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Science 331 (6014): 217-219

Copyright © 2011 by the American Association for the Advancement of Science

The Structure of Human 5-Lipoxygenase

Nathaniel C. Gilbert,1 Sue G. Bartlett,1 Maria T. Waight,1 David B. Neau,2 William E. Boeglin,3 Alan R. Brash,3 Marcia E. Newcomer1,*

Abstract: The synthesis of both proinflammatory leukotrienes and anti-inflammatory lipoxins requires the enzyme 5-lipoxygenase (5-LOX). 5-LOX activity is short-lived, apparently in part because of an intrinsic instability of the enzyme. We identified a 5-LOX–specific destabilizing sequence that is involved in orienting the carboxyl terminus, which binds the catalytic iron. Here, we report the crystal structure at 2.4 angstrom resolution of human 5-LOX stabilized by replacement of this sequence.

1 Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA.
2 Northeastern Collaborative Access Team, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, IL 60439, USA.
3 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

* To whom correspondence should be addressed. E-mail: newcomer{at}

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M. J. Kobe, D. B. Neau, C. E. Mitchell, S. G. Bartlett, and M. E. Newcomer (2014)
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Lipoxygenase pathways in Homo neanderthalensis: functional comparison with Homo sapiens isoforms.
P. Chaitidis, S. Adel, M. Anton, D. Heydeck, H. Kuhn, and T. Horn (2013)
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A. Wennman, F. Jerneren, M. Hamberg, and E. H. Oliw (2012)
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Conversion of human 5-lipoxygenase to a 15-lipoxygenase by a point mutation to mimic phosphorylation at Serine-663.
N. C. Gilbert, Z. Rui, D. B. Neau, M. T. Waight, S. G. Bartlett, W. E. Boeglin, A. R. Brash, and M. E. Newcomer (2012)
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Structure of a Calcium-dependent 11R-Lipoxygenase Suggests a Mechanism for Ca2+ Regulation.
P. Eek, R. Jarving, I. Jarving, N. C. Gilbert, M. E. Newcomer, and N. Samel (2012)
J. Biol. Chem. 287, 22377-22386
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Lipid-cytokine-chemokine cascades orchestrate leukocyte recruitment in inflammation.
C. D. Sadik and A. D. Luster (2012)
J. Leukoc. Biol. 91, 207-215
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Ethanol Promotes Chemically Induced Oral Cancer in Mice through Activation of the 5-Lipoxygenase Pathway of Arachidonic Acid Metabolism.
Y. Guo, X. Wang, X. Zhang, Z. Sun, and X. Chen (2011)
Cancer Prevention Research 4, 1863-1872
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Stereocontrol of Arachidonic Acid Oxygenation by Vertebrate Lipoxygenases: NEWLY CLONED ZEBRAFISH LIPOXYGENASE 1 DOES NOT FOLLOW THE ALA-VERSUS-GLY CONCEPT.
C. Jansen, K. Hofheinz, R. Vogel, J. Roffeis, M. Anton, P. Reddanna, H. Kuhn, and M. Walther (2011)
J. Biol. Chem. 286, 37804-37812
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Molecular Basis for the Reduced Catalytic Activity of the Naturally Occurring T560M Mutant of Human 12/15-Lipoxygenase That Has Been Implicated in Coronary Artery Disease.
K. Schurmann, M. Anton, I. Ivanov, C. Richter, H. Kuhn, and M. Walther (2011)
J. Biol. Chem. 286, 23920-23927
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Cinnamyl-3,4-Dihydroxy-{alpha}-Cyanocinnamate Is a Potent Inhibitor of 5-Lipoxygenase.
C. Pergola, B. Jazzar, A. Rossi, U. Buehring, S. Luderer, F. Dehm, H. Northoff, L. Sautebin, and O. Werz (2011)
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Leukotriene Inflammatory Mediators Meet Their Match.
C. D. Funk (2011)
Science Translational Medicine 3, 66ps3
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