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United States: American Society for Pharmacology and Experimental Therapeutics
Erscheinungsjahr
1976
Quelle
MEDLINE
Beschreibungen/Notizen
The topography of the active sites of rhesus carbonic anhydrases I and II, rabbit carbonic
anhydrase I, sheep carbonic anhydrase II, and dog carbonic anhydrase I has been
studied with the aid of spin-labeled analogues of acetazolamide and sulfanilamide.
Electron spin resonance measurements indicated that the pyrrolidine ring of 2,2,5,5-tetramethyl-3-[( p -sulfamoylphenyl)carbamoyl]-1-pyrrolidinyloxyl became highly immobilized when this label bound to the active site of rhesus
carbonic anhydrase I. As the
chain length between the aromatic and pyrrolidine rings was increased, the mobility of
the nitroxide group of the enzyme-bound inhibitor progressively increased, until with
2,2,5,5-tetramethyl-3-({[( p -sulfamoylphenyl)carbamoyl]methyl}carbamoyl)-1-pyrrolidinyloxyl there was only minimal interaction between the heterocyclic
ring and the active
site of rhesus carbonic anhydrase I. These findings suggest that the active site of rhesus
carbonic anhydrase I is a cleft about 14 A deep. Similar experiments indicated that the
topography of the active sites of rhesus carbonic anhydrase II, dog carbonic anhydrase I,
and sheep carbonic anhydrase II were similar to that of rhesus carbonic anhydrase I,
while the active site of rabbit carbonic anhydrase was somewhat deeper. Spin-labeled
inhibitor 2,2,6,6-tetramethyl-4-( p -sulfamoylbenzamide)piperidinooxyl became highly
immobilized on binding to type II (high-activity) carbonic anhydrase but exhibited
isotropic motion at the active sites of type I (low-activity) isozymes. An attempt is made
to explain these results in terms of the three-dimensional structure of the active sites of
human carbonic anhydrases I and II.