Perfluoroalkyl Substances of Significant Environmental Concern Can Strongly Inhibit Human Carbonic Anhydrase Isozymes
| Autor: | Andrea Angeli, Paola Gratteri, William A. Donald, Alessio Nocentini, Claudiu T. Supuran, Giang T H Nguyen |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Perfluorooctanesulfonic acid Surface Properties Perfluorooctanesulfonamide Crystallography X-Ray Ligands 010402 general chemistry 01 natural sciences Isozyme Mass Spectrometry Analytical Chemistry chemistry.chemical_compound Carbonic anhydrase Humans Particle Size Carbonic Anhydrase Inhibitors Carbonic Anhydrases chemistry.chemical_classification Fluorocarbons biology 010401 analytical chemistry 0104 chemical sciences Isoenzymes Dissociation constant Enzyme Ion homeostasis Alkanesulfonic Acids chemistry Biochemistry biology.protein Perfluorooctanoic acid Environmental Pollutants Caprylates |
| Zdroj: | Analytical Chemistry. 92:4614-4622 |
| ISSN: | 1520-6882 0003-2700 |
| DOI: | 10.1021/acs.analchem.0c00163 |
| Popis: | Perfluoroalkyl substances (PFASs) persist and are ubiquitous in the environment. The origins of PFAS toxicity and how they specifically affect the functions of proteins remain unclear. Herein, we report that PFASs can strongly inhibit the activity of human carbonic anhydrases (hCAs), which are ubiquitous enzymes that catalyze the hydration of CO2, are abundant in the blood and organs of mammals, and involved in pH regulation, ion homeostasis, and biosynthesis. The interactions between PFASs and hCAs were investigated using stopped-flow kinetic enzyme-inhibition measurements, native mass spectrometry (MS), and ligand-docking simulations. Narrow-bore emitters in native MS with inner diameters of ∼300 nm were used to directly and simultaneously measure the dissociation constants of 11 PFASs to an enzyme, which was not possible using conventional emitters. The data from native MS and stopped-flow measurements were in excellent agreement. Of 15 PFASs investigated, eight can inhibit at least one of four hCA isozymes (I, II, IX, and XII) with submicromolar inhibition constants, including perfluorooctanoic acid, perfluorooctanesulfonamide, and perfluorooctanesulfonic acid. Some PFASs, including those with both short and long perfluoromethylene chains, can effectively inhibit at least one hCA isozyme with low nanomolar inhibition constants. |
| Databáze: | OpenAIRE |
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