The Structure of Human 5-Lipoxygenase

Gilbert, Nathaniel C.; Bartlett, Sue G.; Waight, Maria T.; Neau, David; Boeglin, William E.; Brash, Alan R.; Newcomer, Marcia E.

doi:10.1126/science.1197203

Cited by 372 publications

(342 citation statements)

References 29 publications

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“…An impact of dimerization on the reaction kinetics is presumable due to the observation that the predicted dimer interface is located at the proposed substrate and oxygen entry site of LOs (Ivanov et al , 2010 ). Although an entry channel to the active site is not directly present in the crystal structure of 5-LO, substrate entry to the catalytic site is expected via conformational changes by amino acids of the so called ' FY-cork ' in this region that closes the active site (Gilbert et al , 2011 ). However, due to the dynamics of the monomer/dimer equilibrium and the very low enzymatic activity of the covalently linked dimers generated by diamide treatment, kinetic experiments on monomers or dimers are diffi cult to perform.…”

Section: Discussionmentioning

confidence: 99%

“…For establishing a model of the 5-LO/5-LO interaction, we used the just-deposited crystal structure of human 5-LO [PDB ID: 3o8y (Gilbert et al , 2011 )] and restored the WT enzyme ( in silico mutation and insertions of the modifi ed amino acids). 3o8y shows a crystallographic dimer, which is not a thermodynamically stable complex (Shang et al , 2011 ).…”

Section: Discussionmentioning

confidence: 99%

“…The 5-LO structure published recently (Gilbert et al , 2011 ) confi rms that human 5-LO consists of an N-terminal regulatory C2-like domain (residues 1 -114) and a C-terminal catalytic domain (residues 121 -673) which is mainly organized in α -helices and contains the nonheme iron in its catalytic center. The C2-like domain is responsible for the association of 5-LO to the nuclear membrane (Chen and Funk , 2001 ;Kulkarni et al , 2002 ), for diacylglyceride ( H ö rnig et al, 2005 ) and calcium binding and for the interaction with coactosin-like protein (Rakonjac et al , 2006 ).…”

Section: Introductionmentioning

confidence: 95%

“…To establish a model of a 5-LO dimer, we used the crystal structure of engineered human 5-LO {Protein Data Bank [PDB, http://pdb.org, (Berman et al , 2000 )], ID: 3o8y (Gilbert et al , 2011 )}. Gilbert et al mutated or deleted several amino acids to obtain the so-called ' Stable-5LOX ' (Gilbert et al , 2011 ) thereby enabling crystallization and structure determination.…”

Section: Molecular Modeling and Docking Of 5-lomentioning

confidence: 99%

“…Gilbert et al mutated or deleted several amino acids to obtain the so-called ' Stable-5LOX ' (Gilbert et al , 2011 ) thereby enabling crystallization and structure determination. To restore the WT enzyme, we performed in silico mutagenesis …”

Section: Molecular Modeling and Docking Of 5-lomentioning

confidence: 99%

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Dimerization of human 5-lipoxygenase

Häfner¹,

Cernescu²,

Ermisch³

et al. 2011

Biological Chemistry

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Human 5-lipoxygenase (5-LO) can form dimers as shown here via native gel electrophoresis, gel fi ltration chromatography and LILBID (laser induced liquid bead ion desorption) mass spectrometry. After glutathionylation of 5-LO by diamide/glutathione treatment, dimeric 5-LO was no longer detectable and 5-LO almost exclusively exists in the monomeric form which showed full catalytic activity. Incubation of 5-LO with diamide alone led to a disulfi debridged dimer and to oligomer formation which displays a strongly reduced catalytic activity. The bioinformatic analysis of the 5-LO surface for putative protein-protein interaction domains and molecular modeling of the dimer interface suggests a head to tail orientation of the dimer which also explains the localization of previously reported ATP binding sites. This interface domain was confi rmed by the observation that 5-LO dimer formation and inhibition of activity by diamide was largely prevented when four cysteines (C159S, C300S, C416S, C418S) in this domain were mutated to serines.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Molecular Modeling and Docking Of 5-lomentioning

confidence: 99%

Section: Molecular Modeling and Docking Of 5-lomentioning

confidence: 99%

See 3 more Smart Citations

Dimerization of human 5-lipoxygenase

Häfner¹,

Cernescu²,

Ermisch³

et al. 2011

Biological Chemistry

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Lipoxygenase Pathway of the Arachidonate Cascade

Kobe

Newcomer

2013

Encyclopedia of Life Sciences

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Lipoxygenases (LOXs) are iron‐containing enzymes that catalyse the peroxidation of polyunsaturated fatty acids. In mammals, LOX products and their metabolites are potent lipid mediators that provoke diverse biological responses. These eicosanoids, derived from arachidonic acid, play important roles in inflammation and the resolution of inflammation. Moreover, they have been implicated in the development of cardiovascular disease. Although several LOX isoforms are expressed in individual organisms, each generates a specific product. How structurally and mechanistically related enzymes generate different products from a common substrate is not fully understood. In addition, the biological effects of many of the lipid mediators produced through LOX pathways remain to be uncovered. Key Concepts: Arachidonic acid is a substrate for lipoxygenases, iron enzymes that catalyse the peroxidation of polyunsaturated fatty acids. Mammalian lipoxygenases transform the common substrate (arachidonic acid) to a unique stereo‐ and regiospecific product. Leukotriene synthesis is initiated by 5‐lipoxygenase. Lipoxygenase products and their downstream metabolites are potent signalling molecules, some of which play roles in inflammation or its resolution. Lipoxygenase products are associated with cardiovascular diseases, but their molecular mechanism of action remains unclear.

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Recent Advances on 5‐Lipoxygenase Biochemistry

Werz

Rådmark

Steinhilber

2014

Encyclopedia of Life Sciences

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5‐Lipoxygenase (5‐LOX) catalyses two steps in the biosynthesis of leukotrienes (LTs), lipid mediators of inflammation derived from arachidonic acid. LTs function in normal host defence, and have pathophysiological roles in chronic inflammatory diseases, as asthma and atherosclerosis. Also, possible effects of 5‐LOX products in relation to tumorigenesis have been described. 5‐LOX is also involved in the biosynthesis of anti‐inflammatory/pro‐resolving lipoxins. 5‐LOX is mainly expressed in myeloid and lymphoid cells and its expression is upregulated during cell differentiation. Cellular 5‐LOX activity is regulated in a complex manner and depends on cellular localisation, phosphorylation, the intracellular calcium concentration and the redox status of the cell. Thus, insight regarding the biochemistry of 5‐LOX is relevant for better understanding of normal physiology, and for development of pharmacotherapy. Key Concepts: Lipoxygenases oxygenate polyunsaturated fatty acids. 5‐LOX produces 5‐HPETE, leukotrienes and together with other dioxygenases lipoxins. The regulatory C2‐like domain binds Ca 2+ , diacylglycerols and phosphatidylcholine and regulates the activity of the catalytic domain. 5‐LOX interacts with various proteins such as FLAP, CLP and Dicer. The 5‐lipoxygenase pathway is part of the innate immune system. 5‐LOX products are involved in inflammation, allergic reactions, development of cardiovascular disease as well as certain types of cancer.

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The Structure of Human 5-Lipoxygenase

Cited by 372 publications

References 29 publications

Dimerization of human 5-lipoxygenase

Dimerization of human 5-lipoxygenase

Lipoxygenase Pathway of the Arachidonate Cascade

Recent Advances on 5‐Lipoxygenase Biochemistry

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