Review
Recent advances in molecular biology and physiology of the prostaglandin E2-biosynthetic pathway

https://doi.org/10.1016/S0163-7827(03)00037-7Get rights and content

Abstract

Prostanoids represent a group of lipid mediators that are produced from arachidonic acid via the cyclooxygenase pathway. Once formed, the prostanoids are released from the cells and act on their cognate receptors on cell surfaces to exert their biological actions. Of these, prostaglandin E2 (PGE2) is the most common prostanoid, being produced by a wide variety of cells and tissues and has a broad range of bioactivity. Recent advance in this field has led to identification and characterization of a number of enzymes that play roles in the biosynthesis of PGE2, namely phospholipase A2, cyclooxygenase and terminal PGE synthase. Each of these three reactions can be rate-limiting and involves multiple enzymes/isozymes that can act in different phases of cell activation and exhibit distinct functional coupling. In this review, we will overview a recent understanding of the molecular biology, regulatory mechanisms, and physiological functions of these enzymes.

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

References (226)

  • I. Kudo et al.

    Prostaglandins Other Lipid Mediat

    (2002)
  • M. Murakami et al.

    Adv Immunol.

    (2001)
  • Y. Sugimoto et al.

    Prog Lipid Res.

    (2000)
  • R.M. Kramer et al.

    J Biol Chem.

    (1989)
  • J. Chen et al.

    J Biol Chem.

    (1994)
  • J. Chen et al.

    J. Biol. Chem.

    (1994)
  • L. Cupillard et al.

    J Biol Chem.

    (1997)
  • J. Ishizaki et al.

    J Biol Chem.

    (1999)
  • N. Suzuki et al.

    J Biol Chem.

    (2000)
  • E. Valentin et al.

    J Biol Chem.

    (1999)
  • E. Valentin et al.

    J Biol Chem.

    (2000)
  • M.H. Gelb et al.

    J Biol Chem.

    (2000)
  • J.D. Clark et al.

    Cell

    (1991)
  • L.L. Lin et al.

    Cell

    (1993)
  • K.W. Underwood et al.

    J Biol Chem.

    (1998)
  • R.T. Pickard et al.

    J Biol Chem.

    (1999)
  • J. Tang et al.

    J Biol Chem.

    (1997)
  • P.K. Larsson et al.

    J Biol Chem.

    (1998)
  • D.J. Mancuso et al.

    J Biol Chem.

    (2000)
  • H. Arai

    Prostaglandins Other Lipid Mediat

    (2002)
  • P. Chaitidis et al.

    FEBS Lett.

    (1998)
  • M. Murakami et al.

    J Biol Chem.

    (1998)
  • M. Murakami et al.

    J Biol Chem.

    (1999)
  • M. Murakami et al.

    J Biol Chem.

    (2001)
  • G. Lambeau et al.

    Trends Pharmacol Sci.

    (1999)
  • K. Hanasaki et al.

    J Biol. Chem.

    (1997)
  • B.L. Richmond et al.

    Gastroenterology

    (2001)
  • S. Oka et al.

    J Biol Chem.

    (1991)
  • T. Nakano et al.

    J Biol Chem.

    (1990)
  • R.M. Crowl et al.

    J Biol Chem.

    (1991)
  • C. Couturier et al.

    J Biol Chem.

    (1999)
  • M. MacPhee et al.

    Cell

    (1995)
  • R.S. Koduri et al.

    J Biol Chem.

    (1998)
  • M. Murakami et al.

    J Biol Chem.

    (1999)
  • U.J. Tietge et al.

    J Biol Chem.

    (2000)
  • R.S. Koduri et al.

    J Biol Chem.

    (2002)
  • M. Murakami et al.

    Biochem. Biophys. Res. Commun.

    (2002)
  • M. Murakami et al.

    J Biol Chem.

    (2002)
  • C.O. Bingham et al.

    J Biol Chem.

    (1999)
  • S.K. Han et al.

    J Biol Chem.

    (1999)
  • K. Hanasaki et al.

    J Biol Chem.

    (1999)
  • Y. Morioka et al.

    Arch. Biochem. Biophys.

    (2000)
  • Y. Morioka et al.

    FEBS Lett.

    (2000)
  • K. Hanasaki et al.

    J Biol Chem.

    (2002)
  • A. Dessen et al.

    Cell

    (1999)
  • E.A. Nalefski et al.

    J Biol Chem.

    (1998)
  • L.L. Lin et al.

    J Biol Chem.

    (1992)
  • R.W. Loo et al.

    J Biol Chem.

    (1997)
  • J.H. Evans et al.

    J Biol Chem.

    (2001)
  • T. Hirabayashi et al.

    J Biol Chem.

    (1999)
  • Cited by (0)

    View full text