Revival: CRC Handbook of Eicosanoids, Volume II (1989)

Prostaglandins and Related Lipids

A. L. Willis

• Publisher: CRC Press
• Year: 2017
• eBook ISBN:
  9781351367127
• Topic: Medicine
• Subtopic: Biochemistry in Medicine

Building upon the extensive compilation of biochemical data featured in Volume I of the Handbook of Eicosanoids, the new Volume II describes the past, present, and potential future impact of eicosanoid research on new drug development. The reader is taken from a historical perspective through state-of-the-art basic concepts to extensive tabulation of molecular structures of compounds known to act via the eicosanoid system. Much emphasis is given to recent breakthroughs in the mechanism of action of anti-inflammatory corticosteroids and the development of receptor antagonists for prostaglandins and leukotrienes. There is also an introductory chapter that proposes areas that require further investigation and novel approaches using existing technology. This handbook will thus be invaluable for medicinal chemists, pharmacologists, and all those involved in basic research in the eicosanoid area. In addition, many parts of this handbook are suitable for use by university lecturers and students. There are 20 figures and 44 extensive tables as well as a bibliography containing more than 2,000 references that complement the text.

Antiphospholipase Proteins: Introduction and Overview

Donald L. Smith

The following is intended as an overview to the chapters in this volume by Flower et al. (Eicosanoid Release) and Hirata (Phospholipase Modulation), with emphasis on current concepts and recent findings. It is expanded and updated from a nomenclature statement published previously by Di Rosa et al. in Prostaglandins.¹

Until recently, there has been confusion over the nature of the steroid-modulated anti-phospholipase proteins previously named lipomodulin,^2,3 macrocortin,^4,5 and renocortin^6,7 because, despite similar biological properties, there is a disparity in their molecular weights (40 kDa, 15 kDa, and 15 kDa + 30 kDa, respectively). Until very recently, the primary structure of these proteins was not known. Results of collaborative experiments by several investigators^3,7 showed that these proteins seem functionally identical and that the observed discrepancy was produced by proteolysis.

In addition to the commonly observed forms, other species are sometimes seen. These include a very large protein of ~ 125 kDa⁸ and another ~24 kDa.² The apparent molecular weight of the inhibitor in any given preparation depends upon the degree of glycosylation, the extent of proteolysis and method of estimation, and the species of origin.

It was proposed¹ that this family of compounds be known as the lipocortins. This name reflected both their activity as modulators of lipid metabolism and their adrenocortical interrelationships.

Several biological and chemical properties of the lipocortins are now known. They are glycoproteins whose rate of synthesis/secretion by several cell types is dramatically increased by glucocorticoids acting by a receptor-dependent mechanism. Lipocortins inhibit phospholipase A₂ and can thus inhibit release of eicosanoids induced by various stimuli in vitro and in vivo in several systems.^9-13 (See also chapter by Flower et al. in this volume.) However, as for glucocorticoids,¹⁴ they did not inhibit eicosanoid release induced by arachidonic acid or by bradykinin (which might act by stimulating phospholipase C release),⁹ and there is recent evidence that glucocorticoid treatment preferentially inhibits phospholipase A₂ with no effect on phospholipase C.^14,15

Two lipocortins, called lipocortins I and II, have now been identified^16-18 as well as a recently described distinct antiphospholipase molecule (a monomeric 32 kDa protein from human placenta).¹⁹ Sequences of cloned lipocortin I (a 35 to 37 kDa monomer) and lipocortin II (a heterotetramer of 2 copies of a 36 kDa chain 50% homologous with lipocortin I and 2 copies of a 10 kDa chain)^16,17 are shown in Figure 1. Sequencing and mapping of five proteolytic fragments of recombinant lipocortin I showed that amino acid residues 97 to 178, a region that is 70% homologous with another lipocortin, are common to all active fragments.²⁰ Both human and rat lipocortin I show very close structural similarity,^16,21 suggesting a high degree of evolutionary conservation. Both lipocortins I and II are highly polar, and neither lipocortin contains a leader (signal) sequence.

Phospholipase-A₂ activity can be blocked by depletion of Ca^{+ +} with EDTA.^22,23 Although calcium channel blockers can inhibit prostaglandin release,^24,25 such actions might not be mediated through direct inhibition of phospholipase-A₂ activity.²⁴ A hydrophobic interaction at Ca^{+ +} binding sites has been implicated in the inhibition of phospholipase A₂ by lipo-modulin, since the inhibition can be reversed by high Ca^{+ +} concentrations or by detergents.²⁶ (See also chapter by Hirata in this volume.) A...

Table of contents

• Cover
• Title
• Copyright
• Preface
• Foreword
• The Editor
• Advisory Board
• Volume Outline
• Table of Contents
• INTRODUCTION TO THE AREA Therapeutic Promise of the Eicosanoid Area: An Overview
• INHIBITORS OF EICOSANOID PRODUCTION Antiphospholipase Proteins: Introduction and Overview
• MODULATORS OF EICOSANOID ACTIONS Classification of Prostanoid Receptors
• Index