Structure–activity relationships of carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase

Kim, Young Ah; Rawal, Ravindra K.; Yoo, Jakyung; Sharon, Ashoke; Jha, Anal K.; Chu, Chung K.; Rais, Reem H.; Safarjalani, Omar N. Al; Naguib, Fardos N.M.; Kouni, Mahmoud H. el

doi:10.1016/j.bmc.2010.04.003

Cited by 17 publications

(20 citation statements)

References 34 publications

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“…However, the enzyme can also phosphorylate several 6- and 7-substituted Ado and inosine analogues to their respective 5′-monophosphate derivatives (Al Safarjalani et al, 2003, 2008 and 2010, Darling et al, 1999, el Kouni, 2003 and 2007, el Kouni et al, 1999, Iltzsch et al, 1995, Kim et al, 2008 and 2010, Rais et al, 2005 and Yadav et al, 2004). Thus, TgAK is not strictly specific for Ado.…”

Section: Resultsmentioning

confidence: 99%

“…TgAK does not phosphorylate any of the natural purine nucleosides other than Ado (el Kouni et al, 1999, Iltzsch et al, 1995 and Krug et al, 1989). However, TgAK, unlike human Ado kinase, can phosphorylate various 6-substituted-9-β-D-ribofuranosylpurine analogues to their respective nucleoside 5′-monophosphates (Al Safarjalani et al, 2003, 2008 and 2010, Darling et al, 1999, el Kouni, 2003 and 2007, el Kouni et al, 1999, Iltzsch et al, 1995, Kim et al, 2008 and 2010, Rais et al, 2005 and Yadav et al, 2004). When certain 6-substituted-9-β-D-ribofuranosylpurine analogues are used as subversive substrates they are selectively phosphorylated by TgAK and become toxic only against the parasites but not their host (Al Safarjalani et al, 2008 and 2010, el Kouni, 2003 and 2007, el Kouni et al, 1999, Rais et al, 2005 and Yadav et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Kinetic mechanism of Toxoplasma gondii adenosine kinase and the highly efficient utilization of adenosine

Naguib

Rais

Safarjalani

et al. 2015

Comparative Biochemistry and Physiology Part B: Biochemistry an

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Toxoplasma gondii has an extraordinarily ability to utilize adenosine (Ado) as the primary source of all necessary purines in this parasite which lacks de novo purine biosynthesis. The activity of T. gondii adenosine kinase (TgAK, EC 2.7.1.20) is responsible for this efficient salvage of Ado in T. gondii. To fully understand this remarkable efficiency of TgAK in the utilization of Ado, complete kinetic parameters of this enzyme are necessary. Initial velocity and product inhibition studies of TgAK demonstrated that the basic mechanism of this enzyme is a hybrid random bi-uni ping-pong uni-bi. Initial velocity studies showed an intersecting pattern, consistent with substrate-enzyme-co-substrate complex formation and a binding pattern indicating that binding of the substrate interferes with the binding of the co-substrate and vice versa. Estimated kinetic parameters were KAdo = 0.002 ± 0.0002 mM, KATP = 0.05 ± 0.008 mM, and Vmax = 920 ± 35 μmol/min/mg protein. Ado exhibited substrate inhibition suggesting the presence of more than one binding site for Ado on the enzyme. ATP relieved substrate inhibition by Ado. Thus, Ado also binds to the ATP binding site. AMP was competitive with ATP, inferring that AMP binds to the same site as ATP. AMP, ADP and ATP were non-competitive with Ado, therefore, none of these nucleotides binds to the Ado binding site. Combining ATP with ADP was additive. Therefore, the binding of either ATP or ADP does not interfere with the binding of the other. It is concluded that for every ATP consumed, TgAK generates three new AMPs. These findings along with the fact that a wide range of nucleoside 5′-mono, di, and triphosphates could substitute for ATP as phosphate donors in this reaction may explain the efficient and central role played by TgAK in the utilization of Ado as the major source from which all other purines can be synthesized in T. gondii.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kinetic mechanism of Toxoplasma gondii adenosine kinase and the highly efficient utilization of adenosine

Naguib

Rais

Safarjalani

et al. 2015

Comparative Biochemistry and Physiology Part B: Biochemistry an

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“…Inosine-5=-monophosphate dehydrogenase, an important component of guanine synthesis, is inhibited by phthalazinones (40) through interaction at the NAD binding site (41). Additionally, parasite adenosine kinase, used in purine incorporation, binds 6-benzylthioinosine analogues as subversive substrates (42).…”

Section: Compounds With Proposed Modes Of Actionmentioning

confidence: 99%

Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

McFarland

Zach

Wang

et al. 2016

Antimicrob Agents Chemother

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Toxoplasma gondii is a ubiquitous apicomplexan parasite capable of infecting humans and other animals. Current treatment options for T. gondii infection are limited and most have drawbacks, including high toxicity and low tolerability. Additionally, no FDA-approved treatments are available for pregnant women, a high-risk population due to transplacental infection. Therefore, the development of novel treatment options is needed. To aid this effort, this review highlights experimental compounds that, at a minimum, demonstrate inhibition of in vitro growth of T. gondii. When available, host cell toxicity and in vivo data are also discussed. The purpose of this review is to facilitate additional development of anti-Toxoplasma compounds and potentially to extend our knowledge of the parasite.

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“…Structure-activity relationships [23-26], biochemical [24-31], metabolic [19,27-31], and molecular [32] investigations have demonstrated that the substrate specificity, as well as other characteristics of T. gondii adenosine kinase, differs significantly from those of the human enzyme, and have established the enzyme as an excellent potential chemotherapeutic target for the treatment of toxoplasmosis [19,20]. It was also demonstrated that 6-benzylthioinosine, among other 6-substituted purine nucleoside analogues, is a substrate for the parasite, but not human adenosine kinase [19,23,27-29].…”

Section: Introductionmentioning

confidence: 99%

Carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase: Biological activities and selective toxicities

Safarjalani

Rais

Kim

et al. 2010

Biochemical Pharmacology

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Toxoplasma gondii adenosine kinase (EC.2.7.1.20) is the major route of adenosine metabolism in this parasite. The enzyme is significantly more active than any other enzyme of the purine salvage in T. gondii and has been established as a potential chemotherapeutic target for the treatment of toxoplasmosis. Several 6-benzylthioinosines have already been identified as subversive substrates of the T. gondii but not human adenosine kinase. Therefore, these compounds are preferentially metabolized to their respective nucleotides and become selectively toxic against the parasites but not its host. In the present study, we report the testing of the metabolism of several carbocyclic 6-benzylthioinosines, as well as their efficacy as anti-toxoplasmic agents in cell culture. All the carbocyclic 6-benzylthioinosine analogues were metabolized to their 5'-monophosphate derivatives, albeit to different degrees. These results indicate that these compounds are not only ligands but also substrates of T. gondii adenosine kinase. All the carbocyclic 6-benzylthioinosine analogues showed a selective anti-toxoplasmic effect against wild type parasites, but not mutants lacking adenosine kinase. These results indicate that the oxygen atom of the sugar is not critical for substrate-binding. The efficacy of these compounds varied with the position and nature of the substitution on their phenyl ring. Moreover, none of these analogues exhibited host toxicity. The best compounds were carbocyclic 6-(p-methylbenzylthio)inosine (IC50 = 11.9 μM), carbocyclic 6-(p-methoxybenzylthio)inosine (IC50 = 12.1 μM), and carbocyclic 6-(p-methoxycarbonylbenzylthio)inosine ( IC50 = 12.8 μM). These compounds have about a 1.5-fold better efficacy relative to their corresponding 6-benzylthioinosine analogues (Rais et al., Biochem Pharmacol 2005;69:1409-19). The results further confirm that T. gondii adenosine kinase is an excellent target for chemotherapy and that carbocyclic 6-benzylthioinosines are potential antitoxoplasmic agents.

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Structure–activity relationships of carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase

Cited by 17 publications

References 34 publications

Kinetic mechanism of Toxoplasma gondii adenosine kinase and the highly efficient utilization of adenosine

Kinetic mechanism of Toxoplasma gondii adenosine kinase and the highly efficient utilization of adenosine

Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

Carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase: Biological activities and selective toxicities

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