Crystal structures of leukotriene C4 synthase in complex with product analogs: implications for the enzyme mechanism.

The Journal of Biological Chemistry
Damian NiegowskiJesper Z Haeggström

Abstract

Leukotriene (LT) C4 synthase (LTC4S) catalyzes the conjugation of the fatty acid LTA4 with the tripeptide GSH to produce LTC4, the parent compound of the cysteinyl leukotrienes, important mediators of asthma. Here we mutated Trp-116 in human LTC4S, a residue proposed to play a key role in substrate binding, into an Ala or Phe. Biochemical and structural characterization of these mutants along with crystal structures of the wild type and mutated enzymes in complex with three product analogs, viz. S-hexyl-, 4-phenyl-butyl-, and 2-hydroxy-4-phenyl-butyl-glutathione, provide new insights to binding of substrates and product, identify a new conformation of the GSH moiety at the active site, and suggest a route for product release, aided by Trp-116.

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Citations

May 9, 2014·PloS One·Damian NiegowskiJesper Z Haeggström
Jul 30, 2014·Applied Microbiology and Biotechnology·Anita EmmerstorferHarald Pichler
Oct 4, 2015·Methods : a Companion to Methods in Enzymology·Sarah J RoutledgeRoslyn M Bill
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Sep 25, 2017·Critical Reviews in Biotechnology·Fereniki PerperopoulouNikolaos E Labrou
Aug 19, 2015·The Journal of Pharmacology and Experimental Therapeutics·Thea K KleinschmidtJesper Z Haeggström
Jan 23, 2018·Future Medicinal Chemistry·Nisha S DeviMukesh Doble
Oct 8, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Charlotte C JouveneCharles N Serhan
Jul 2, 2016·The Journal of Biological Chemistry·Shabbir AhmadJesper Z Haeggström
Apr 20, 2018·International Journal of Molecular Sciences·Krizia SaginiLorena Urbanelli
Aug 4, 2020·Journal of Molecular Biology·Madhuranayaki Thulasingam, Jesper Z Haeggström

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