Leukotriene A4 hydrolase: selective abrogation of leukotriene B4 formation by mutation of aspartic acid 375

Proceedings of the National Academy of Sciences of the United States of America
Peter C RudbergJ Z Haeggström

Abstract

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 p...Continue Reading

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Citations

Sep 23, 2011·Chemical Reviews·Jesper Z Haeggström, Colin D Funk
Jul 17, 2003·Journal of the National Cancer Institute·Xiaoxin ChenChung S Yang
Jan 7, 2004·Drug Metabolism Reviews·Michael ArandT Alwyn Jones
Dec 15, 2010·Journal of Molecular Biology·Charlotte HelgstrandMarjolein M G M Thunnissen
May 8, 2007·Prostaglandins & Other Lipid Mediators·Jesper Z HaeggströmAnders Wetterholm
Mar 16, 2007·Proteins·Fredrik Tholander, Jesper Z Haeggström
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Dec 2, 2010·Microbiology and Molecular Biology Reviews : MMBR·Elizabeth A MischThomas R Hawn
Sep 2, 2004·The Journal of Biological Chemistry·Jesper Z Haeggström
Aug 5, 2020·Molecular Biology Reports·Roger Gregory Biringer
Aug 23, 2017·Proceedings of the National Academy of Sciences of the United States of America·Alena StsiapanavaJesper Z Haeggström

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