ABSTRACT
Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is the first member of the lipocalin family to be recognized as an enzyme. L-PGDS catalyzes the isomerization o f PGH2, a common precursor o f various prostanoids, to produce PGD 2, a potent endogenous somnogen and a nociceptive modulator as well as an allergic mediator. Mammalian L-PGDS is a highly glycosylated lipocalin of Mr = 26,000 with 2 N-glycosylation sites. L-PGDS is mainly localized in the central nervous system and male genital organs o f various mammals and in the human heart. In the brain, L-PGDS is localized in the rough endoplasmic reticulum and nuclear membrane of oligodendrocytes and arachnoid trabecular cells, coupled with cyclooxygenase to produce PGD2, and then secreted into the cerebrospinal fluid as β-trace, a major protein in human cerebrospinal fluid. L-PGDS/β-trace is also secreted from those production sites into the seminal plasma and plasma. L-PGDS binds various lipophilic ligands, such as PGD2, biliverdin, bilirubin, retinoic acid, and retinal with high affinities of Kd = 20 to 80 nM, suggesting the m ultifunctionality o f L-PG D S as a P G D 2-producing enzyme, an extracellular PGD2-transporter, and a lipophilic ligand-binding protein. We generated L-PGDS gene knock out mice and human enzyme-overexpressing mice transgenic for L-PGDS and found them to be functionally abnormal in the regulation of sleep, pain, and cardiovascular responses. The X-ray crystallographic structure o f L-PGDS was determined to possess the typical lipocalin fold, i.e., a β-barrel, with a hydrophobic interior in which Cys65 has been identified as the active thiol residue essential for the catalysis.
