Observation of Two Modes
of Inhibition of Human Microsomal
Prostaglandin E Synthase 1 by the Cyclopentenone 15-Deoxy-Δ<sup>12,14</sup>-prostaglandin J<sub>2</sub>
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Abstract
Microsomal prostaglandin E synthase 1 (MPGES1) is an
enzyme that
produces the pro-inflammatory molecule prostaglandin E<sub>2</sub> (PGE<sub>2</sub>). Effective inhibitors of MPGES1 are of considerable
pharmacological interest for the selective control of pain, fever,
and inflammation. The isoprostane, 15-deoxy-Δ<sup>12,14</sup>-prostaglandin J<sub>2</sub> (15d-PGJ<sub>2</sub>), a naturally occurring
degradation product of prostaglandin D<sub>2</sub>, is known to have
anti-inflammatory properties. In this paper, we demonstrate that 15d-PGJ<sub>2</sub> can inhibit MPGES1 by covalent modification of residue C59
and by noncovalent inhibition through binding at the substrate (PGH<sub>2</sub>) 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<sub>2</sub> were determined. The question
of whether the anti-inflammatory properties of 15d-PGJ<sub>2</sub> are due to inhibition of MPGES1 is discussed
