Ornithine decarboxylase and S-adenosylmethionine decarboxylase in trypanosomatids

Persson, Lo

doi:10.1042/bst0350314

Cited by 10 publications

(5 citation statements)

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“…This additional internal source of Spd may further decrease the control exerted by SpdT. Furthermore, de novo Spd synthesis from ornithine is possible in T. brucei and Leishmania [9,70]; hence, redistribution of the control coefficients is expected in these trypanosomatids.…”

Section: Discussionmentioning

confidence: 99%

“…Spd can be de novo synthesized by spermidine synthase (SpdS, http://www.chem.qmul.ac.uk/iubmb/enzyme/EC2/5/1/16.html) from putrescine (Put) and decarboxylated‐ S ‐adenosyl methionine (dAdoMet); SpdS has only been kinetically characterized in T. brucei [83], although the corresponding gene is found in the T. cruzi genome. dAdoMet is synthesized from S ‐adenosylmethione (AdoMet) by S ‐adenosylmethionine decarboxylase (AdoMetDC, http://www.chem.qmul.ac.uk/iubmb/enzyme/EC4/1/1/50.html), an enzyme that has been characterized in the three trypanosomatid species ( T. cruzi , T. brucei and Leishmania ) [70]. In T. brucei and Leishmania , Put can be de novo synthesized by ornithine decarboxylase (ODC, http://www.chem.qmul.ac.uk/iubmb/enzyme/EC4/1/1/17.html) [70]; Leishmania can also take up Put from the medium using diamine transporters [84].…”

Section: Introductionmentioning

confidence: 99%

“…dAdoMet is synthesized from S ‐adenosylmethione (AdoMet) by S ‐adenosylmethionine decarboxylase (AdoMetDC, http://www.chem.qmul.ac.uk/iubmb/enzyme/EC4/1/1/50.html), an enzyme that has been characterized in the three trypanosomatid species ( T. cruzi , T. brucei and Leishmania ) [70]. In T. brucei and Leishmania , Put can be de novo synthesized by ornithine decarboxylase (ODC, http://www.chem.qmul.ac.uk/iubmb/enzyme/EC4/1/1/17.html) [70]; Leishmania can also take up Put from the medium using diamine transporters [84]. T. cruzi lacks ODC activity, and therefore relies on transport of Put and Spd from the extracellular environment by high affinity and catalytically efficient diamine/polyamine transporters [65–68].…”

Section: Introductionmentioning

confidence: 99%

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Drug target validation of the trypanothione pathway enzymes through metabolic modelling

et al. 2012

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A kinetic model of trypanothione [T(SH) 2 ] metabolism in Trypanosoma cruzi was constructed based on enzyme kinetic parameters determined under near-physiological conditions (including glutathione synthetase), and the enzyme activities, metabolite concentrations and fluxes determined in the parasite under control and oxidizing conditions. The pathway structure is characterized by a T(SH) 2 synthetic module of low flux and low catalytic capacity, and another more catalytically efficient T(SH) 2 -dependent antioxidant ⁄ regenerating module. The model allowed quantification of the contribution of each enzyme to the control of T(SH) 2 synthesis and concentration (flux control and concentration control coefficients, respectively). The main control of flux was exerted by c-glutamylcysteine synthetase (cECS) and trypanothione synthetase (TryS) (control coefficients of 0.58-0.7 and 0.49-0.58, respectively), followed by spermidine transport (0.24); negligible flux controls by trypantothione reductase (TryR) and the T(SH) 2 -dependent antioxidant machinery were determined. The concentration of reduced T(SH) 2 was controlled by TryR (0.98) and oxidative stress ()0.99); however, cECS and TryS also exerted control on the cellular level of T(SH 2 ) when they were inhibited by more than 70%. The model predicted that in order to diminish the T(SH) 2 synthesis flux by 50%, it is necessary to inhibit cECS or TryS by 58 or 63%, respectively, or both by 50%, whereas more than 98% inhibition was required for TryR. Hence, simultaneous and moderate inhibition of cECS and TryS appears to be a promising multi-target therapeutic strategy. In contrast, use of highly potent and specific inhibitors for TryR and the antioxidant machinery is necessary to affect the antioxidant capabilities of the parasites. DatabaseThe glutathione synthetase gene sequences from the Ninoa and Queretaro strains have been submitted to the GenBank database under accession numbers HQ398240 and HQ398239, respectively Abbreviations

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Drug target validation of the trypanothione pathway enzymes through metabolic modelling

et al. 2012

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“…ADOMETDC expression in mammals is highly regulated by polyamine levels in the cell and putrescine stimulates both the cleavage and the enzymatic activity of the enzyme [ 60 , 163 , 164 , 165 ]. The ADOMETDC cleavage and activation site, Glu-Ser-Ser, is conserved among trypanosomatid ADOMETDC sequences [ 166 , 167 ]; however, unlike in mammalian cells, putrescine does not stimulate ADOMETDC processing in trypanosomatids. Putrescine stimulates the activity of the ADOMETDC/prozyme complex in T. cruzi but not in T. brucei [ 168 ].…”

Section: S -Adenosylmethionine Decarboxylase (Adometdc)mentioning

confidence: 99%

Polyamine Metabolism in Leishmania Parasites: A Promising Therapeutic Target

Carter¹,

Kawasaki²,

Nahata³

et al. 2022

Medical Sciences

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Parasites of the genus Leishmania cause a variety of devastating and often fatal diseases in humans and domestic animals worldwide. The need for new therapeutic strategies is urgent because no vaccine is available, and treatment options are limited due to a lack of specificity and the emergence of drug resistance. Polyamines are metabolites that play a central role in rapidly proliferating cells, and recent studies have highlighted their critical nature in Leishmania. Numerous studies using a variety of inhibitors as well as gene deletion mutants have elucidated the pathway and routes of transport, revealing unique aspects of polyamine metabolism in Leishmania parasites. These studies have also shed light on the significance of polyamines for parasite proliferation, infectivity, and host–parasite interactions. This comprehensive review article focuses on the main polyamine biosynthetic enzymes: ornithine decarboxylase, S-adenosylmethionine decarboxylase, and spermidine synthase, and it emphasizes recent discoveries that advance these enzymes as potential therapeutic targets against Leishmania parasites.

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“…The decarboxylated S-adenosylmethionine (dAdoMet) donates an aminopropyl group to putrescine to form spermidine. This reaction is catalyzed by spermidine synthase (SpdS) [5].…”

Section: Introductionmentioning

confidence: 99%

In vitro antileishmanial activity of fisetin flavonoid via inhibition of glutathione biosynthesis and arginase activity in Leishmania infantum

Adinehbeigi

Jalali

Shahriari

et al. 2017

Pathogens and Global Health

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With the increasing emergence of drug resistant Leishmania sp. in recent years, combination therapy has been considered as a useful way to treat and control of Leishmaniasis. The present study was designed to evaluate the antileishmanial effects of the fisetin alone and combination of fisetin plus Meglumine antimoniate (Fi-MA) against Leishmania infantum. The IC50 values for fisetin were obtained 0.283 and 0.102 μM against promastigotes and amastigote forms, respectively. Meglumine antimoniate (MA, Glucantime) as control drug also revealed IC50 values of 0.247 and 0.105 μM for promastigotes and amastigotes of L. infantum, respectively. In order to determine the mode of action of fisetin and Meglumine antimoniate (MA, Glucantime), the activities of arginase (ARG), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) were measured. Moreover, intracellular glutathione (GSH) and nitric oxide (NO) levels in L. infantum-infected macrophages and L. infantum promastigotes which were treated with IC50 concentrations of fisetin, MA and Fi-MA were investigated. Our results showed that MA decreased CAT and SOD activity and increased NO levels in L. infantum-infected macrophages. In promastigotes, MA inhibited parasite SOD activity and reduced parasite NO production. The decreased levels of most of the antioxidant enzymes, accompanying by the raised level of NO in treated macrophages with MA, were observed to regain their normal profiles due to Fi-MA treatment. Furthermore, fisetin could prevent the growth of promastigotes by inhibition of ARG activity and reduction of GSH levels and NO production. In conclusion, these findings showed that fisetin improves MA side effects.

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Ornithine decarboxylase and S-adenosylmethionine decarboxylase in trypanosomatids

Cited by 10 publications

References 50 publications

Drug target validation of the trypanothione pathway enzymes through metabolic modelling

Drug target validation of the trypanothione pathway enzymes through metabolic modelling

Polyamine Metabolism in Leishmania Parasites: A Promising Therapeutic Target

In vitro antileishmanial activity of fisetin flavonoid via inhibition of glutathione biosynthesis and arginase activity in Leishmania infantum

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