Human Group IIA Phospholipase A2—Three Decades on from Its Discovery

Abstract

Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA2, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA2 field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Functionally-selective inhibitors together with isoform-selective inhibitors are necessary to limit the apparent toxicity of previous drugs. There is also a need to define the relevance of the catalytic function of hGIIA to human inflammatory pathology relative to its recently-discovered catalysis-independent function.

Multimodal regulation of the osteoclastogenesis process by secreted group IIA phospholipase A2

“…In addition, treatment of RAW264.7 macrophages with the alkylating agent BPB, which halts the sPLA 2 -IIA enzymatic activity without changing the overall conformation of the protein surface ( Lee et al, 2013 ), induced a significant reduction of the osteoclastogenesis marker transcription, without affecting the osteoclast fusion. Although this inhibitor is a general alkylating agent and its administration to intact cells cannot guarantee for a sPLA 2 -IIA specific targeting ( Scott et al, 2021 ), we verified that under BPB treatment the sPLA 2 -IIA enzymatic activity is significantly impaired in RANKL-differentiated RAW264.7 macrophages ( Table 2 ). However, off-target effects cannot be completely ruled out.…”

“…Indeed, the sPLA 2 -IIA exhibits compartmentalization, not only for the enzymatic activity primarily occurring in the extracellular environment with a requirement of millimolar calcium concentrations. Even if the binding with a PLA 2 receptor on the cell surface can occur, several other sPLA 2 -IIA interactions occur upon its internalization ( Scott et al, 2021 ).…”

“…Studies over the last decade have revealed that dysregulated lipid metabolism is one of the fundamental metabolic alterations that enable cancer cell survival and sustain rapid tumor growth and cell proliferation ( Kroemer and Pouyssegur, 2008 ). The expression of several sPLA 2 s is altered in various cancer cells, and in the neighboring stromal and immune cells at primary or metastatic tumor sites ( Cummings, 2007 ; Murakami et al, 2011 ; Brglez et al, 2014 ; Sukocheva et al, 2019 ; Scott et al, 2021 ). Once secreted, sPLA 2 s can have both autocrine and paracrine roles, to induce metabolic and signaling changes in a tumor ( Kamphorst et al, 2013 ).…”

“…Secreted PLA 2 s are typically characterized by a low molecular mass (13–18 kDa), a conserved three-dimensional helical structure with high disulfide bond content, and a calcium-dependent enzymatic activity through the conserved His-Asp catalytic dyad ( Lambeau and Gelb, 2008 ; Murakami et al, 2010 ; Murakami et al, 2020 ). The most studied member, sPLA 2 -IIA, has a demonstrated primary function in host defense against invading pathogens ( Doré and Boilard, 2019 ; Scott et al, 2021 ; Miki et al, 2022 ). As a secreted lipolytic enzyme, sPLA 2 -IIA shows bactericidal activity through hydrolysis of Gram-positive membranes ( Weinrauch et al, 1998 ), and anti-parasitic function through hydrolysis of oxidized phospholipids in the plasma lipoproteins of malaria patients, thus promoting P lasmodium falciparum killing effect ( Dacheux et al, 2019 ; Dacheux et al, 2021 ).…”

“…The sPLA 2 -IIA cellular functions account for the enzymatic hydrolysis of glycerophospholipids, but can also occur in a catalysis-independent manner ( Murakami et al, 2017 ; Doré and Boilard, 2019 ; Scott et al, 2021 ; Ivanusec et al, 2022 ). Several cellular and soluble receptors for sPLA 2 -IIA have been characterized until now, starting from the cell surface M-type receptor for secreted phospholipases ( Cupillard et al, 1999 ; Lambeau and Lazdunski, 1999 ), and these may be involved in the activation of downstream cellular signaling pathways with hydrolytic activity-independent mechanisms ( Saegusa et al, 2008 ; Ivanusec et al, 2022 ).…”