Mapping the ribonucleolytic active site of bovine seminal ribonuclease. The binding of pyrimidinyl phosphonucleotide inhibitors

0333998 - ÚŽFG 2010 RIV FR eng J - Článek v odborném periodiku
Dossi, K. - Tsirkone, V.G. - Hayes, J.M. - Matoušek, Josef - Poučková, P. - Souček, J. - Zadinová, M. - Zographos, S.E. - Leonidas, D.D.
Mapping the ribonucleolytic active site of bovine seminal ribonuclease. The binding of pyrimidinyl phosphonucleotide inhibitors.
European Journal of Medicinal Chemistry. Roč. 44, č. 11 (2009), s. 4496-4508. ISSN 0223-5234. E-ISSN 1768-3254
Výzkumný záměr: CEZ:AV0Z50450515
Klíčová slova: bovine seminal ribonuclease * antitumor agent
Kód oboru RIV: GJ - Choroby a škůdci zvířat, veterinární medicína
Impakt faktor: 3.269, rok: 2009

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.
Trvalý link: http://hdl.handle.net/11104/0178846