Crystal Structure and Possible Catalytic Mechanism of Microsomal Prostaglandin E Synthase Type 2 (mPGES-2)

Yamada, Taro; Komoto, Junichi; Watanabe, Kikuko; Ohmiya, Yoshihiro; Takusagawa, Fusao

doi:10.1016/j.jmb.2005.03.035

Cited by 67 publications

(55 citation statements)

References 59 publications

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“…The structure has been determined in complex with GSH and indomethacin (IMN), a nonsteroidal anti-inflammatory drug and cyclooxygenase inhibitor. Indomethicin is a weak inhibitor of mPGES-2 (IC50 ≈ 1mM) (Yamada et al 2005) (Figure 11a, b). The mechanism is unclear but appears to involve the first cysteine of the CPXC motif (C110).…”

Section: Leukotrienesmentioning

confidence: 99%

“…The kappa-class enzymes have a thioredoxin-like domain, but with a DsbA-like α-helical domain inserted between helix-α2 and strand-β3 (Figure 1b). The mPGES-2 protein represents a special case: the structure contains the topological features of the cytosolic GSTs but with additional structural elements (Yamada et al 2005) (Figure 1c). In cytosolic GSTs, cytosolic GST-like proteins and mitochondrial GSTs, the binding-site for GSH (the "G-site") is formed by the thioredoxin-like domain.…”

Section: General Structural Features Of Gsts Cytosolic Gsts and Mitocmentioning

confidence: 99%

“…PGE 2 is a regulator of biological activities including smooth muscle dilation and contraction (Jakobsson et al 1999b). The N-terminal domain of mPGES-2 contains a CPXC active-site motif resembling that found in thioredoxins (Yamada et al 2005). Noteworthy is the fact that mPGES-2 does not require GSH for its catalytic activity, although the catalytic rate can be increased from two-to fourfold by DTT, dihydrolipoic acid, GSH or other thiol compounds (Tanikawa et al 2002).…”

Section: Leukotrienesmentioning

confidence: 99%

“…These include the intracellular chloride ion channels (CLICs) (Harrop et al 2001;Cromer et al 2007;Littler et al 2010), microsomal prostaglandin E synthase type-2 (mPGES-2) (Yamada et al 2005), yeast elongation factor 1Bγ (Jeppesen et al 2003), and the yeast prion protein Ure2p (a nitrogen catabolite repression regulator) (Bousset et al 2001). It is noteworthy that Ure2p shows glutathione-dependent peroxidase (GPx) activity, (a frequent adjunct activity of GSTs), but no GST activity toward the classic GST substrate 1-chloro-2,4-dinitrobenzene (CDNB).…”

Section: Introductionmentioning

confidence: 99%

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Glutathione transferases: a structural perspective

Oakley

2011

Drug Metabolism Reviews

319

240

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The glutathione transferases (GSTs) are one of the most important families of detoxifying enzymes in nature. The classic activity of the GSTs is conjugation of compounds with electrophilic centers to the tripeptide glutathione (GSH), but many other activities are now associated with GSTs, including steroid and leukotriene biosynthesis, peroxide degradation, double-bond cis-trans isomerization, dehydroascorbate reduction, Michael addition, and noncatalytic "ligandin" activity (ligand binding and transport). Since the first GST structure was determined in 1991, there has been an explosion in structural data across GSTs of all three families: the cytosolic GSTs, the mitochondrial GSTs, and the membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG family). In this review, the major insights into GST structure and function will be discussed. AbstractThe glutathione transferases (GSTs) are one of the most important families of detoxifying enzymes in nature. The classic activity of the GSTs is conjugation of compounds with electrophilic centers to the tripeptide glutathione (GSH), but many other activities are now associated with GSTs, including steroid and leukotriene biosynthesis, peroxide degradation, double-bond cis-trans isomerization, dehydroascorbate reduction, Michael addition, and non-catalytic "ligandin" activity (ligand binding and transport). Since the first GST structure was determined in 1991, there has been an explosion in structural data across GSTs of all three families: the cytosolic GSTs, the mitochondrial GSTs and the membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG family). In this review, the major insights into GST structure and function will be discussed.

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Section: Leukotrienesmentioning

confidence: 99%

Section: General Structural Features Of Gsts Cytosolic Gsts and Mitocmentioning

confidence: 99%

Section: Leukotrienesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glutathione transferases: a structural perspective

Oakley

2011

Drug Metabolism Reviews

319

240

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“…The crystal structure of mPGES2 reveals that mPGES2 forms a dimer and that each subunit is composed of two domains, the N-terminal domain (residues 100 -175) and the C-terminal domain (residues 220 -370), which are connected to form a V-shaped hydrophobic cavity (12). There is no significant electron density in the V-shaped cavity of SeMet-mPGES2.…”

Section: Heme Content In Recombinant Mpges2 Increases Along With An Imentioning

confidence: 99%

Microsomal Prostaglandin E Synthase Type 2 (mPGES2) Is a Glutathione-dependent Heme Protein, and Dithiothreitol Dissociates the Bound Heme to Produce Active Prostaglandin E2 Synthase in Vitro

Takusagawa

2013

Journal of Biological Chemistry

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Why PGD₂ has different functions from PGE₂

Fujino

2020

BioEssays

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Prostaglandin (PG) D2 and PGE2 are positional isomers; however, they sometimes exhibit opposite physiological functions, such as in cancer development. Because DP receptors are considered to be a duplicated copy of EP2 receptors, PGD2 and PGE2 cross‐react with both receptors. These prostanoids may act as biased agonists for each receptor. In reviewing this field, a hypothesis was proposed to explain the opposed effects of these prostanoids from the viewpoints of the evolution of, mutations in, and biased activities of their receptors. Previous findings showing more mutations/variations in DP receptors than EP2 receptors among individuals worldwide indicate that DP receptors are still in a rapid evolutionary stage. The opposing effects of these prostanoids on cancer development may be attributed to the biased activity of PGE2 for DP receptors, which may incidentally develop during the process of the old ligand, PGE2 gaining selectivity to newly diverged DP receptors.

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Crystal Structure and Possible Catalytic Mechanism of Microsomal Prostaglandin E Synthase Type 2 (mPGES-2)

Cited by 67 publications

References 59 publications

Glutathione transferases: a structural perspective

Glutathione transferases: a structural perspective

Microsomal Prostaglandin E Synthase Type 2 (mPGES2) Is a Glutathione-dependent Heme Protein, and Dithiothreitol Dissociates the Bound Heme to Produce Active Prostaglandin E2 Synthase in Vitro

Why PGD₂ has different functions from PGE₂

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Crystal Structure and Possible Catalytic Mechanism of Microsomal Prostaglandin E Synthase Type 2 (mPGES-2)

Cited by 67 publications

References 59 publications

Glutathione transferases: a structural perspective

Glutathione transferases: a structural perspective

Microsomal Prostaglandin E Synthase Type 2 (mPGES2) Is a Glutathione-dependent Heme Protein, and Dithiothreitol Dissociates the Bound Heme to Produce Active Prostaglandin E2 Synthase in Vitro

Why PGD2 has different functions from PGE2

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Why PGD₂ has different functions from PGE₂