Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation
Abstract The aminopeptidase activity (AP) of the leukotriene A4 hydrolase (LTA4H) enzyme has emerged as a therapeutic target to modulate host immunity. Initial reports focused on the benefits of augmenting the LTA4H AP activity and clearing its putative pro-inflammatory substrate Pro-Gly-Pro (PGP)....
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| Format: | Article |
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Nature Portfolio
2022-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-13238-6 |
| _version_ | 1818207662136885248 |
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| author | Kyung Hyeon Lee Nadia Fazal Ali Soo Hyeon Lee Zhimin Zhang Marie Burdick Zachary J. Beaulac Greg Petruncio Linxia Li Jiangdong Xiang Ezra M. Chung Kenneth W. Foreman Schroeder M. Noble Yun M. Shim Mikell Paige |
| author_facet | Kyung Hyeon Lee Nadia Fazal Ali Soo Hyeon Lee Zhimin Zhang Marie Burdick Zachary J. Beaulac Greg Petruncio Linxia Li Jiangdong Xiang Ezra M. Chung Kenneth W. Foreman Schroeder M. Noble Yun M. Shim Mikell Paige |
| author_sort | Kyung Hyeon Lee |
| collection | DOAJ |
| description | Abstract The aminopeptidase activity (AP) of the leukotriene A4 hydrolase (LTA4H) enzyme has emerged as a therapeutic target to modulate host immunity. Initial reports focused on the benefits of augmenting the LTA4H AP activity and clearing its putative pro-inflammatory substrate Pro-Gly-Pro (PGP). However, recent reports have introduced substantial complexity disconnecting the LTA4H modulator 4-methoxydiphenylmethane (4MDM) from PGP as follows: (1) 4MDM inhibits PGP hydrolysis and subsequently inhibition of LTA4H AP activity, and (2) 4MDM activates the same enzyme target in the presence of alternative substrates. Differential modulation of LTA4H by 4MDM was probed in a murine model of acute lung inflammation, which showed that 4MDM modulates the host neutrophilic response independent of clearing PGP. X-ray crystallography showed that 4MDM and PGP bind at the zinc binding pocket and no allosteric binding was observed. We then determined that 4MDM modulation is not dependent on the allosteric binding of the ligand, but on the N-terminal side chain of the peptide. In conclusion, our study revealed that a peptidase therapeutic target can interact with its substrate and ligand in complex biochemical mechanisms. This raises an important consideration when ligands are designed to explain some of the unpredictable outcomes observed in therapeutic discovery targeting LTA4H. |
| first_indexed | 2024-12-12T04:32:29Z |
| format | Article |
| id | doaj.art-5e035599853c418c91141324ae6d3acc |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-12T04:32:29Z |
| publishDate | 2022-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-5e035599853c418c91141324ae6d3acc2022-12-22T00:38:02ZengNature PortfolioScientific Reports2045-23222022-06-0112111110.1038/s41598-022-13238-6Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammationKyung Hyeon Lee0Nadia Fazal Ali1Soo Hyeon Lee2Zhimin Zhang3Marie Burdick4Zachary J. Beaulac5Greg Petruncio6Linxia Li7Jiangdong Xiang8Ezra M. Chung9Kenneth W. Foreman10Schroeder M. Noble11Yun M. Shim12Mikell Paige13Department of Chemistry & Biochemistry, George Mason UniversityDepartment of Chemistry & Biochemistry, George Mason UniversityWound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of ResearchDivision of Pulmonary and Critical Care Medicine, Department of Medicine, University of VirginiaDivision of Pulmonary and Critical Care Medicine, Department of Medicine, University of VirginiaDepartment of Chemistry & Biochemistry, George Mason UniversityDepartment of Chemistry & Biochemistry, George Mason UniversityDepartment of Obstetrics and Gynecology, Seventh People’s Hospital of Shanghai University of Traditional Chinese MedicineDepartment of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineSTCube Pharmaceutical, Inc.Department of Chemistry & Biochemistry, George Mason UniversityWound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of ResearchDivision of Pulmonary and Critical Care Medicine, Department of Medicine, University of VirginiaDepartment of Chemistry & Biochemistry, George Mason UniversityAbstract The aminopeptidase activity (AP) of the leukotriene A4 hydrolase (LTA4H) enzyme has emerged as a therapeutic target to modulate host immunity. Initial reports focused on the benefits of augmenting the LTA4H AP activity and clearing its putative pro-inflammatory substrate Pro-Gly-Pro (PGP). However, recent reports have introduced substantial complexity disconnecting the LTA4H modulator 4-methoxydiphenylmethane (4MDM) from PGP as follows: (1) 4MDM inhibits PGP hydrolysis and subsequently inhibition of LTA4H AP activity, and (2) 4MDM activates the same enzyme target in the presence of alternative substrates. Differential modulation of LTA4H by 4MDM was probed in a murine model of acute lung inflammation, which showed that 4MDM modulates the host neutrophilic response independent of clearing PGP. X-ray crystallography showed that 4MDM and PGP bind at the zinc binding pocket and no allosteric binding was observed. We then determined that 4MDM modulation is not dependent on the allosteric binding of the ligand, but on the N-terminal side chain of the peptide. In conclusion, our study revealed that a peptidase therapeutic target can interact with its substrate and ligand in complex biochemical mechanisms. This raises an important consideration when ligands are designed to explain some of the unpredictable outcomes observed in therapeutic discovery targeting LTA4H.https://doi.org/10.1038/s41598-022-13238-6 |
| spellingShingle | Kyung Hyeon Lee Nadia Fazal Ali Soo Hyeon Lee Zhimin Zhang Marie Burdick Zachary J. Beaulac Greg Petruncio Linxia Li Jiangdong Xiang Ezra M. Chung Kenneth W. Foreman Schroeder M. Noble Yun M. Shim Mikell Paige Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation Scientific Reports |
| title | Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation |
| title_full | Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation |
| title_fullStr | Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation |
| title_full_unstemmed | Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation |
| title_short | Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation |
| title_sort | substrate dependent modulation of the leukotriene a4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation |
| url | https://doi.org/10.1038/s41598-022-13238-6 |
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