First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity.
Human tuberculosis is a chronic infectious disease affecting millions of lives. Because of emerging resistance to current medications, new therapeutic drugs are needed. One potential new target is hypoxanthine-guanine phosphoribosyltransferase (MtHGPRT), a key enzyme of the purine salvage pathway. Here, newly synthesized acyclic nucleoside phosphonates (ANPs) have been shown to be competitive inhibitors of MtHGPRT with Ki values as low as 0.69 μM. Prodrugs of these compounds arrest the growth of a virulent strain of M. tuberculosis with MIC50 values as low as 4.5 μM and possess low cytotoxicity in mammalian cells (CC50 values as high as >300 μM). In addition, the first crystal structures of MtHGPRT (2.03-2.76 Å resolution) have been determined, three of these in complex with novel ANPs and one with GMP and pyrophosphate. These data provide a solid foundation for the further development of ANPs as selective inhibitors of MtHGPRT and as antituberculosis agents.
†The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072 QLD Australia.
Wai Soon
WS
Eng
‡Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i. Flemingovo nam. 2, CZ-166 10 Prague 6, Czech Republic.
Dana
D
Hocková
‡Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i. Flemingovo nam. 2, CZ-166 10 Prague 6, Czech Republic.
Petr
P
Špaček
‡Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i. Flemingovo nam. 2, CZ-166 10 Prague 6, Czech Republic.
Zlatko
Z
Janeba
†The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072 QLD Australia.
Nicholas P
NP
West
†The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072 QLD Australia.
Kyra
K
Woods
§Rega Institute for Medical Research, KU Leuven - University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Lieve M J
LM
Naesens
†The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072 QLD Australia.
Dianne T
DT
Keough
†The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072 QLD Australia.
Luke W
LW
Guddat
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D011756:Diphosphates / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006157:Guanosine Monophosphate / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000737:chemistry / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D063065:Organophosphonates / Q000737:chemistry / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000995:Antitubercular Agents; D011756:Diphosphates; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011355:Prodrugs; C107241:diphosphoric acid; D006157:Guanosine Monophosphate; D007041:Hypoxanthine Phosphoribosyltransferase