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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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Importantmetabolites of the regulation of inflammation made by5-LOX with AA.
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fig1: Importantmetabolites of the regulation of inflammation made by5-LOX with AA.

Mentions: Human 5-lipoxygenase (5-LOX)is a non-heme iron-containing enzyme responsible for catalyzing thestereospecific and regiospecific peroxidation of natural polyunsaturatedfatty acid (PUFA) substrates, specifically converting arachidonicacid (AA) into 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid [5(S)-HpETE].1,2 5-LOX shares this hydroperoxidation activitywith other lipoxygenases, such as 12-LOX and 15-LOX, although thesegenerate different products with different biological roles in thecell [e.g., 12(S)-HpETE and 15(S)-HpETE, respectively]. A unique feature of 5-LOX is the additionalcatalytic step of converting 5(S)-HpETE into theepoxide, leukotriene A4 (LTA4) (Figure 1). This biomolecule is the first in a line of highlypro-inflammatory mediators that act as potent chemoattractants andare implicated in a variety of diseases from asthma to cancer.3−6 Distinguishing the biological role of 5-LOX further is the factthat LTA4 can also be shuttled into neighboring cells expressing12- and 15-LOX via mechanisms of transcellular biosynthesis.7,8 Ultimately, LTA4 is converted to a series of inflammatorybiomolecules (e.g., leukotrienes and lipoxins), both of which areimportant in initiating and terminating inflammation.9,10


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)

Importantmetabolites of the regulation of inflammation made by5-LOX with AA.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Importantmetabolites of the regulation of inflammation made by5-LOX with AA.
Mentions: Human 5-lipoxygenase (5-LOX)is a non-heme iron-containing enzyme responsible for catalyzing thestereospecific and regiospecific peroxidation of natural polyunsaturatedfatty acid (PUFA) substrates, specifically converting arachidonicacid (AA) into 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid [5(S)-HpETE].1,2 5-LOX shares this hydroperoxidation activitywith other lipoxygenases, such as 12-LOX and 15-LOX, although thesegenerate different products with different biological roles in thecell [e.g., 12(S)-HpETE and 15(S)-HpETE, respectively]. A unique feature of 5-LOX is the additionalcatalytic step of converting 5(S)-HpETE into theepoxide, leukotriene A4 (LTA4) (Figure 1). This biomolecule is the first in a line of highlypro-inflammatory mediators that act as potent chemoattractants andare implicated in a variety of diseases from asthma to cancer.3−6 Distinguishing the biological role of 5-LOX further is the factthat LTA4 can also be shuttled into neighboring cells expressing12- and 15-LOX via mechanisms of transcellular biosynthesis.7,8 Ultimately, LTA4 is converted to a series of inflammatorybiomolecules (e.g., leukotrienes and lipoxins), both of which areimportant in initiating and terminating inflammation.9,10

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