Adenosine cycle in African trypanosomes

Ogbunude, P. O. J.; Ikediobi, Christopher O.; Ukoha, A. I.

doi:10.1080/00034983.1985.11811883

Cited by 17 publications

(18 citation statements)

References 15 publications

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“…Based on AMP production assays with cell extracts, bloodstream-form T. brucei was even suggested to lack adenosine kinase (40). On the other hand, adenosine was reported to be the preferred purine nucleoside for salvage by trypanosomes (26).…”

Section: Discussionmentioning

confidence: 99%

“…Homozygous disruption of TbAT1 in T. brucei bloodstream forms caused resistance to melarsoprol, diamidines, cordyce-pin, and tubercidin (21,35). Cordycepin was found to be a potent and selective trypanocide in vitro (34,53) but not in vivo (40). However, when cordycepin was coadministered with an adenosine deaminase inhibitor to prevent it from being converted to 3Ј-deoxyinosine in plasma (44), it cured T. bruceiinfected mice even from (supposedly) late-stage trypanosomiasis (45).…”

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confidence: 99%

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Adenosine Kinase ofTrypanosoma bruceiand Its Role in Susceptibility to Adenosine Antimetabolites

Lüscher

Önal

Schweingruber

et al. 2007

Antimicrob Agents Chemother

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Trypanosoma brucei cannot synthesize purines de novo and relies on purine salvage from its hosts to build nucleic acids. With adenosine being a preferred purine source of bloodstream-form trypanosomes, adenosine kinase (AK; EC 2.7.1.20) is likely to be a key player in purine salvage. Adenosine kinase is also of high pharmacological interest, since for many adenosine antimetabolites, phosphorylation is a prerequisite for activity. Here, we cloned and functionally characterized adenosine kinase from T. brucei (TbAK). TbAK is a tandem gene, expressed in both procyclic-and bloodstream-form trypanosomes, whose product localized to the cytosol of the parasites. The RNA interference-mediated silencing of TbAK suggested that the gene is nonessential under standard growth conditions. Inhibition or downregulation of TbAK rendered the trypanosomes resistant to cordycepin (3-deoxyadenosine), demonstrating a role for TbAK in the activation of adenosine antimetabolites. The expression of TbAK in Saccharomyces cerevisiae complemented a null mutation in the adenosine kinase gene ado1. The concomitant expression of TbAK with the T. brucei adenosine transporter gene TbAT1 allowed S. cerevisiae ado1 ade2 double mutants to grow on adenosine as the sole purine source and, at the same time, sensitized them to adenosine antimetabolites. The coexpression of TbAK and TbAT1 in S. cerevisiae ado1 ade2 double mutants proved to be a convenient tool for testing nucleoside analogues for uptake and activation by T. brucei adenosine salvage enzymes.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Adenosine Kinase ofTrypanosoma bruceiand Its Role in Susceptibility to Adenosine Antimetabolites

Lüscher

Önal

Schweingruber

et al. 2007

Antimicrob Agents Chemother

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“…Alternatively, the inability of NBMPR-P and NBMPR to interfere with the uptake of tubercidin in schistosomes may arise from differences in the mechanism of nucleoside transport between the schistosomes and their host. Recently, the combination of NBMPR-P plus tubercidin was successfully used for the treatment of Trypanosoma gambiense-infected mice (15). Highly selective toxicity against the parasite was achieved.…”

Section: Discussionmentioning

confidence: 99%

Combination therapy of schistosomiasis by tubercidin and nitrobenzylthioinosine 5'-monophosphate.

Kouni¹,

Diop²,

Cha³

1983

Proc. Natl. Acad. Sci. U.S.A.

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Nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) inhibits the transport of nucleosides, including tubercidin, in mammalian systems but not in Schistosoma mansoni. Administration of NBMPR-P with high doses of tubercidin (lethal doses if injected alone) by intraperitoneal injection into S. mansoni-infected mice was highly toxic to the parasite but not to the host. Combination therapy resulted in a striking decrease in the number and copulation of worms. The few worms that could be found were so stunted that it was difficult to identify their sex. Mice receiving the combination of tubercidin plus NBMPR-P appeared healthy and had normal-sized livers and spleens. Combination therapy also caused a drastic decrease in the number of eggs in the liver (from 32,500 to 1,800 eggs per liver) and in the intestine (from 1,295 to 2 eggs per cm2). All eggs found were dead, indicating the termination of oviposition. Very few granulomas were detected in livers of treated animals. Sections of these livers showed lesions containing dead worms and what appeared to be a process of regeneration of normal tissue around old granulomas. Thus, combination therapy reduced the number and the progress of the primary pathological lesions associated with schistosomiasis. These results demonstrate that through combination therapy, highly selective toxicity against a parasite can be achieved. The effectiveness, simplicity, and practicality of host protection afforded by this method may yield a promising chemotherapeutic approach for the treatment of schistosomiasis and other parasitic diseases.

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“…Nucleoside hydrolases play a key role in the purine salvage pathway of protozoan parasites. This salvage pathway is vital for these organisms because they lack a de novo purine biosynthesis pathway (5)(6)(7). Since neither nucleoside hydrolase activity, nor the encoding genes, have been found in mammals they constitute an attractive target for drug design against a variety of pathogens.…”

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Enzyme-Substrate Interactions in the Purine-specific Nucleoside Hydrolase from Trypanosoma vivax

Versées

Decanniere

Holsbeke

et al. 2002

Journal of Biological Chemistry

131

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Nucleoside hydrolases are key enzymes in the purine salvage pathway of Trypanosomatidae and are considered as targets for drug design. We previously reported the first x-ray structure of an inosine-adenosineguanosine preferring nucleoside hydrolase (IAG-NH) from Trypanosoma vivax (1). Here we report the 2.0-Å crystal structure of the slow D10A mutant in complex with the inhibitor 3-deaza-adenosine and the 1.6-Å crystal structure of the same enzyme in complex with a genuine substrate inosine. The enzyme-substrate complex shows the substrate bound to the enzyme in a different conformation from 3-deaza-adenosine and provides a snapshot along the reaction coordinate of the enzyme-catalyzed reaction. The chemical groups on the substrate important for binding and catalysis are mapped. The 2-OH, 3-OH, and 5-OH contribute 4.6, 7.5, and 5.4 kcal/mol to k cat /K m , respectively. Specific interactions with the exocyclic groups on the purine ring are not required for catalysis. Site-directed mutagenesis indicates that the purine specificity of the IAG-NHs is imposed by a parallel aromatic stacking interaction involving Trp 83 and Trp 260. The pH profiles of k cat and k cat /K m indicate the existence of one or more proton donors, possibly involved in leaving group activation. However, mutagenesis of the active site residues around the nucleoside base and an alanine scan of a flexible loop near the active site fail to identify this general acid. The parallel aromatic stacking seems to provide the most likely alternative mechanism for leaving group activation.

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Adenosine cycle in African trypanosomes

Cited by 17 publications

References 15 publications

Adenosine Kinase ofTrypanosoma bruceiand Its Role in Susceptibility to Adenosine Antimetabolites

Adenosine Kinase ofTrypanosoma bruceiand Its Role in Susceptibility to Adenosine Antimetabolites

Combination therapy of schistosomiasis by tubercidin and nitrobenzylthioinosine 5'-monophosphate.

Enzyme-Substrate Interactions in the Purine-specific Nucleoside Hydrolase from Trypanosoma vivax

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