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

Kieran F Scott; Timothy J Mann; Shadma Fatima; Mila Sajinovic; Anshuli Razdan; Ryung Rae Kim; Adam Cooper; Aflah Roohullah; Katherine J Bryant; Kasuni K Gamage; David G Harman; Fatemeh Vafaee; Garry G Graham; W Bret Church; Pamela J Russell; Qihan Dong; Paul de Souza

doi:10.3390/molecules26237267

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

Molecules. 2021 Nov 30;26(23):7267. doi: 10.3390/molecules26237267.

Authors

Kieran F Scott^{1

2}, Timothy J Mann^{1

2}, Shadma Fatima^{1

2

3}, Mila Sajinovic², Anshuli Razdan², Ryung Rae Kim⁴, Adam Cooper^{1

2

5}, Aflah Roohullah^{1

2

5}, Katherine J Bryant⁶, Kasuni K Gamage⁷, David G Harman⁷, Fatemeh Vafaee^{3

8}, Garry G Graham^{9

10}, W Bret Church⁴, Pamela J Russell¹¹, Qihan Dong¹², Paul de Souza^{1

2

13}

Affiliations

¹ School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia.
² Ingham Institute of Applied Medical Research, Liverpool, NSW 2170, Australia.
³ School of Biotechnology and Biological Sciences, University of New South Wales (UNSW Sydney), Sydney, NSW 2052, Australia.
⁴ School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia.
⁵ Liverpool Cancer Therapy Centre, Liverpool Hospital, Liverpool, NSW 2170, Australia.
⁶ School of Photovoltaic and Renewable Energy Engineering, UNSW Sydney, Sydney, NSW 2052, Australia.
⁷ School of Science, Western Sydney University, Campbelltown, NSW 2560, Australia.
⁸ UNSW Data Science Hub, UNSW Sydney, Sydney, NSW 2052, Australia.
⁹ Department of Clinical Pharmacology, St Vincent's Hospital Sydney, Darlinghurst, NSW 2010, Australia.
¹⁰ School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia.
¹¹ Australian Prostate Cancer Research Centre-QUT, Brisbane, QLD 4102, Australia.
¹² Chinese Medicine Anti-Cancer Evaluation Program, Greg Brown Laboratory, Central Clinical School and Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.
¹³ School of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.

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.

Keywords: cancer; chronic inflammation; drug development; eicosanoid; prostaglandin.

Publication types

Review

MeSH terms

Drug Development
Group II Phospholipases A2 / antagonists & inhibitors
Group II Phospholipases A2 / metabolism*
Group II Phospholipases A2 / pharmacology
Humans
Neoplasms / diagnosis
Neoplasms / enzymology
Prognosis

Substances

Group II Phospholipases A2