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| {{STRUCTURE_1gw6| PDB=1gw6 | SCENE= }} | | {{STRUCTURE_1gw6| PDB=1gw6 | SCENE= }} |
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| '''STRUCTURE OF LEUKOTRIENE A4 HYDROLASE D375N MUTANT'''
| | ===STRUCTURE OF LEUKOTRIENE A4 HYDROLASE D375N MUTANT=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_11917124}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 11917124 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_11917124}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Hydrolase]] | | [[Category: Hydrolase]] |
| [[Category: Mutagenesis study]] | | [[Category: Mutagenesis study]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 18:05:08 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 06:12:09 2008'' |
