Crystal Structures of Acyclic Nucleoside Phosphonates in Complex with Escherichia coli Hypoxanthine Phosphoribosyltransferase

0469893 - ÚOCHB 2017 RIV DE eng J - Článek v odborném periodiku
Eng, W. S. - Hocková, Dana - Špaček, Petr - Baszczyňski, Ondřej - Janeba, Zlatko - Naesens, L. - Keough, D. T. - Guddat, L. W.
Crystal Structures of Acyclic Nucleoside Phosphonates in Complex with Escherichia coli Hypoxanthine Phosphoribosyltransferase.
ChemistrySelect. Roč. 1, č. 19 (2016), s. 6267-6276. ISSN 2365-6549. E-ISSN 2365-6549
Grant CEP: GA ČR(CZ) GA16-06049S
Institucionální podpora: RVO:61388963
Klíčová slova: enzyme inhibitors * nucleotide analogues * HPRT
Obor OECD: Organic chemistry

Drug resistant uropathogenic E. coli associated with urinary tract infections (UTIs) are a serious and debilitating health threat. Therefore new drug targets to treat this disease need to be explored. One possible approach is to block the synthesis of the nucleoside monophosphates required for DNA/RNA production in these pathogens. In E. coli, the purine salvage pathway has two 6-oxopurine phosphoribosyltransferases (PRTs), xanthine-guanine PRT (EcXGPRT) and hypoxanthine PRT (EcHPRT). Here, we investigate acyclic nucleoside phosphonates (ANPs) as inhibitors of EcHPRT and have determined six crystal structures of EcHPRT in complex with ANPs. These data reveal the binding modes of these compounds and can assist in future rational structure-based design efforts. It is suggested that a combination of inhibitors that block de novo and salvage pathways is a plausible approach to developing new antibiotics for E. coli UTIs. In addition, we provide details of a novel approach to accelerating the crystallization of this enzyme that may be of general applicability for rational drug discovery.
Trvalý link: http://hdl.handle.net/11104/0267662