Cis-trans isomerization of an angiotensin I-converting enzyme inhibitor. An enzyme kinetic and nuclear magnetic resonance study
| Autor: | Anders Skoglöf, Per-Olof Göthe, Ingemar Nilsson, Stina Gustafsson, Johanna Deinum |
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| Rok vydání: | 1990 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy Stereochemistry Biophysics Molecular Conformation Angiotensin-Converting Enzyme Inhibitors Nuclear Overhauser effect Peptidyl-Dipeptidase A Biochemistry Nuclear magnetic resonance Isomerism Ramipril Structural Biology Hydrolase Peptide bond Dimethyl Sulfoxide Pyrroles Molecular Biology Conformational isomerism biology Molecular Structure Chemistry Cis trans isomerization Kinetics Enzyme inhibitor biology.protein Isomerization Cis–trans isomerism Protein Binding |
| Zdroj: | Biochimica et biophysica acta. 1041(1) |
| ISSN: | 0006-3002 |
| Popis: | The angiotensin I-converting enzyme (peptidyl-dipeptide hydrolase, EC 3.4.15.1) inhibitor, ramiprilat ( 2-[N-[(S)-1- ethoxycarbonyl -3- phenylpropyl]- l -Ala ]-(1S,3S5S)-2- azabicyclo [3.3.0] octane -3- carboxylic acid), is shown to exist in two conformational isomers, cis and trans , which interconvert around the amide bond. The two conformers were separated by reversed-phase high-performance liquid chromatography. The conformers were identified by nuclear Overhauser effect measurements. From line shape analysis the isomerization rate constants were determined to be k cis → trans = 15 s −1 and k trans → cis = 5 s −1 at 368 K in [ 2 H]phosphate buffer (p 2 H 7.5). By enzyme kinetic studies, using 3-(2-furylacryloyl)- l -Phe-Gly-Gly as substrate, the trans conformer was found to be the most potent enzyme inhibitor, whereas the cis conformer had a very low inhibitory effect. A new inhibition mechanism is presented for this type of slow, tight-binding inhibitors that contain an amide bond. This mechanism involves an equilibrium between the two conformers and the enzyme-bound inhibitor complex. |
| Databáze: | OpenAIRE |
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