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Observation of two modes of inhibition of human microsomal prostaglandin E synthase 1 by the cyclopentenone 15-deoxy-Δ(12,14)-prostaglandin J(2).
- Source :
-
Biochemistry [Biochemistry] 2012 Mar 20; Vol. 51 (11), pp. 2348-56. Date of Electronic Publication: 2012 Mar 08. - Publication Year :
- 2012
-
Abstract
- Microsomal prostaglandin E synthase 1 (MPGES1) is an enzyme that produces the pro-inflammatory molecule prostaglandin E(2) (PGE(2)). Effective inhibitors of MPGES1 are of considerable pharmacological interest for the selective control of pain, fever, and inflammation. The isoprostane, 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), a naturally occurring degradation product of prostaglandin D(2), is known to have anti-inflammatory properties. In this paper, we demonstrate that 15d-PGJ(2) can inhibit MPGES1 by covalent modification of residue C59 and by noncovalent inhibition through binding at the substrate (PGH(2)) binding site. The mechanism of inhibition is dissected by analysis of the native enzyme and the MPGES1 C59A mutant in the presence of glutathione (GSH) and glutathione sulfonate. The location of inhibitor adduction and noncovalent binding was determined by triple mass spectrometry sequencing and with backbone amide H/D exchange mass spectrometry. The kinetics, regiochemistry, and stereochemistry of the spontaneous reaction of GSH with 15d-PGJ(2) were determined. The question of whether the anti-inflammatory properties of 15d-PGJ(2) are due to inhibition of MPGES1 is discussed.
- Subjects :
- Anti-Inflammatory Agents metabolism
Anti-Inflammatory Agents pharmacology
Binding Sites
Glutathione analogs & derivatives
Glutathione chemistry
Glutathione metabolism
Humans
Inflammation drug therapy
Intramolecular Oxidoreductases chemistry
Intramolecular Oxidoreductases metabolism
Mass Spectrometry
Microsomes metabolism
Prostaglandin D2 metabolism
Prostaglandin D2 pharmacology
Prostaglandin-E Synthases
Intramolecular Oxidoreductases antagonists & inhibitors
Microsomes enzymology
Prostaglandin D2 analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4995
- Volume :
- 51
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22356188
- Full Text :
- https://doi.org/10.1021/bi2019332