A computational and experimental study of the inhibition of pyroglutamyl peptidase II by thyrotropin-releasing hormone analogs.
Item
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Title
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A computational and experimental study of the inhibition of pyroglutamyl peptidase II by thyrotropin-releasing hormone analogs.
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Identifier
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AAI9130339
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identifier
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9130339
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Creator
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Lanzara, Richard Gene.
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Contributor
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Adviser: Michael N. Liebman
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Date
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1991
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Language
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English
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Publisher
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City University of New York.
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Subject
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Health Sciences, Pharmacology | Biology, Neuroscience | Biophysics, Medical
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Abstract
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Thyrotropin releasing hormone (TRH) is a tripeptide (pGlu-His-Pro-NH2) cleaved by the brain, synaptosomal, ectoenzyme pyroglutamyl peptidase II (PPII). PPII is a metallo-enzyme which likely contains a zinc atom at the active site. The interaction of TRH and nine TRH-analogs with PPII was examined by experimental and computational methods. The ten molecules were classified into three distinguishable experimental classes. These three classes were the: (1) substrates, (2) competitive inhibitors and (3) noncompetitive inhibitors. The experimental classes were modeled by comparing the electrostatic and steric patterns from the single molecules and their respective x-ray crystal environments. Four computational methods were used for the analyses of these three experimental classes. The four computational methods were the: (1) partitioned distance matrix method (PDM), (2) superpositioning by minimization of the root mean square distance between paired atoms (RMS method), (3) superpositioning by searching for the smallest absolute difference between the molecular electrostatic potentials (MEPs) within the crystal contacts (CCs) of the crystal environment (CC method) and (4) placement of the relative orientations within carboxypeptidase-A as a representative metalloprotease. The CC superpositioning method superpositioned the calculated physicochemical properties of the molecules, rather than the atoms. From the comparisons of the competitive inhibitors with the substrates, all of the computer analyses were in general agreement. The PDM together with the RMS superpositioning methods identified constraints near the histidyl and prolineamide residues which were associated with the cleavage of the molecules by PPII. Regions surrounding the imadazole and prolineamide rings were found which may be important for the design of new inhibitors. Other regions near the proline ring may explain why the TRH analogs, RX74355 and RX77368 are poorly degraded in vivo. For the comparisons of the competitive inhibitors with the noncompetitive inhibitors, the four computer analyses allowed for differing interpretations. The CC superpositioning method produced alternative orientations for the noncompetitive inhibitors. These orientations may be germain to the further study of these inhibitors. This approach may also be extended to the studies of other classes of molecules.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
