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0031-6997/07/5903-207-224$7.00
Pharmacol Rev 59:207-224, 2007

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Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target

Bengt Samuelsson, Ralf Morgenstern and Per-Johan Jakobsson

Department of Medical Biochemistry and Biophysics (B.S.), Institute of Environmental Medicine (R.M.), and Department of Medicine and Rheumatology Unit and Karolinska Biomic Center (P.-J.J.), Karolinska Institutet, Stockholm, Sweden

Abstract
I. Introduction
II. Discovery and Characterization
    A. Identification
    B. Purification and Structure
    C. Assays and Kinetic Properties
    D. Inhibition
    E. Phylogeny
    F. Tissue and Cellular Distribution
    G. Regulation and Gene Structure
    H. Membrane Prostaglandin E Synthase-2, Cytosolic Prostaglandin E Synthase, and Other Proteins with Prostaglandin E Synthase Activity
III. Inflammation
    A. Constitutive Expression of Membrane Prostaglandin E Synthase-1
    B. Induction of Membrane Prostaglandin E Synthase-1 Expression
    C. Membrane Prostaglandin E Synthase-1 in Arthritis and Osteoarthritis
    D. Membrane Prostaglandin E Synthase-1 in Fever and Pain
    E. Membrane Prostaglandin E Synthase-1 in the Cardiovascular System and Kidney
IV. Disruption of the Membrane Prostaglandin E Synthase-1 Gene
    A. Endotoxin-Induced Shock
    B. Experimental Models of Arthritis
    C. Role of Membrane Prostaglandin E Synthase-1 in Fever, Pain, and Anorexia
V. Cardiovascular Diseases
    A. Atherosclerosis
    B. Blood Pressure
    C. Stroke
VI. Cancer
VII. Reproductive Endocrinology
VIII. Therapeutic Implications
Prostaglandin E2 (PGE2) is the most abundant prostaglandin in the human body. It has a large number of biological actions that it exerts via four types of receptors, EP1–4. PGE2 is formed from arachidonic acid by cyclooxygenase (COX-1 and COX-2)-catalyzed formation of prostaglandin H2 (PGH2) and further transformation by PGE synthases. The isomerization of the endoperoxide PGH2 to PGE2 is catalyzed by three different PGE synthases, viz. cytosolic PGE synthase (cPGES) and two membrane-bound PGE synthases, mPGES-1 and mPGES-2. Of these isomerases, cPGES and mPGES-2 are constitutive enzymes, whereas mPGES-1 is mainly an induced isomerase. cPGES uses PGH2 produced by COX-1 whereas mPGES-1 uses COX-2-derived endoperoxide. mPGES-2 can use both sources of PGH2. mPGES-1 is a member of the membrane associated proteins involved in eicosanoid and glutathione metabolism (MAPEG) superfamily. It requires glutathione as an essential cofactor for its activity. mPGES-1 is up-regulated in response to various proinflammatory stimuli with a concomitant increased expression of COX-2. The coordinate increased expression of COX-2 and mPGES-1 is reversed by glucocorticoids. Differences in the kinetics of the expression of the two enzymes suggest distinct regulatory mechanisms for their expression. Studies, mainly from disruption of the mPGES-1 gene in mice, indicate key roles of mPGES-1-generated PGE2 in female reproduction and in pathological conditions such as inflammation, pain, fever, anorexia, atherosclerosis, stroke, and tumorigenesis. These findings indicate that mPGES-1 is a potential target for the development of therapeutic agents for treatment of several diseases.

Address correspondence to: Dr. Bengt Samuelsson, Karolinska Institutet, 171 77 Stockholm, Sweden. E-mail: bengt.samuelsson{at}ki.se






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