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

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...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2021-11, Vol.26 (23), p.7267
Main Authors: Scott, Kieran F., Mann, Timothy J., Fatima, Shadma, Sajinovic, Mila, Razdan, Anshuli, Kim, Ryung Rae, Cooper, Adam, Roohullah, Aflah, Bryant, Katherine J., Gamage, Kasuni K., Harman, David G., Vafaee, Fatemeh, Graham, Garry G., Church, W. Bret, Russell, Pamela J., Dong, Qihan, de Souza, Paul
Format: Article
Language:English
Subjects:
Anti-inflammatory agents
Arthritis
cancer
Catalysis
Cell culture
chronic inflammation
Cloning
Drug development
eicosanoid
Enzymatic activity
Enzyme activity
Enzymes
Gram-positive bacteria
Homology
Inflammation
Inhibitors
Lipids
Pathology
Phospholipase
Phospholipase A2
Physiology
Plasma
prostaglandin
Review
Toxicity
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Summary: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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules26237267