Biochemical, structural, genetic, physiological, and pathophysiological features of lipocalin-type prostaglandin D synthase.
Lipocalin-type prostaglandin (PG) D synthase (PGDS) catalyzes the isomerization of PGH(2), a common precursor of various prostanoids, to produce PGD(2), a potent endogenous somnogen and nociceptive modulator, in the presence of sulfhydryl compounds. PGDS is an N-glycosylated monomeric protein with an M(r) of 20000-31000 depending on the size of the glycosyl moiety. PGDS is localized in the central nervous system and male genital organs of various mammals and in the human heart and is secreted into the cerebrospinal fluid, seminal plasma, and plasma, respectively, as beta-trace. The PGDS concentrations in these body fluids are useful for the diagnosis of several neurological disorders, dysfunction of sperm formation, and cardiovascular and renal diseases. The cDNA and gene for PGDS have been isolated from several animal species, and the tissue distribution and cellular localization have also been determined. This enzyme is considered to be a dual functional protein; i.e. it acts as a PGD(2)-producing enzyme and also as a lipophilic ligand-binding protein, because the enzyme binds biliverdin, bilirubin (K(d)=30 nM), retinaldehyde, retinoic acid (K(d)=80 nM) with high affinities. X-ray crystallographic analyses revealed that PGDS possesses a beta-barrel structure with a hydrophobic pocket in which an active thiol, Cys(65), the active center for the catalytic reaction, was located facing to the inside of the pocket. Gene-knockout and transgenic mice for PGDS were generated and found to have abnormalities in the regulation of nociception and sleep.
Urade
Y
Y
Department of Molecular Behavioral Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan. uradey@obi.or.jp
Hayaishi
O
O
D000595:Amino Acid Sequence; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002874:Chromosome Mapping; D018076:DNA, Complementary / Q000032:analysis; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D054834:Lipocalins; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D014018:Tissue Distribution
D015415:Biomarkers; D018076:DNA, Complementary; D054834:Lipocalins; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase