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Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. (Pär Nordlund)
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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2007 (English)In: Nature, ISSN 0028-0836, Vol. 448, no 7153, 613-616 p.Article in journal (Refereed) Published
Abstract [en]

Cysteinyl leukotrienes are key mediators in inflammation and have an important role in acute and chronic inflammatory diseases of the cardiovascular and respiratory systems, in particular bronchial asthma. In the biosynthesis of cysteinyl leukotrienes, conversion of arachidonic acid forms the unstable epoxide leukotriene A4 (LTA4). This intermediate is conjugated with glutathione (GSH) to produce leukotriene C4 (LTC4) in a reaction catalysed by LTC4 synthase1: this  eaction is the key step in cysteinyl leukotriene formation. Here we present the rystal structure of the human LTC4 synthase in its apo and GSH-complexed forms to 2.00 and 2.15 A ̊resolution, respectively. The structure reveals a homotrimer,  here each monomer is composed of four transmembrane segments. The structure of the enzyme in complex with substrate reveals that the active site enforces a  orseshoe-shaped conformation on GSH, and effectively positions the thiol group or activation by a nearby arginine at the membrane–enzyme interface. In addition, the structure provides a model for how the v-end of the lipophilic co-substrate is pinned at one end of a hydrophobic cleft, providing a molecular ‘ruler’ to align the  eactive epoxide at the thiol of glutathione. This provides new structural insights nto the mechanism of LTC4 formation, and also suggests that the observed inding and activation of GSH might be common for a family of homologous proteins mportant for inflammatory and detoxification responses.

Place, publisher, year, edition, pages
2007. Vol. 448, no 7153, 613-616 p.
Keyword [en]
ltc4, leukotriene synthase, lipid binding, cysteinyl leokotrienes
National Category
Natural Sciences
Research subject
Structural Biology
URN: urn:nbn:se:su:diva-29990DOI: 10.1038/nature06009OAI: diva2:241102
Available from: 2009-10-01 Created: 2009-09-27 Last updated: 2009-10-01Bibliographically approved

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