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Lipocalin-Type Prostaglandin D Synthase as an Enzymic Lipocalin

,* , and .

* Corresponding Author: Department of Molecular Behavioral Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita City, Osaka 565-0874, Japan. Email: uradey@obi.or.jp

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 of PGH2, a common precursor of various prostanoids, to produce PGD2, 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 of 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 multifunctionality of L-PGDS as a PGD2-producing enzyme, an extracellular PGD2-transporter, and a lipophilic ligand-binding protein. We generated L-PGDS gene knockout 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 of 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.

Introduction

In 1985, we isolated lipocalin-type prostaglandin (PG) D synthase (L-PGDS) from rat brain as a monomeric enzyme with a molecular weight of 26,000,1 although the enzyme had previously been misidentified to be a protein with a molecular weight of 80,000 to 85,000.2,3 L-PGDS catalyzes the isomerization of 9,11-endoperoxide of PGH2 to produce PGD2 with 9-hydroxy and 11-keto groups at the low turnover number of 170 min-1in the presence of various sulfhydryl compounds, such as glutathione (GSH), dithiothreitol, β-mercaptoethanol, cysteine, and cysteamine (Fig. 1). L-PGDS was previously termed as brain-type PGD synthase or GSH-independent PGD synthase to distinguish it from GSH-requiring PGD synthase purified from rat spleen,4,5 which is now named hematopoietic PGDS (H-PGDS).6-8 L-PGDS and H-PGDS are quite different from each other in terms of amino acid sequence, tertiary structure, evolutional origin, cellular distribution etc., although both enzymes catalyze the same reaction. Thus, these 2 enzymes are a novel example of functional conversion.6,7 During 20 years after the first report of the purification of L-PGDS,1 we have extensively studied the chemical and functional properties of L-PGDS and reported cloning of the cDNA and the chromosomal gene of the human and mouse enzymes, its X-ray crystallographic structure and immunohistochemical localization, and functional abnormalities of L-PGDS gene knockout (KO) mice and human enzyme-overexpressing mice transgenic (TG) for L-PGDS. A part of those findings have already been reviewed elsewhere.6,7,9 In this chapter, we summarize the progress in the research of L-PGDS as a unique member of the lipocalin family.

Figure 1. Biosynthetic and metabolic pathway of PGD2.

Figure 1

Biosynthetic and metabolic pathway of PGD2. cPLA2: cytosolic phospholipase A2; TXA2: thromboxane A2.

Amino Acid Sequence and Secondary and Tertiary Structures

The cDNA for L-PGDS was first isolated from a rat brain cDNA library10 and subsequently from many other mammalian species, including human11 and mouse,12 and also from 2 amphibians.13,14 The cDNA for L-PGDS encodes a protein composed of 189 and 190 amino acid residues in mouse and human enzyme, respectively. Figure 2, shows sequence alignment of the human and mouse enzymes. L-PGDS is post-translationally modified by the cleavage of an N-terminal hydrophobic signal peptide comprising 24 and 22 amino acid residues in the mouse and human enzyme, respectively. Two N-glycosylation sites at positions of Asn51 and Asn78 of the mouse and human enzymes10 are conserved in all mammalian enzymes thus far identified but were not found in the amphibian homologs. Mammalian L-PGDS is highly glycosylated with 2 N-glycosylated sugar chains, each with a molecular weight of 3,000. The carbohydrate structures of L-PGDS were determined in samples purified from human cerebrospinal fluid (CSF),15 serum,16 urine16,17 and amniotic fluid.17 However, the functional significance of sugar chains remains to be determined.

Figure 2. Sequence alignment of human and mouse L-PGDS's.

Figure 2

Sequence alignment of human and mouse L-PGDS's. Cleavage site of the signal sequence (arrows), the catalytic cysteine residue (star), a cystine (open circles) and 2 glycosylation sites (closed circles) of L-PGDS are shown on the top of sequence. Positions (more...)

Protein chemical and structural properties of L-PGDS have been analyzed by using the recombinant protein heterologously expressed in E. coli or yeast. L-PGDS is a very stable enzyme and is highly resistant against heat treatment1 and protease digestion.18 For example, more than 50% of the activity was retained after heating the enzyme for 5 min at 100°C and alkaline pH.1 L-PGDS was almost completely refolded by dilution and cooling of the enzyme denatured with 1% SDS at 100°C for 10 min or with 6 M guanidine hydrochloride.19 Thus, L-PGDS is an interesting protein for the study of protein refolding.

Circular dichroism spectroscopy of the recombinant rat L-PGDS revealed that the enzyme is composed of mainly β-strands,19 similar to other lipocalins. We have already crystallized the recombinant mouse L-PGDS.6,9 However, the quality of the X-ray diffraction data obtained from the originally prepared crystals were insufficient to determine reliable coordinates of L-PGDS. Most recently, by modifying the crystallization conditions and using the selenomethionyl Cys65Ala mutant,20 we successfully determined the X-ray crystallographic structure of L-PGDS with 2 different conformers of the open and closed calyxes at 2.1Å resolution (Kumasaka T, Irikura D, Ago H, Aritake K, Yamamoto M, Miyano M, Y.U. and O.H., unpublished results). X-ray crystallographic analysis revealed that L-PGDS possesses a typical lipocalin-fold, β-barrel structure. However, L-PGDS contains 2 hydrophobic pockets; one is the catalytic site corresponding to the ligand-binding pocket of other lipocalins and the other, the lipophilic ligand-binding site, located on the side of the L-PGDS molecule opposite to that containing the retinoid-binding site.

Ligand-Binding Properties

Similar to other lipocalins, L-PGDS binds retinoids,21 bilirubin, and biliverdin22 with high affinities (Kd = 30-80 nM). By monitoring the quenching of the intrinsic tryptophan fluorescence of L-PGDS and by circular dichroism spectroscopy of the bound ligands, we showed that L-PGDS binds all-trans- or 9-cis-retinoic acid and all-trans- or 13-cis-retinaldehyde, but not all-trans-retinol, at a molar ratio of 1:1 with a Kd of 70 to 80 nM.21 The affinities of L-PGDS for retinoids are comparable to or slightly higher than those of other lipocalins acting as extracellular retinoid transporters, such as β-lactoglobulin, plasma retinol-binding protein, and plasma retinoic acid-binding protein (reviewed in other chapters). L-PGDS also binds thyroid hormone with a Kd of 0.7-2 μM and biliverdin and bilirubin with high affinities, i.e., with a Kd of 30-40 nM.22 We recently found that L-PGDS binds its product PGD2 with high affinity, (Kd of 20 nM; Aritake K, Y.U.; unpublished results), suggesting that L-PGDS acts not only as a PGD2-producing enzyme but also as an extracellular transporter of PGD2 to prevent its metabolism and nonenzymatic dehydration.

Among those nonsubstrate hydrophobic ligands, retinoids,21 bilirubin, and biliverdin22 inhibited the PGDS activity in a noncompetitive manner. However, their inhibitory potencies were remarkably weak (IC50 = 4˜10 μM) in contrast to their high affinities (Kd = 30-80 nM) of binding to L-PGDS as assessed by quenching of the intrinsic tryptophan fluorescence. Therefore, the catalytic site and the binding site for those hydrophobic ligands are considered to be different from each other. On the other hand, we predicted that PGD2 is bound to the catalytic pocket. Two distinct binding-pockets were finally identified by the crystallographic study of mouse L-PGDS, as described above.

Therefore, we propose that L-PGDS is a multifunctional protein; it acts as a PGD2-producing enzyme by coupling with cyclooxygenase-1 or -2, the upstream enzymes in the PG cascade, within the cells and also functions as a lipophilic ligand-binding protein after having been secreted into the extracellular spaces and various body fluids. As described in the next paragraph, PGD2 is less chemically stable than PGE2 or PGF, being dehydrated to the J series of PGs. Once bound to L-PGDS, PGD2 is remarkably stabilized to slow down the conversion to the J series PGs. Moreover, the binding affinity of L-PGDS for PGD2 is slightly weaker than those affinities of 2 distinct types of PGD2 receptor, i.e., the D type of prostanoid (DP, DP1) receptors and CRTH2 (DP2). Therefore, we predict that L-PGDS binds the chemically unstable PGD2, transports PGD2 within the extracellular space to the action sites, and transfer PGD2 to its receptors.

Enzymatic Properties as PGD Synthase

L-PGDS is the first lipocalin recognized as an enzyme. L-PGDS has originally been purified from rat brain1 as PGD synthase (PGH2 D-isomerase, EC 5.3.99.2), which catalyzes the isomerization of the 9,11-endoperoxide group of PGH2, a common precursor of various prostanoids, to produce PGD2 with 9-hydroxy and 11-keto groups in the presence of sulfhydryl compounds. PGD2 is the major PG produced in the central nervous system of various mammals and is involved in the regulation of sleep23,24 and nociception12 through DP (DP1) receptors.25,26 PGD2 is also actively produced and secreted by mast cells,18 basophils, and Th2 cells27 by evolutionally different H-PGDS's,6-8 acting as an allergic and inflammatory mediator through the DP (DP1)25,28 and CRTH2 (DP2)29 receptors in an autocrine and/or paracrine manner.

The intracellular localization of L-PGDS was most intensely investigated in the brain.30-32 By immunoelectron microscopy, the immunoreactive deposits of L-PGDS were seen in rough-surfaced endoplasmic reticulum, outer nuclear membrane, Golgi apparatus, and secretory vesicles of oligodendroglial cells30 and arachnoid trabecular cells in the adult rats31 and of human arachnoid and meningioma cells.32 The colocalization of L-PGDS and cyclooxygenase, which produce PGH2, was demonstrated in virtually all cells of the leptomeninges, choroid plexus epithelial cells, and perivascular microglial cells, suggesting that these cells synthesize PGD2 actively.31

As mentioned above, PGD2 is chemically unstable and nonenzymically dehydrated to produce the J series of PGs with a cyclopentenone structure, such as PGJ2, Δ12-PGJ2, and 15-deoxy-Δ12,14-PGJ2, all of which show pharmacological activities quite different from those of PGD2. Since 15-deoxy-Δ12,14-PGJ2 has been demonstrated to act as a ligand for PPARγ, a nuclear receptor involved in differentiation of adipocytes, macrophages, and monocytes,33,34 many researchers have studied the possible involvement of 15-deoxy-Δ12,14-PGJ2 in the various types of physiological function. However, those J-series PGs have not been detected in fresh physiological samples. The physiological relevance of the J series of PGs is thus unlikely.35 PGD2 is also metabolized by 11-keto PGD2 reductase (PGF2 synthase), belonging to the aldo-keto reductase family, to 9α,11β-PGF2, 36-38 a stereoisomer of PGF, having pharmacological activities different from those of PGF.

L-PGDS requires free sulfhydryl compounds, such as β-mercaptoethanol, DTT or GSH, for its reaction. The enzyme activity is inhibited by SeCl439 and SH modifiers, such as N-ethylmaleimide and iodo acetoamide, indicating that Cys residue is involved in the catalytic reaction of L-PGDS.1 Three Cys residues, Cys65, Cys89, and Cys186, in human L-PGDS, are conserved among all species. Two of these Cys residues, Cys89 and Cys186, form a disulfide bridge, which is highly conserved among most, but not all, lipocalins. On the other hand, Cys65 is unique to L-PGDS, as it has never been found in other lipocalins. Chemical modification and site-directed mutagenesis revealed that the Cys65 residue is the key residue for the catalytic reaction of L-PGDS.20,40 Thus, L-PGDS is considered to have evolved from a common ancestral nonenzymic lipocalin to the enzyme by acquiring an active residue, Cys65.

Inhibition of sleep by central or systemic administration of Se4+ was demonstrated in freely moving rats41,42 and in unanesthetized fetal sheep,43 suggesting that PGD2 produced by L-PGDS plays an important role in the induction and maintenance of sleep.

Gene Structure and Regulation

The gene for L-PGDS was cloned from rat,44 human,45 and mouse12 sources and shown to span about 3 kb and to contain 7 exons split by 6 introns. The gene organization is remarkably analogous to that of other lipocalins in terms of number and size of exons and phase of splicing of introns.44,45 The human and mouse genes were mapped to chromosome 9q34.2-34.3 45 and 2B-C1,46 respectively, both of which were localized within the lipocalin gene cluster.

The transcriptional regulation of the L-PGDS gene has been studied after stimulation with various hormones. For example, the thyroid hormone activates L-PGDS expression through a thyroid hormone response element in human brain-derived TE671 cells.47 Dexamethasone, a synthetic glucocorticoid, induces L-PGDS expression via glucocorticoid receptors in mouse neuronal GT1-7 cells.48 17β-Estradiol regulates L-PGDS gene expression in a tissue and region-specific manner. It activates the expression via estrogen β receptors in the mouse heart49 and increases the L-PGDS expression in the arcuate and ventromedial nuclei of the rat hypothalamus but decreases it in the ventrolateral preoptic area of the hypothalamus, which area is a sleep center.50,51

L-PGDS gene expression is down-regulated by the binding of Hes-1, a mammalian homolog of Drosophila Hairy and enhancer of split, to the N-box of the promoter in rat primary cultured leptomeningeal cells52 and human TE671 cells.53 We recently demonstrated that human L-PGDS gene expression is activated by protein kinase C signaling through de-repression of Notch-HES signaling and enhancement of AP-2β function in TE671 cells.53 Fluid shear stress induces L-PGDS gene expression in human vascular endothelial cells54 by binding of c-Fos and c-Jun to the AP-1 binding site of the promoter.55

L-PGDS (β-Trace) as a Clinical Marker

L-PGDS is localized in the central nervous system and male genital organs of various mammals, 53 as well as in the human heart54 and the cellular localization of L-PGDS has been extensively studied in these tissues of various mammals. For example, L-PGDS is dominantly localized in the leptomeninges, choroids plexus, and oligodendrocytes of the rat, mouse, and human brain12,30-32,58 and is secreted into the CSF. In the testis and epididymis of humans59 and other mammals,60-68 L-PGDS is localized in Leydig cells, Serotoli cells, and ductal epithelial cells and is secreted from them into the seminal plasma. Among various human tissues, the heart expresses L-PGDS mRNA the most intensely.57 In the human heart, L-PGDS is localized in myocardial cells and atrial endocardial cells, and most interestingly has been detected in smooth muscle cells (having the synthesis phenotype) in the arteriosclerotic intima and in the atherosclerotic plaque of coronary arteries with severe stenosis, being secreted by these cells into the plasma.57

L-PGDS is the same protein as β-trace,69,70 which was originally discovered in 1961 as a major protein of human CSF71 and later identified in the seminal plasma, serum, and urine. Therefore, the L-PGDS/β-trace concentration in body fluids may be a useful clinical marker for various diseases.7,9 The L-PGDS/β-trace concentrations in seminal plasma, serum, and urine have been extensively evaluated in recent years as a biomarker for diagnosis of several neurological disorders,72-78 dysfunction of sperm formation,59 and cardiovascular57,79-81 and renal82-87 diseases. The serum L-PGDS/β-trace concentration shows a circadian change with a nocturnal increase, which is suppressed during total sleep deprivation but not affected by rapid eye movement (REM) sleep deprivation.88 The L-PGDS concentration in cervicovaginal secretions of pregnant women with ruptured membranes was reported to be significantly higher than that of normal pregnant women.89

Moreover, the upregulation of L-PGDS gene expression was reported in a genetic demyelinating model mice, twitcher90 and in patients with multiple sclerosis,91,92 Tay-Sachs or Sandohof disease.93 A single nucleotide polymorphism found in the 3'-untranslated region of the human L-PGDS gene (4111 A>C) was shown to be associated with carotid atherosclerosis in Japanese hypertensive patients.94 In them, the serum levels of high-density lipoprotein cholesterol were higher in subjects with the A/A genotype than in those with the A/C or C/C genotype and the maximum intima-media thickness in the common carotid artery was smaller in the A/A group than in the A/C and C/C groups. RT-PCR analysis in microdissected rat nephron segments revealed that L-PGDS mRNA is widely expressed in the cortex and outer medulla, and mainly in the thick ascending limb and the collecting duct.95 In a mouse model of adriamycin-induced nephropathy, urinary L-PGDS excretion was shown to precede overt albuminuria.96

Functional Abnormalities of L-PGDS KO Mice and Human L-PGDS-Overexpressing TG-Mice

We generated L-PGDS KO mice with the null mutation by homologous recombination12 and demonstrated that the KO mice grow normally but show several functional abnormalities in the regulation of nociception,12 sleep,24,97 and energy metabolism.98 L-PGDS KO mice do not exhibit allodynia (touch-evoked pain), which is a typical phenomenon of neuropathic pain, after an intrathecal administration of PGE2 or bicuculline, a γ-aminobutyric acid (GABA)A receptor antagonist.12 The KO mice do not accumulate PGD2 in their brain during sleep deprivation nor show the nonREM sleep rebound after sleep deprivation; whereas the wild-type mice show an increase in the PGD2 content in their brain during sleep deprivation, which induces the nonREM sleep rebound.24,97 L-PGDS KO mice become glucose intolerant and insulin resistant at an accelerated rate as compared with the wild-type mice.98 The KO mice possess adipocytes of larger size than do wild-type mice and develop nephropathy and an aortic thickening when fed a high-fat diet.98

We also generated TG mice99 that over-expressed the human L-PGDS under the control of the β-actin promoter. We serendipitously discovered that these TG mice showed a transient increase in nonREM sleep after their tails had been clipped for DNA sampling used for genetic analysis.97,99 We showed that the noxious stimulation of tail clipping induced a remarkable increase in the PGD2 content in the brain of the TG mice but not in that of the wild-type ones,97,99 although we do not yet understand in detail the mechanism responsible for this increase. Alternatively, in an ovalbumin-induced asthma model, the TG-mice showed a remarkably increased PGD2 production in the lung after the antigen challenge and developed pronounced eosinophilic lung inflammation and Th2 cytokine release as compared with their wild-type littermates.100 These TG mice also exhibited accelerated adipogenesis (Fujitani Y, Aritake K, and Y.U., unpublished results). Therefore, L-PGDS TG mice are useful as a unique animal model to study the functional abnormalities caused by the overproduction of PGD2.

Closing Remarks

Recently, exogenously administered L-PGDS was demonstrated to inhibit the growth of vascular smooth muscle cells obtained from spontaneously hypertensive rats, but not from normotensive control animals80 and L-PGDS was also identified as a cellular target of the immediate-early protein, BICP0, of bovine herpesvirus 1.101 However, the action mechanisms of L-PGDS operating in those processes remain to be elucidated. Most recently we determined the three-dimensional coordinates of L-PGDS complexed with retinoic acid and also found an orally active inhibitor of L-PGDS. These results are useful for designing inhibitors of L-PGDS, which will promote further pharmacological evaluation of L-PGDS as an enzyme and a retinoid-transporter. Several groups are now trying to identify endogenous ligands of L-PGDS in various body fluids. The screening for functional abnormalities of L-PGDS gene-manipulated mice is still on going by collaborative researches with many groups.

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