Unique Peroxidase Reaction Mechanism in Prostaglandin Endoperoxide H Synthase-2

Ichimura, S.; Uchida, Takeshi; Taniguchi, S.; Hira, Shusuke; Tosha, Takehiko; Morishima, Isao; Kitagawa, Teizo; Ishimori, Koichiro

doi:10.1074/jbc.m610785200

Cited by 8 publications

(2 citation statements)

References 61 publications

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“…5). Recent mutagenic results, however, indicate that removal of the side chain amine group from Gln203 in either PGHS-1 [32] or PGHS-2 [39] has little effect on heterolytic cleavage of peroxide. Thus, His207 may by itself exert sufficient “pull” to achieve peroxide cleavage, so that Gln203 only provide H-bonding to help orient His207.…”

Section: Peroxidase Reaction Mechanismmentioning

confidence: 99%

Prostaglandin H synthase: Resolved and unresolved mechanistic issues

Tsai

Kulmacz

2010

Archives of Biochemistry and Biophysics

146

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The cyclooxygenase and peroxidase activities of prostaglandin H synthase (PGHS)-1 and -2 have complex kinetics, with the cyclooxygenase exhibiting feedback activation by product peroxide and irreversible self-inactivation, and the peroxidase undergoing an independent self-inactivation process. The mechanistic bases for these complex, non-linear steady-state kinetics have been gradually elucidated by a combination of structure/function, spectroscopic and transient kinetic analyses. It is now apparent that most aspects of PGHS-1 and -2 catalysis can be accounted for by a branched chain mechanism involving a classic heme-based peroxidase cycle and a radical-based cyclooxygenase cycle. The two cycles are linked by the Tyr385 radical, which originates from an oxidized peroxidase intermediate and begins the cyclooxygenase cycle by abstracting a hydrogen atom from the fatty acid substrate. Peroxidase cycle intermediates have been well characterized, and peroxidase self-inactivation has been kinetically linked to a damaging side reaction involving the oxyferryl heme oxidant in an intermediate that also contains the Tyr385 radical. The cyclooxygenase cycle intermediates are poorly characterized, with the exception of the Tyr385 radical and the initial arachidonate radical, which has a pentadiene structure involving C11-C15 of the fatty acid. Oxygen isotope effect studies suggest that formation of the arachidonate radical is reversible, a conclusion consistent with electron paramagnetic resonance spectroscopic observations, radical trapping by NO, and thermodynamic calculations, although moderate isotope selectivity was found for the Habstraction step as well. Reaction with peroxide also produces an alternate radical at Tyr504 that is linked to cyclooxygenase activation efficiency and may serve as a reservoir of oxidizing equivalent. The interconversions among radicals on Tyr385, on Tyr504, and on arachidonate, and their relationships to regulation and inactivation of the cyclooxygenase, are still under active investigation for both PGHS isozymes.Prostaglandin H synthase (PGHS) is a key enzyme in prostanoid biosynthesis. Mammalian systems have two distinct PGHS isozymes sharing ~60% sequence identity. The constitutive isozyme, PGHS-1, is thought to function usually as a housekeeping enzyme, whereas the inducible isozyme, PGHS-2, is associated with cytokine and mitogen dependent processes, such as inflammation and cell proliferation [1,2]. Both PGHS isozymes catalyze the same two reactions: dioxygenation of arachidonic acid (AA) to yield prostaglandin G 2 (PGG 2 ), containing both a 9-11 endoperoxide and a 15-peroxide group; and a peroxidase reaction, which converts PGG 2 to prostaglandin H 2 (PGH 2 ) where the 15-peroxide is reduced to an alcohol © 2009 Elsevier Inc. All rights reserved. *CORRESPONDING AUTHOR: FAX: 713 500-6810; Ah-Lim.Tsai@uth.tmc.edu.. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this e...

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Section: Peroxidase Reaction Mechanismmentioning

confidence: 99%

Prostaglandin H synthase: Resolved and unresolved mechanistic issues

Tsai

Kulmacz

2010

Archives of Biochemistry and Biophysics

146

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“…[24] As for surprisingly poor activity of Fe 1 -SAzyme at pH 3, it might be attributed to the low affinity of protonated H 2 O 2 to isolated FeN 4 center (int1!int2, Figure 5b). [25] To derive the intrinsic rate-determining step (R.D.S) for both of Fe 2 -and Fe 1 -SAzyme, the corresponding Gibbs freeenergy profiles were further investigated. (Figure 5c) The R.D.S in Fe 2 -SAzyme cycle was determined as the finial regeneration step of Fe 2 -SAzyme with 0.14 eV barrier (int5!int1, Figure 5a), in contrast to a much higher R.D.S barrier for Fe 1 -SAzyme (0.40 eV, int2!int3, Figure 5b).…”

Section: Methodsmentioning

confidence: 99%

Boosting the Catalase‐Like Activity of SAzymes via Facile Tuning of the Distances between Neighboring Atoms in Single‐Iron Sites

Zhang,

Wang,

Zhang

et al. 2023

Angew Chem Int Ed

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A nanozyme with neighboring single‐iron sites (Fe2‐SAzyme) was introduced as a bioinspired catalase mimic, featuring excellent activity under varied conditions, twice as high as that of random Fe1‐SAzyme and ultrahigh H2O2 affinity as that of bioenzymes. Surprisingly, the interatomic spacing tuning between adjacent iron sites also suppressed the competitive peroxidase pathway, remarkably increasing the catalase/peroxidase selectivity up to ~6 times compared to Fe1‐SAzyme. This dramatically switched the catalytic activity of Fe‐SAzymes from generating (i.e. Fe1‐SAzymes, preferably mimicking peroxidase) to scavenging ROS (i.e. Fe2‐SAzymes, dominantly mimicking catalase). Theoretical and experimental investigations suggested that the pairwise single‐iron sites may serve as a robust molecular tweezer to efficiently trap and decompose H2O2 into O2, via cooperative hydrogen‐bonding induced end‐bridge adsorption. The versatile mechano‐assisted in situ MOF capsulation strategy enabled facile access to neighboring M2‐SAzyme (M=Fe, Ir, Pt), even up to a 1000 grams scale, but with no obvious scale‐up effect for both structures and performances.

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The Cyclooxygenases

Malkowski

2017

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Cyclooxygenases (COX‐1 and COX‐2) are membrane‐associated, heme‐containing enzymes that oxygenate arachidonic acid to generate prostaglandin H 2 in the committed step of prostanoid biosynthesis. The resulting prostanoids play a key role in the maintenance of numerous physiological processes within the body. Abnormal changes in COX‐mediated prostanoid production are associated with various disease pathologies, including inflammation, cardiovascular disease, and cancer. Aspirin, nonselective nonsterroidal anti‐inflammatory drugs, and COX‐2‐selective drugs target COX‐1 and COX‐2 to reduce acute and chronic inflammation. As such, the crystal structures of COX‐1 and COX‐2 have been extensively characterized in the presence of substrates and inhibitors in order to gain a deeper understanding at the molecular level of the mechanistic nuances that underlie catalysis and inhibition. This review serves to summarize the recent advances in COX structural biology.

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Unique Peroxidase Reaction Mechanism in Prostaglandin Endoperoxide H Synthase-2

Cited by 8 publications

References 61 publications

Prostaglandin H synthase: Resolved and unresolved mechanistic issues

Prostaglandin H synthase: Resolved and unresolved mechanistic issues

Boosting the Catalase‐Like Activity of SAzymes via Facile Tuning of the Distances between Neighboring Atoms in Single‐Iron Sites

The Cyclooxygenases

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