Investigating Active Site Binding of Ligands to High and Low Activity Carbonic Anhydrase Enzymes Using Native Mass Spectrometry DOI

Yezhou Yu,

Louise M. Sternicki, David H. Hilko

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(17), P. 15862 - 15872

Published: Aug. 20, 2024

Carbonic anhydrases (CAs) are a family of enzymes that play an important pH regulatory role in health and disease. While different CA isozymes have high degree structural similarity, they variable enzymatic activity, with III being the least active having less than 1% activity II, most active. Furthermore, ligand binding studies for limited, resulting lack chemical probes impedes understanding this isozyme comparison to other members where abundant. Therefore, we employed native mass spectrometry (nMS), also known as intact spectrometry, assess II discovered two novel compounds first time display strong III. We present new data visualization quantification tool developed spectra intuitive stacked heat map representation rapidly interpreting results ligand-protein from nMS screening.

Language: Английский

Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy DOI Creative Commons
Md. Ataur Rahman,

Mahesh Kumar Yadab,

Meser M. Ali

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(22), P. 1924 - 1924

Published: Nov. 20, 2024

Identifying definitive biomarkers that predict clinical response and resistance to immunotherapy remains a critical challenge. One emerging factor is extracellular acidosis in the tumor microenvironment (TME), which significantly impairs immune cell function contributes failure. However, acidic conditions TME disrupt interaction between cancer cells, driving tumor-infiltrating T cells NK into an inactivated, anergic state. Simultaneously, promotes recruitment activation of immunosuppressive such as myeloid-derived suppressor regulatory (Tregs). Notably, acidity enhances exosome release from Tregs, further amplifying immunosuppression. Tumor thus acts "protective shield," neutralizing anti-tumor responses transforming pro-tumor allies. Therefore, targeting lactate metabolism has emerged promising strategy overcome this barrier, with approaches including buffer agents neutralize pH inhibitors block production or transport, thereby restoring efficacy TME. Recent discoveries have identified genes involved (pHe) regulation, presenting new therapeutic targets. Moreover, ongoing research aims elucidate molecular mechanisms acidification develop treatments modulate levels enhance outcomes. Additionally, future studies are crucial validate safety pHe-targeted therapies patients. Thus, review explores regulation pHe its potential role improving immunotherapy.

Language: Английский

Citations

7
Investigating Active Site Binding of Ligands to High and Low Activity Carbonic Anhydrase Enzymes Using Native Mass Spectrometry DOI

Yezhou Yu,

Louise M. Sternicki, David H. Hilko

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(17), P. 15862 - 15872

Published: Aug. 20, 2024

Carbonic anhydrases (CAs) are a family of enzymes that play an important pH regulatory role in health and disease. While different CA isozymes have high degree structural similarity, they variable enzymatic activity, with III being the least active having less than 1% activity II, most active. Furthermore, ligand binding studies for limited, resulting lack chemical probes impedes understanding this isozyme comparison to other members where abundant. Therefore, we employed native mass spectrometry (nMS), also known as intact spectrometry, assess II discovered two novel compounds first time display strong III. We present new data visualization quantification tool developed spectra intuitive stacked heat map representation rapidly interpreting results ligand-protein from nMS screening.

Language: Английский

Citations

0