Biochemical and Structural Characteristics, Gene Regulation, Physiological, Pathological and Clinical Features of Lipocalin-Type Prostaglandin D2 Synthase as a Multifunctional Lipocalin.

Yoshihiro Urade

doi:10.3389/fphys.2021.718002

Abstract

Lipocalin-type prostaglandin (PG) D2 synthase (L-PGDS) catalyzes the isomerization of PGH2, a common precursor of the two series of PGs, to produce PGD2. PGD2 stimulates three distinct types of G protein-coupled receptors: (1) D type of prostanoid (DP) receptors involved in the regulation of sleep, pain, food intake, and others; (2) chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) receptors, in myelination of peripheral nervous system, adipocyte differentiation, inhibition of hair follicle neogenesis, and others; and (3) F type of prostanoid (FP) receptors, in dexamethasone-induced cardioprotection. L-PGDS is the same protein as β-trace, a major protein in human cerebrospinal fluid (CSF). L-PGDS exists in the central nervous system and male genital organs of various mammals, and human heart; and is secreted into the CSF, seminal plasma, and plasma, respectively. L-PGDS binds retinoic acids and retinal with high affinities (Kd < 100 nM) and diverse small lipophilic substances, such as thyroids, gangliosides, bilirubin and biliverdin, heme, NAD(P)H, and PGD2, acting as an extracellular carrier of these substances. L-PGDS also binds amyloid β peptides, prevents their fibril formation, and disaggregates amyloid β fibrils, acting as a major amyloid β chaperone in human CSF. Here, I summarize the recent progress of the research on PGD2 and L-PGDS, in terms of its “molecular properties,” “cell culture studies,” “animal experiments,” and “clinical studies,” all of which should help to understand the pathophysiological role of L-PGDS and inspire the future research of this multifunctional lipocalin.

Highlights

In 1985, I purified lipocalin-type prostaglandin (PG) D2 synthase (L-PGDS) from rat brain as a prostaglandin H2 (PGH2) D-isomerase (EC:5.3.99.2), that catalyzes the isomerization of a 9,11endoperoxide group of PGH2, a common intermediate of the two series of prostanoids, to produce prostaglandin D2 (PGD2) with 9-hydroxy and 11-keto groups (Urade et al, 1985)
I classify the reports concerning with Lipocalin-type prostaglandin (PG) D2 synthase (L-PGDS) mainly after publication of those reviews and summarize the new finding of each section as follows: 1) Biological function of prostaglandin D2 produced by lipocalin-type prostaglandin D2 synthase, 2) Ligand binding properties of lipocalin-type prostaglandin D2 synthase as an extracellular transporter, 3) Structural characterization of lipocalin-type prostaglandin D2 synthase by nuclear magnetic resonance (NMR) and X-ray crystallography, 4) Cell culture studies of lipocalin-type prostaglandin D2 synthase, 5) Mammalian experiments for the study of lipocalin-type prostaglandin D2 synthase, 6) Pharmacokinetic analyses and functionalization with recombinant lipocalin-type prostaglandin D2 synthase, 7) Studies of nonmammalian orthologs of lipocalin-type prostaglandin D2 synthase, 8) Clinical studies of pathophysiological function of lipocalintype prostaglandin D2 synthase, 9) Future subjects
L-PGDS is upregulated in oligodendrocytes and a few neurons in the brain of murine models of various lysosomal storage diseases, such as Krabbe’s disease (Taniike et al, 1999; Mohri et al, 2006b), Tay–Sachs disease, Sandhoff disease, GM1 gangliosidosis and Niemann–Pick type C1 disease (Mohri et al, 2006a). These results suggest that L-PGDS plays a protective role on oligodendrocytes in scavenging harmful lipophilic substrates accumulated by malfunction of myelin metabolism in lysosomal storage diseases, as demonstrated by using double mutant mice with L-Pgds gene KO mice as shown later (Taniike et al, 2002)

Summary

Introduction

In 1985, I purified lipocalin-type prostaglandin (PG) D2 synthase (L-PGDS) from rat brain as a prostaglandin H2 (PGH2) D-isomerase (EC:5.3.99.2), that catalyzes the isomerization of a 9,11endoperoxide group of PGH2, a common intermediate of the two series of prostanoids, to produce prostaglandin D2 (PGD2) with 9-hydroxy and 11-keto groups (Urade et al, 1985). The sleepinducing activity by an intracerebroventricular infusion of PGD2 is significantly reduced in L-Pgds gene KO mice than wild-type mice, suggesting that L-PGDS binds and transport PGD2 in the brain to stimulate effectively DP receptors in the sleep-promoting system (Shimamoto et al, 2021). Serum starvation induces PGD2 production in TE671 cells through transcriptional activation of Pghs-2 and L-Pgds genes.

Results

Conclusion