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Mapping the ribonucleolytic active site of bovine seminal ribonuclease. The binding of pyrimidinyl phosphonucleotide inhibitors
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SYSNO ASEP 0333998 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Mapping the ribonucleolytic active site of bovine seminal ribonuclease. The binding of pyrimidinyl phosphonucleotide inhibitors Author(s) Dossi, K. (GR)
Tsirkone, V.G. (GR)
Hayes, J.M. (GR)
Matoušek, Josef (UZFG-Y) RID
Poučková, P. (CZ)
Souček, J. (CZ)
Zadinová, M. (CZ)
Zographos, S.E. (GR)
Leonidas, D.D. (GR)Source Title European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 44, č. 11 (2009), s. 4496-4508Number of pages 13 s. Language eng - English Country FR - France Keywords bovine seminal ribonuclease ; antitumor agent Subject RIV GJ - Animal Vermins ; Diseases, Veterinary Medicine CEZ AV0Z50450515 - UZFG-Y (2005-2011) UT WOS 000271225800028 DOI 10.1016/j.ejmech.2009.06.039 Annotation Bovine seminal ribonuclease(BS-RNase) is a 27 kDa homodimeric enzyme and a member of the pancreatic RNase A superfamily.It is the only RNase with a quaternary structure and it is a mixture of two dimeric forms.In the most abundant form the active site is formed by the swapping of the N-terminal segments.BS-RNase is a potent antitumor agent with severe side effects such as aspermatogenicity,and immunosuppression.As a first step towards the design of potent inhibitors of this enzyme we mapped its active site through the study of the binding of uridine 2'-phosphate(U2'p),uridine T-phosphate(U3'p),uridine 5'-diphosphate UDP),cytidine T-phosphate(C3'p),and cytidine 5-phosphate (C5'p),by kinetics,and Xray crystallography.These phosphonucleotides are potent inhibitors with C3'p being the most potent with a K-i value of 22 mu M. Absorption,distribution, metabolism, and excretion pharmacokinetic property predictions reveal U2'p, U3'p, and C5'p as the most promising with respect to oral bioavailability.In vivo studies on the aspermatogenic effect have shown that C3'p and C5'p inhibitsignificantly this biological action of BS-RNase. Workplace Institute of Animal Physiology and Genetics Contact Jana Zásmětová, knihovna@iapg.cas.cz, Tel.: 315 639 554 Year of Publishing 2010
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