ReviewRecent advances in molecular biology and physiology of the prostaglandin E2-biosynthetic pathway
Introduction
Biosynthesis of PGE2 is regulated by three enzymatic reactions (Fig. 1). Arachidonic acid (AA), a precursor of eicosanoids including prostanoids [products of the cyclooxygenase (COX) pathway] and leukotrienes [products of the 5-lipoxygenase (LOX) pathway], is stored at the sn-2 position of membrane glycerophospholipids, and is released by the hydrolytic action of phospholipase A2 (PLA2) enzymes. At least 19 PLA2 enzymes have been identified in mammals, amongst which the cytosolic PLA2 (cPLA2), secretory PLA2 (sPLA2) and Ca2+-independent PLA2 (iPLA2) families have been implicated in eicosanoid production [1], [2]. AA is metabolized to the unstable intermediate prostanoid, PGH2, by the action of COX enzymes and then to various prostanoids by specific terminal PG synthases, of which PGE synthase (PGES) enzymes convert PGH2 to PGE2 specifically. The PGE2 produced thus far is then released from the cells and act on four types of the PGE receptor, EP1, EP2, EP3 and EP4, all of which are coupled with the trimeric G-protein signaling [3], [4]. By analyses of mice with targeted disruption of each type of the PGE receptor, it has now become clear that PGE2 plays crucial roles in various biological events, such as neuronal functions via EP1, female reproduction, vascular hypertension and tumorigenesis via EP2, fever, gastric mucosal protection, pain hypersensitivity, kidney function and anti-allergic response via EP3, and ductus arteriosus closure and inflammation-associated bone resorption via EP4 [3], [4]. Since overproduction of PGE2 is often associated with various diseases, it would be of quite important to understand the properties, functions and regulations of the PGE2-biosynthetic enzymes.
In this review, we overview our current understanding of the enzymes involved in the PGE2 biosynthesis, namely PLA2s, COXs and PGESs. We will not point out detailed enzymology and pharmacology, but rather focus on cellular biology and physiology of each enzyme.
Section snippets
Classification
Historically, only one mammalian PLA2 enzyme, which is abundantly present in pancreatic juice and is now called group IB PLA2, was known before 1986 [5]. The second sPLA2 or group IIA PLA2, which is stored in secretory granules of immune cells and is markedly induced at various inflamed sites such as rheumatoid arthritis, was cloned in 1989 [6]. A new period of sPLA2 was opened by the cloning of two novel isozymes, group IIC and V, in 1994 [7], [8]. Afterwards, search for novel sPLA2s by
Structures and enzymatic properties
COX, also known as prostaglandin H synthase, is a heme-containing enzyme that catalyzes two sequential enzymatic reactions; (1) the bis-oxygenation of AA leading to production of PGG2 (COX reaction) and (2) reduction of 15-hydroperoxide of PGG2 leading to formation of PGH2 (hydroperoxidase reaction) [110]. Two COX isoforms, COX-1 and COX-2, are found in mammals. It is generally considered that COX-1 is constitutively expressed in a wide variety of cells and plays a housekeeping role, whereas
Classification
In 1999, Jakobsson et al. [194] reported, for the first time, that recombinant human microsomal glutathione-S-transferase (GST)-1-like 1 (MGST1-L1), a member of the MAPEG [for membrane-associated proteins involved in eicosanoid and glutathione (GSH) metabolism] superfamily that had been listed in the nucleic acid data bases, has the ability to catalyze the conversion of PGH2 to PGE2 with strict substrate specificity. Following this report, orthologs of this protein were cloned from several
Perspectives
In this paper, we have overviewed recent advances in molecular and cell biology, regulatory functions, and pathophysiological roles of various PLA2, COX and PGES enzymes. Clinically, NSAIDs (COX inhibitors) have been used most frequently as prophylactic and therapeutic drugs for various diseases. Thus, agents that inhibit PLA2 or PGES enzymes could be also effective on the therapy of diseases.
Since the PLA2 reaction can initiate multiple lipid mediator production cascades, controlling the
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