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Crystal structures of Giardia lamblia guanine phosphoribosyltransferase at 1.75 A(,).
The G. lamblia GPRTase exhibits substantial structural differences from known purine phosphoribosyltransferases at positions remote from the catalytic site, but conserves most contacts to the bound inhibitor.
Discovery of a novel class of highly potent, selective, ATP-competitive, and orally bioavailable inhibitors of the mammalian target of rapamycin (mTOR).
Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity and good pharmacokinetics and oral exposure in multiple species with moderate bioavailability.
Adenosine is the primary precursor of all purine nucleotides in Trichomonas vaginalis.
Rational design of selective submicromolar inhibitors of Tritrichomonas foetus hypoxanthine-guanine-xanthine phosphoribosyltransferase.
- A. Aronov, N. Munagala, P. Ortiz de Montellano, I. Kuntz, C. Wang
- Biology, ChemistryBiochemistry
- 25 April 2000
These studies underscore the efficiency of combining structure-based drug design with combinatorial chemistry to produce effective species-specific enzyme inhibitors of medicinal importance.
Virtual Screening of Combinatorial Libraries across a Gene Family: in Search of Inhibitors of Giardia lamblia Guanine Phosphoribosyltransferase
- A. Aronov, N. Munagala, I. Kuntz, Ching C. Wang
- Biology, ChemistryAntimicrobial Agents and Chemotherapy
- 1 September 2001
As a second step in this process, altering the phthalimide moiety to optimize interactions in the guanine-binding pocket of GPRT is expected to lead to compounds with promising activity against G. lamblia PRT.
Altering the purine specificity of hypoxanthine-guanine-xanthine phosphoribosyltransferase from Tritrichomonas foetus by structure-based point mutations in the enzyme protein.
The HGXPRTase from Tritrichomonas foetus was characterized using site-directed mutagenesis and the conserved Lys134 was proven to be the primary determinant in conferring the specificity of the enzyme toward 6-oxopurines.
The purine nucleoside phosphorylase from Trichomonas vaginalis is a homologue of the bacterial enzyme.
The catalytic efficiency of this enzyme with adenine as substrate is 58-fold higher than that with either hypoxanthine or guanine, representing a distinct disparity with the mammalian PNPs, which have negligible activity with eitherAdenine or adenosine.
Converting the Guanine Phosphoribosyltransferase from Giardia lamblia to a Hypoxanthine-guanine Phosphoribosyltransferase*
- N. Munagala, A. Sarver, C. Wang
- Biology, ChemistryThe Journal of Biological Chemistry
- 24 November 2000
By characterizing specifically designed site-specific mutants of GPRTase, essential moieties in the active site for substrate binding were identified and by increasing the binding affinity of 6-oxopurine, it was able to convert the G PRTase to a HGPRTases.
Steady-state kinetics of the hypoxanthine-guanine-xanthine phosphoribosyltransferase from Tritrichomonas foetus: the role of threonine-47.
The lack of ionic interactions between Thr-47 and PPi and an increased distance between the loop and the active site as compared to the human HGPRTase are proposed to be responsible for the high Km for PPi in the T. foetus HGXPRT enzyme-catalyzed reaction.
Rational design of novel antimicrobials: blocking purine salvage in a parasitic protozoan.
Rationally targeting an essential enzyme in a parasitic organism has yielded specific enzyme inhibitors capable of suppressing that parasite's growth.