Human Group IIA Phospholipase A<sub>2</sub>—Three Decades on from Its Discovery
Phospholipase A<sub>2</sub> (PLA<sub>2</sub>) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA<sub>2</sub>) enzymes were the first of the five major classes of human PLA<sub>2</sub>s to be identified and now number...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/23/7267 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Kieran F. Scott |
| collection | DOAJ |
| description | Phospholipase A<sub>2</sub> (PLA<sub>2</sub>) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA<sub>2</sub>) enzymes were the first of the five major classes of human PLA<sub>2</sub>s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA<sub>2</sub>, 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 sPLA<sub>2</sub> 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. |
| first_indexed | 2024-03-10T04:47:53Z |
| format | Article |
| id | doaj.art-eb2e06cdc5944953ae3c4aad2d98fc41 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T04:47:53Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-eb2e06cdc5944953ae3c4aad2d98fc412023-11-23T02:49:54ZengMDPI AGMolecules1420-30492021-11-012623726710.3390/molecules26237267Human Group IIA Phospholipase A<sub>2</sub>—Three Decades on from Its DiscoveryKieran F. Scott0Timothy J. Mann1Shadma Fatima2Mila Sajinovic3Anshuli Razdan4Ryung Rae Kim5Adam Cooper6Aflah Roohullah7Katherine J. Bryant8Kasuni K. Gamage9David G. Harman10Fatemeh Vafaee11Garry G. Graham12W. Bret Church13Pamela J. Russell14Qihan Dong15Paul de Souza16School of Medicine, Western Sydney University, Campbelltown, NSW 2560, AustraliaSchool of Medicine, Western Sydney University, Campbelltown, NSW 2560, AustraliaSchool of Medicine, Western Sydney University, Campbelltown, NSW 2560, AustraliaIngham Institute of Applied Medical Research, Liverpool, NSW 2170, AustraliaIngham Institute of Applied Medical Research, Liverpool, NSW 2170, AustraliaSchool of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, AustraliaSchool of Medicine, Western Sydney University, Campbelltown, NSW 2560, AustraliaSchool of Medicine, Western Sydney University, Campbelltown, NSW 2560, AustraliaSchool of Photovoltaic and Renewable Energy Engineering, UNSW Sydney, Sydney, NSW 2052, AustraliaSchool of Science, Western Sydney University, Campbelltown, NSW 2560, AustraliaSchool of Science, Western Sydney University, Campbelltown, NSW 2560, AustraliaSchool of Biotechnology and Biological Sciences, University of New South Wales (UNSW Sydney), Sydney, NSW 2052, AustraliaDepartment of Clinical Pharmacology, St Vincent’s Hospital Sydney, Darlinghurst, NSW 2010, AustraliaSchool of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, AustraliaAustralian Prostate Cancer Research Centre—QUT, Brisbane, QLD 4102, AustraliaChinese Medicine Anti-Cancer Evaluation Program, Greg Brown Laboratory, Central Clinical School and Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, AustraliaSchool of Medicine, Western Sydney University, Campbelltown, NSW 2560, AustraliaPhospholipase A<sub>2</sub> (PLA<sub>2</sub>) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA<sub>2</sub>) enzymes were the first of the five major classes of human PLA<sub>2</sub>s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA<sub>2</sub>, 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 sPLA<sub>2</sub> 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.https://www.mdpi.com/1420-3049/26/23/7267eicosanoiddrug developmentchronic inflammationcancerprostaglandin |
| spellingShingle | 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 Human Group IIA Phospholipase A<sub>2</sub>—Three Decades on from Its Discovery Molecules eicosanoid drug development chronic inflammation cancer prostaglandin |
| title | Human Group IIA Phospholipase A<sub>2</sub>—Three Decades on from Its Discovery |
| title_full | Human Group IIA Phospholipase A<sub>2</sub>—Three Decades on from Its Discovery |
| title_fullStr | Human Group IIA Phospholipase A<sub>2</sub>—Three Decades on from Its Discovery |
| title_full_unstemmed | Human Group IIA Phospholipase A<sub>2</sub>—Three Decades on from Its Discovery |
| title_short | Human Group IIA Phospholipase A<sub>2</sub>—Three Decades on from Its Discovery |
| title_sort | human group iia phospholipase a sub 2 sub three decades on from its discovery |
| topic | eicosanoid drug development chronic inflammation cancer prostaglandin |
| url | https://www.mdpi.com/1420-3049/26/23/7267 |
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