Purine salvage networks in Giardia lamblia.

Wang, Ching Chung; Aldritt, S M

doi:10.1084/jem.158.5.1703

Cited by 77 publications

(36 citation statements)

References 16 publications

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“…Studies of purine metabolism using radiolabeled precursors have demonstrated the incorporation of adenine, adenosine, guanine, and guanosine into nucleotides but no incorporation of components of the de novo synthetic pathway, such as formate, glycine, hypoxanthine, inosine, or xanthine (23,224,339). The likely scenario is that the purine nucleosides (adenosine and guanosine) are imported by a transporter with broad specificity for nucleosides as well as deoxyribonucleosides (19,63).…”

Section: Purine and Pyrimidine Salvagementioning

confidence: 99%

“…Many of the pathogenic protozoa, including G. lamblia (339), depend on salvage pathways for obtaining purine nucleosides. In addition, G. lamblia (13), as well as T. vaginalis (340) and Tritrichomonas foetus (341), lack pyrimidine synthetic pathways and depends on salvage pathways for obtaining both purine and pyrimidine nucleosides.…”

Section: Purine and Pyrimidine Salvagementioning

confidence: 99%

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Biology ofGiardia lamblia

2001

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Giardia lamblia is a common cause of diarrhea in humans and other mammals throughout the world. It can be distinguished from other Giardia species by light or electron microscopy. The two major genotypes of G. lamblia that infect humans are so different genetically and biologically that they may warrant separate species or subspecies designations. Trophozoites have nuclei and a well-developed cytoskeleton but lack mitochondria, peroxisomes, and the components of oxidative phosphorylation. They have an endomembrane system with at least some characteristics of the Golgi complex and encoplasmic reticulum, which becomes more extensive in encysting organisms. The primitive nature of the organelles and metabolism, as well as small-subunit rRNA phylogeny, has led to the proposal that Giardia spp. are among the most primitive eukaryotes. G. lamblia probably has a ploidy of 4 and a genome size of approximately 10 to 12 Mb divided among five chromosomes. Most genes have short 5′ and 3′ untranslated regions and promoter regions that are near the initiation codon. Trophozoites exhibit antigenic variation of an extensive repertoire of cysteine-rich variant-specific surface proteins. Expression is allele specific, and changes in expression from one vsp gene to another have not been associated with sequence alterations or gene rearrangements. The Giardia genome project promises to greatly increase our understanding of this interesting and enigmatic organism

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Section: Purine and Pyrimidine Salvagementioning

confidence: 99%

Section: Purine and Pyrimidine Salvagementioning

confidence: 99%

Biology ofGiardia lamblia

2001

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“…Adenine PRT and guanine PRT (GPRT) catalyze the synthesis of AMP and GMP, respectively. Due to a lack of interconversion between the two purine nucleotide pools, either of the two enzymes could serve as a potential target for giardiasis chemotherapy (33).…”

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confidence: 99%

Virtual Screening of Combinatorial Libraries across a Gene Family: in Search of Inhibitors of Giardia lamblia Guanine Phosphoribosyltransferase

Aronov

Munagala

Kuntz

et al. 2001

Antimicrob Agents Chemother

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Parasitic protozoa lack the ability to synthesize purine nucleotides de novo, relying instead on purine salvage enzymes for their survival. Guanine phosphoribosyltransferase (GPRT) from the protozoan parasite Giardia lamblia is a potential target for rational antiparasitic drug design, based on the experimental evidence, which indicates the lack of interconversion between adenine and guanine nucleotide pools. The present study is a continuation of our efforts to use three-dimensional structures of parasitic phosphoribosyltransferases (PRTs) to design novel antiparasitic agents. Two micromolar phthalimide-based GPRT inhibitors were identified by screening the in-house phthalimide library. A combination of structure-based scaffold selection using virtual library screening across the PRT gene family and solid phase library synthesis led to identification of smaller (molecular weight, <300) ligands with moderate to low specificity for GPRT; the best inhibitors, GP3 and GP5, had K i values in the 23 to 25 M range. These results represent significant progress toward the goal of designing potent inhibitors of purine salvage in Giardia parasites. 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.Computer-aided drug design in combination with combinatorial chemistry approaches, whereby focused or diverse combinatorial libraries can be designed using computational methods, is becoming increasingly important in the process of drug discovery for parasitic targets (7,11). A number of groups have reported on the successful design of inhibitors directed against trypanosomal (2,4,(15)(16), leishmanial (6), malarial (19), and tritrichomonal (3, 27) targets active in the 10 nM to 50 M range. However, with the number of compounds that could be generated by combinatorial chemistry growing exponentially, it has become apparent that chemical diversity has surpassed the capacity of high-throughput screening. In the case of antiparasitics research, which is concentrated in a limited number of mostly academic labs, the need for more rapid ligand screening tools has become apparent. Recently, in silico methods for database screening have come to the forefront of drug discovery (30). By accelerating the screening process, these methods are able to capitalize on the potential of virtual combinatorial libraries. While a number of recent reports have focused on structure-based pruning of the virtual combinatorial libraries built around a given preselected scaffold, there has been a growing trend toward combinatorial scaffold evaluation against a number of biological targets. Evaluation of binding preferences for combinatorial libraries across a range of targets could, in principle, provide information about scaffold generality or selectivity as related to the target selection (M. L. Lamb, K. W. Burdick, S. Toba, M. M. Young, A. G. Skillman, X. Zou, J. R. Arnold, and I. D. Kuntz, unpubl...

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“…In Giardia, hydrolysis of exogenous nucleosides by NH has been previously described as the first step of one of two distinct salvage pathways to form purine (see e.g. Wang & Aldritt, 1983;Aldritt & Wang, 1986) and pyrimidine ribonucleotides (Aldritt et al, 1985; for review see Jarroll et al, 1989). Moreover, a low-affinity transporter for purine nucleobases has been described as a potential adenine and guanine donor for the second salvage pathway (Ey et al, 1992).…”

Section: Discussionmentioning

confidence: 99%