Prostaglandin E synthase: a novel drug target for inflammation and cancer.
Prostaglandin E synthase (PGES), which converts cyclooxygenase (COX)-derived prostaglandin (PG) H(2) to PGE(2), occurs in multiple forms with distinct enzymatic properties, modes of expression, cellular and subcellular localizations and intracellular functions. Two of them are membrane-bound enzymes and have been designated as mPGES-1 and mPGES-2. mPGES-1 is a perinuclear protein belonging to the MAPEG (for membrane-associated proteins involved in eicosanoid and GSH metabolism) family. This enzyme is markedly induced by proinflammatory stimuli, is down-regulated by anti-inflammatory glucocorticoids, and is functionally coupled with cyclooxygenase (COX)-2 in marked preference to COX-1. mPGES-2 is synthesized as a Golgi membrane-associated protein, and the proteolytic removal of the N-terminal hydrophobic domain leads to the formation of a mature cytosolic enzyme. This enzyme is rather constitutively expressed in various cells and tissues and is functionally coupled with both COX-1 and COX-2. Cytosolic PGES (cPGES) is constitutively expressed in a wide variety of cells and is functionally linked to COX-1 to promote immediate PGE(2) production. This review highlights the latest understanding of the expression, regulation and functions of these three PGES enzymes. In particular, recent gene targeting studies of mPGES-1 have revealed that this enzyme represents a novel target for anti-inflammatory and anti-cancer drugs.
Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, Shinagawa-ku, Tokyo, Japan. mako@rinshoken.or.jp
Makoto
M
Murakami
Ichiro
I
Kudo
D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; C000605863:PTGES2 protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone