title: Crystal structures and inhibition of Trypanosoma brucei hypoxanthine-guanine phosphoribosyltransferase.
abstract: Human African Trypanosomiasis (HAT) is a life-threatening infectious disease caused by the protozoan parasite, Trypanosoma brucei (Tbr). Due to the debilitating side effects of the current therapeutics and the emergence of resistance to these drugs, new medications for this disease need to be developed. One potential new drug target is 6-oxopurine phosphoribosyltransferase (PRT), an enzyme central to the purine salvage pathway and whose activity is critical for the production of the nucleotides (GMP and IMP) required for DNA/RNA synthesis within this protozoan parasite. Here, the first crystal structures of this enzyme have been determined, these in complex with GMP and IMP and with three acyclic nucleoside phosphonate (ANP) inhibitors. The Kivalues for GMP and IMP are 30.5 μM and 77 μM, respectively. Two of the ANPs have Kivalues considerably lower than for the nucleotides, 2.3 μM (with guanine as base) and 15.8 μM (with hypoxanthine as base). The crystal structures show that when two of the ANPs bind, they induce an unusual conformation change to the loop where the reaction product, pyrophosphate, is expected to bind. This and other structural differences between the Tbr and human enzymes suggest selective inhibitors for the Tbr enzyme can be designed.
authors: The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072 QLD, Australia.
authors: David
authors: D
authors: Terán
authors: The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nam. 2, CZ-166 10 Prague 6, Czech Republic.
authors: Dana
authors: D
authors: Hocková
authors: The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nam. 2, CZ-166 10 Prague 6, Czech Republic.
authors: Michal
authors: M
authors: Česnek
authors: Biology Centre CAS, Institute of Parasitology, Branišovská 31, České Budějovice, Czech Republic.
authors: Alena
authors: A
authors: Zíková
authors: Rega Institute for Medical Research, KU Leuven-University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors: Lieve
authors: L
authors: Naesens
authors: The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072 QLD, Australia.
authors: Dianne T
authors: DT
authors: Keough
authors: The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072 QLD, Australia.
authors: Luke W
authors: LW
authors: Guddat
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D007700:Kinetics; D008958:Models, Molecular; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014344:Trypanocidal Agents / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D014349:Trypanosoma cruzi / Q000201:enzymology / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D007041:Hypoxanthine Phosphoribosyltransferase