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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.

Smyrniotis CJ, Barbour SR, Xia Z, Hixon MS, Holman TR - Biochemistry (2014)

Bottom Line: 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 A4, from a single polyunsaturated fatty acid.This work investigates the kinetic mechanism of these two processes and the role of ATP in their activation.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.

ABSTRACT
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 A4, 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 (Vmax/Km) 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.

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Kinetic Scheme for Allosteric Activation of 5-LOX5-LOX catalysis includinghyperbolic partial activation induced by ATP. Similar hyperbolic allosteryhas been observed for other LOX isozymes with different allostericregulators, such as soybean 15-LOX-1 with oleyl sulfate37 and human 15-LOX-2 with 13(S)-HODE.38
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sch1: Kinetic Scheme for Allosteric Activation of 5-LOX5-LOX catalysis includinghyperbolic partial activation induced by ATP. Similar hyperbolic allosteryhas been observed for other LOX isozymes with different allostericregulators, such as soybean 15-LOX-1 with oleyl sulfate37 and human 15-LOX-2 with 13(S)-HODE.38


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 CJ, Barbour SR, Xia Z, Hixon MS, Holman TR - Biochemistry (2014)

Kinetic Scheme for Allosteric Activation of 5-LOX5-LOX catalysis includinghyperbolic partial activation induced by ATP. Similar hyperbolic allosteryhas been observed for other LOX isozymes with different allostericregulators, such as soybean 15-LOX-1 with oleyl sulfate37 and human 15-LOX-2 with 13(S)-HODE.38
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215895&req=5

sch1: Kinetic Scheme for Allosteric Activation of 5-LOX5-LOX catalysis includinghyperbolic partial activation induced by ATP. Similar hyperbolic allosteryhas been observed for other LOX isozymes with different allostericregulators, such as soybean 15-LOX-1 with oleyl sulfate37 and human 15-LOX-2 with 13(S)-HODE.38
Bottom Line: 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 A4, from a single polyunsaturated fatty acid.This work investigates the kinetic mechanism of these two processes and the role of ATP in their activation.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.

ABSTRACT
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 A4, 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 (Vmax/Km) 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.

Show MeSH
Related in: MedlinePlus