Transition-state analogs as inhibitors of human and malarial hypoxanthine-guanine phosphoribosyltransferases.
The proposed transition state for hypoxanthine-guanine phosphoribosyltransferases (HGPRTs) has been used to design and synthesize powerful inhibitors that contain features of the transition state. The iminoribitols (1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate (immucillinHP) and (1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate (immucillinGP) are the most powerful inhibitors yet reported for both human and malarial HGPRTs. Equilibrium binding constants are >1,000-fold tighter than the binding of the nucleotide substrate. The NMR spectrum of malaria HGXPRT in the Michaelis complex reveals downfield hydrogen-bonded protons. The chemical shifts move farther downfield with bound inhibitor. The inhibitors are lead compounds for species-specific antibiotics against parasitic protozoa. The high-resolution crystal structure of human HGPRT with immucillinGP is reported in the companion paper.
Li
C M
CM
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Tyler
P C
PC
Furneaux
R H
RH
Kicska
G
G
Xu
Y
Y
Grubmeyer
C
C
Girvin
M E
ME
Schramm
V L
VL
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002384:Catalysis / Q000187:drug effects; D011756:Diphosphates / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006157:Guanosine Monophosphate / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D019271:Hypoxanthine / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007291:Inosine Monophosphate / Q000378:metabolism; D007700:Kinetics; D017616:Magnesium Compounds / Q000378:metabolism / Q000494:pharmacology; D019906:Nuclear Magnetic Resonance, Biomolecular; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000201:enzymology*; D011485:Protein Binding / Q000187:drug effects; D011522:Protons; D011684:Purine Nucleosides; D011744:Pyrimidinones / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use
D011756:Diphosphates; D004791:Enzyme Inhibitors; D017616:Magnesium Compounds; D011522:Protons; D011684:Purine Nucleosides; D011744:Pyrimidinones; D011758:Pyrroles; C113100:immucillin G; D007291:Inosine Monophosphate; D019271:Hypoxanthine; C113101:forodesine; D010754:Phosphoribosyl Pyrophosphate; D006157:Guanosine Monophosphate; C034732:magnesium pyrophosphate; D007041:Hypoxanthine Phosphoribosyltransferase