberg, P C.]] |
[[Category: Samuelsson, B.]] | [[Category: Samuelsson, B.]] | ||
[[Category: Tholander, F.]] | [[Category: Tholander, F.]] | ||
| - | [[Category: Thunnissen, M | + | [[Category: Thunnissen, M M.G M.]] |
[[Category: ACT]] | [[Category: ACT]] | ||
[[Category: BES]] | [[Category: BES]] | ||
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[[Category: mutagenesis studies]] | [[Category: mutagenesis studies]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:54:40 2008'' |
Revision as of 10:54, 21 February 2008
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STRUCTURE OF LEUKOTRIENE A4 HYDROLASE D375N MUTANT
Overview
Leukotriene A4 (LTA4, 5S-trans-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid) hydrolase (LTA4H)/aminopeptidase is a bifunctional zinc metalloenzyme that catalyzes the final and rate-limiting step in the biosynthesis of leukotriene B4 (LTB4, 5S,12R-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid), a classical chemoattractant and immune modulating lipid mediator. Two chemical features are key to the bioactivity of LTB4, namely, the chirality of the 12R-hydroxyl group and the cis-trans-trans geometry of the conjugated triene structure. From the crystal structure of LTA4H, a hydrophilic patch composed of Gln-134, Tyr-267, and Asp-375 was identified in a narrow and otherwise hydrophobic pocket, believed to bind LTA4. In addition, Asp-375 belongs to peptide K21, a previously characterized 21-residue active site-peptide to which LTA4 binds during suicide inactivation. In the present report we used site-directed mutagenesis and x-ray crystallography to show that Asp-375, but none of the other candidate residues, is specifically required for the epoxide hydrolase activity of LTA4H. Thus, mutation of Asp-375 leads to a selective loss of the enzyme's ability to generate LTB4 whereas the aminopeptidase activity is preserved. We propose that Asp-375, possibly assisted by Gln-134, acts as a critical determinant for the stereoselective introduction of the 12R-hydroxyl group and thus the biological activity of LTB4.
About this Structure
1GW6 is a Single protein structure of sequence from Homo sapiens with , , , and as ligands. Active as Leukotriene-A(4) hydrolase, with EC number 3.3.2.6 Known structural/functional Site: . Full crystallographic information is available from OCA.
Reference
Leukotriene A4 hydrolase: selective abrogation of leukotriene B4 formation by mutation of aspartic acid 375., Rudberg PC, Tholander F, Thunnissen MM, Samuelsson B, Haeggstrom JZ, Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4215-20. Epub 2002 Mar 26. PMID:11917124
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