Biochemical, structural, genetic, physiological, and pathophysiological features of lipocalin-type prostaglandin D synthase

Lipocalin-type prostaglandin (PG) D synthase (PGDS) catalyzes the isomeriza tion 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 a n M-r of 20 000 31 000 depending on the size of the glycosyl moiety. PGDS i s localized in the central nervous system and male genital organs of variou s mammals and in the human heart and is secreted into the cerebrospinal flu id, seminal plasma, and plasma, respectively, as beta -trace. The PGDS conc entrations in these body fluids are useful for the diagnosis of several neu rological 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 pr otein; i.e. it acts as a PGD(2)-producing enzyme and also as a lipophilic l igand-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 a nd found to have abnormalities in the regulation of nociception and sleep. (C) 2000 Elsevier Science B.V. All rights reserved.