Molecular basis for the origin of differential spectral and binding profiles of dansylamide with human carbonic anhydrase I and II.
Sulfonamide derivatives serve as potent inhibitors of carbonic anhydrases (CAs), and a few such inhibitors have been currently used as drugs for the treatment of different pathogenic conditions in humans. In pursuit of designing the isozyme-specific inhibitors of human CAs, we observed that the fluorescence spectral properties and binding profiles of a fluorogenic sulfonamide derivative, 5-(dimethylamino)-1-naphthalenesulfonamide (dansylamide, DNSA), were markedly different between the recombinant forms of human carbonic anhydrase I (hCA I) and II (hCA II). The kinetic evaluation of the overall microscopic pathways for the binding of DNSA to hCA I versus hCA II revealed that the protein isomerization step served as a major determinant of the above discrepancy. Arguments are presented that the detailed structural-functional investigations of enzyme-ligand interactions may provide insights into designing the isozyme-specific inhibitors of CAs.
Banerjee
Abir L
AL
Department of Chemistry and Molecular Biology, North Dakota State University, Fargo, North Dakota 58105, USA.
Tobwala
Shakila
S
Ganguly
Bratati
B
Mallik
Sanku
S
Srivastava
D K
DK
D001665:Binding Sites; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D003619:Dansyl Compounds / Q000737:chemistry / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008024:Ligands; D046911:Macromolecular Substances; D008956:Models, Chemical; D011485:Protein Binding; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D003619:Dansyl Compounds; D005456:Fluorescent Dyes; D008024:Ligands; D046911:Macromolecular Substances; C001026:5-dimethylaminonaphthalene-1-sulfonamide; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II