Phospholipase A2 enzymes

doi:10.1016/S0090-6980(02)00020-5

Prostaglandins & Other Lipid Mediators

Volumes 68–69, August 2002, Pages 3-58

https://doi.org/10.1016/S0090-6980(02)00020-5 Get rights and content

Abstract

Phospholipase A₂ (PLA₂) catalyzes the hydrolysis of the sn-2 position of membrane glycerophospholipids to liberate arachidonic acid (AA), a precursor of eicosanoids including prostaglandins and leukotrienes. The same reaction also produces lysophosholipids, which represent another class of lipid mediators. So far, at least 19 enzymes that possess PLA₂ activity have been identified and cloned in mammals. The secretory PLA₂ (sPLA₂) family, in which 10 isozymes have been identified, consists of low-molecular weight, Ca²⁺-requiring secretory enzymes that have been implicated in a number of biological processes, such as modification of eicosanoid generation, inflammation, and host defense. The cytosolic PLA₂ (cPLA₂) family consists of three enzymes, among which cPLA₂α has been paid much attention by researchers as an essential component of the initiation of AA metabolism. The activation of cPLA₂α is tightly regulated by Ca²⁺ and phosphorylation. The Ca²⁺-independent PLA₂ (iPLA₂) family contains two enzymes and may play a major role in phospholipid remodeling. The platelet-activating factor (PAF) acetylhydrolase (PAF-AH) family contains four enzymes that exhibit unique substrate specificity toward PAF and/or oxidized phospholipids. Degradation of these bioactive phospholipids by PAF-AHs may lead to the termination of inflammatory reaction and atherosclerosis.

Introduction

Phospholipase A₂ (PLA₂) enzymes catalyze the hydrolysis of the sn-2 position of membrane glycerophospholipids, leading to production of free fatty acids and lysophospholipids. This reaction is of particular importance if the esterified fatty acid is arachidonic acid (AA), which is converted by downstream metabolic enzymes to various bioactive lipophilic compounds called eicosanoids, including prostaglandins (PGs) and leukotrienes (LTs). The other reaction products, lysophospholipids such as lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC), are also biologically active by themselves and are the precursors of other potent bioactive mediators, such as platelet-activating factor (PAF). Since the production of these lipid mediators is highly regulated by a variety of extracellular stimuli, it is important to understand the diversity, regulatory mechanisms and functions of PLA₂ enzymes, which can control the initial, rate-limiting step of the biosynthetic cascades. Conversely, the actions of PLA₂s can be important for down-regulating signals, as is seen with the PLA₂-catalyzed hydrolysis of the bioactive phospholipid PAF. PLA₂s also play a role in membrane remodeling, a critical process for maintenance of cellular homeostasis, in which PLA₂-catalyzed deacylation is followed by reacylation by transacylases or acyltransferases, eventually resulting in replacement of fatty acid moieties at the sn-2 position of the membrane glycerophospholipids. In this chapter, we will overview the up-to-date diversity, expression, and functions of mammalian PLA₂ enzymes.

Section snippets

Classification of PLA₂s

Historically, only one mammalian PLA₂ enzyme, which is abundantly present in pancreatic juice, was known before 1986 [1], [2]. The second PLA₂, which is stored in secretory granules of platelets and other immune cells and is markedly induced in various inflamed sites such as in synovial fluid of rheumatoid arthritis, was cloned in 1989 [3], [4], [5]. Because of their sequence similarities to soluble PLA₂s present in snake venoms, pancreatic and synovial PLA₂s were termed groups I and II,

Structures

The structures of 10 mammalian sPLA₂s are illustrated in Fig. 1. sPLA₂s belonging to the groups I/II/V/X collection are closely related, 14–17 kDa secreted enzymes with a highly conserved Ca²⁺-binding loop (XCGXGG) and a catalytic site (DXCCXXHD). Beside these elements, there are six absolutely conserved disulfide bonds and up to two additional unique disulfide bonds, which contributes to the high degree of stability of these enzymes. Substrate hydrolysis proceeds through the activation and

Structures

Group IV cPLA₂s that have been cloned thus far consist of three isozymes, cPLA₂α, cPLA₂β and cPLA₂γ, with molecular masses of 85, 110 and 60 kDa, respectively [8], [9], [22], [23], [24]. The three isoforms contain two catalytic domains A and B interspaced with isoform-specific sequences (Fig. 5). The lipase consensus sequence, GXSGS, is located in the catalytic domain A. cPLA₂α and cPLA₂β have an N-terminal C2 domain, which is critical for Ca²⁺-dependent association with phopholipid membranes [8]

Structures

The classical iPLA₂, iPLA₂-VIA, exists in an aggregated form and occurs in several splice variants (Fig. 7) [25], [26], [27], [28], [29]. The human iPLA₂-VIA gene resides on chromosome 22q13.1 and contains 16 exons. The exon-skipping and insertion of intron sequences, leading to production of several variant forms, occur between exon 7 and 10. At least two enzymatically active forms of the enzyme, termed VIA-1 and VIA-2, have been identified. iPLA₂-VIA-1 is an 85 kDa protein that contains eight

Plasma-type PAF-AH

The plasma-type PAF-AH, or group VIIA PLA₂, is a 45 kDa secreted protein containing a lipase consensus motif GXS²⁷³XG [34], [336]. The catalytic serine in this motif, in combination with Asp²⁹⁶ and His³⁵¹, forms a classical hydrolase triad [336]. The enzyme hydrolyzes the ester bond at the sn-2 position of PAF, which is a form of PC having an sn-1 ether-linked 16–18 carbon alkyl chain and an sn-2 acetyl group, to liberate acetate and lysoPAF. It also hydrolyzes phospholipids with oxidized fatty

Concluding remarks

Recent nucleic acid data base searches have allowed the identification of 19 mammalian PLA₂s, including 10 sPLA₂s, 3 cPLA₂s, 2 iPLA₂s and 4 PAF-AHs. A molecular diversity of PLA₂s in each subgroup also occurs in non-mammalian organisms. The understanding of the biological functions of all of these different PLA₂s is now a challenging area of research. The in vivo functions of most of these PLA₂s, either redundant or segregated, will be clarified in the next 5–10 years. The control of particular

Acknowledgements

We would like to thank Dr. M.H. Gelb (University of Washington, Seattle) for reviewing this manuscript.

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Phospholipase A2 enzymes

Abstract

Introduction

Section snippets

Classification of PLA2s

Structures

Structures

Structures

Plasma-type PAF-AH

Concluding remarks

Acknowledgements

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Phospholipase A₂ enzymes

Classification of PLA₂s