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ATP Allosterically Activates the Human 5-Lipoxygenase Molecular Mechanism of Arachidonic Acid and 5(S)-Hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic Acid
[Image: see text] 5-Lipoxygenase (5-LOX) reacts with arachidonic acid (AA) to first generate 5(S)-hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid [5(S)-HpETE] and then an epoxide from 5(S)-HpETE to form leukotriene A(4), from a single polyunsaturated fatty acid. This work investigates the ki...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical Society
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215895/ https://www.ncbi.nlm.nih.gov/pubmed/24893149 http://dx.doi.org/10.1021/bi401621d |
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author | Smyrniotis, Christopher J. Barbour, Shannon R. Xia, Zexin Hixon, Mark S. Holman, Theodore R. |
author_facet | Smyrniotis, Christopher J. Barbour, Shannon R. Xia, Zexin Hixon, Mark S. Holman, Theodore R. |
author_sort | Smyrniotis, Christopher J. |
collection | PubMed |
description | [Image: see text] 5-Lipoxygenase (5-LOX) reacts with arachidonic acid (AA) to first generate 5(S)-hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid [5(S)-HpETE] and then an epoxide from 5(S)-HpETE to form leukotriene A(4), from a single polyunsaturated fatty acid. This work investigates the kinetic mechanism of these two processes and the role of ATP in their activation. Specifically, it was determined that epoxidation of 5(S)-HpETE (dehydration of the hydroperoxide) has a rate of substrate capture (V(max)/K(m)) significantly lower than that of AA hydroperoxidation (oxidation of AA to form the hydroperoxide); however, hyperbolic kinetic parameters for ATP activation indicate a similar activation for AA and 5(S)-HpETE. Solvent isotope effect results for both hydroperoxidation and epoxidation indicate that a specific step in its molecular mechanism is changed, possibly because of a lowering of the dependence of the rate-limiting step on hydrogen atom abstraction and an increase in the dependency on hydrogen bond rearrangement. Therefore, changes in ATP concentration in the cell could affect the production of 5-LOX products, such as leukotrienes and lipoxins, and thus have wide implications for the regulation of cellular inflammation. |
format | Online Article Text |
id | pubmed-4215895 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American
Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-42158952015-06-03 ATP Allosterically Activates the Human 5-Lipoxygenase Molecular Mechanism of Arachidonic Acid and 5(S)-Hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic Acid Smyrniotis, Christopher J. Barbour, Shannon R. Xia, Zexin Hixon, Mark S. Holman, Theodore R. Biochemistry [Image: see text] 5-Lipoxygenase (5-LOX) reacts with arachidonic acid (AA) to first generate 5(S)-hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid [5(S)-HpETE] and then an epoxide from 5(S)-HpETE to form leukotriene A(4), from a single polyunsaturated fatty acid. This work investigates the kinetic mechanism of these two processes and the role of ATP in their activation. Specifically, it was determined that epoxidation of 5(S)-HpETE (dehydration of the hydroperoxide) has a rate of substrate capture (V(max)/K(m)) significantly lower than that of AA hydroperoxidation (oxidation of AA to form the hydroperoxide); however, hyperbolic kinetic parameters for ATP activation indicate a similar activation for AA and 5(S)-HpETE. Solvent isotope effect results for both hydroperoxidation and epoxidation indicate that a specific step in its molecular mechanism is changed, possibly because of a lowering of the dependence of the rate-limiting step on hydrogen atom abstraction and an increase in the dependency on hydrogen bond rearrangement. Therefore, changes in ATP concentration in the cell could affect the production of 5-LOX products, such as leukotrienes and lipoxins, and thus have wide implications for the regulation of cellular inflammation. American Chemical Society 2014-06-03 2014-07-15 /pmc/articles/PMC4215895/ /pubmed/24893149 http://dx.doi.org/10.1021/bi401621d Text en Copyright © 2014 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) |
spellingShingle | Smyrniotis, Christopher J. Barbour, Shannon R. Xia, Zexin Hixon, Mark S. Holman, Theodore R. ATP Allosterically Activates the Human 5-Lipoxygenase Molecular Mechanism of Arachidonic Acid and 5(S)-Hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic Acid |
title | ATP Allosterically Activates the Human 5-Lipoxygenase
Molecular Mechanism of Arachidonic Acid and 5(S)-Hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic Acid |
title_full | ATP Allosterically Activates the Human 5-Lipoxygenase
Molecular Mechanism of Arachidonic Acid and 5(S)-Hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic Acid |
title_fullStr | ATP Allosterically Activates the Human 5-Lipoxygenase
Molecular Mechanism of Arachidonic Acid and 5(S)-Hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic Acid |
title_full_unstemmed | ATP Allosterically Activates the Human 5-Lipoxygenase
Molecular Mechanism of Arachidonic Acid and 5(S)-Hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic Acid |
title_short | ATP Allosterically Activates the Human 5-Lipoxygenase
Molecular Mechanism of Arachidonic Acid and 5(S)-Hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic Acid |
title_sort | atp allosterically activates the human 5-lipoxygenase
molecular mechanism of arachidonic acid and 5(s)-hydroperoxy-6(e),8(z),11(z),14(z)-eicosatetraenoic acid |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215895/ https://www.ncbi.nlm.nih.gov/pubmed/24893149 http://dx.doi.org/10.1021/bi401621d |
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