Purification, kinetics and inhibition by antimonials of recombinant phosphofructokinase from Schistosoma mansoni

Su, Jyan-Gwo J.; Mansour, Joan M.; Mansour, Tag E.

doi:10.1016/0166-6851(96)02702-8

Cited by 19 publications

(15 citation statements)

References 10 publications

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“…Phosphofuctokinase from mammalian tissues are considered to be less sensitive to antimony inhibition than that from parasites be- cause IC 50 for rat brain and sheep heart are 4 mM and k1 mM, respectively, while that for Schistosomal Mansoni is 0.02 mM (14,15). It is clear from the present study that PFK from rat erythrocytes, with an IC 50 of 0.02 mM for Sb, is as sensitive toward antimony inhibition as that isolated from helminthic parasites.…”

Section: Discussionmentioning

confidence: 62%

“…Data on the biochemical effects of antimony available to date are almost exclusively related to their anthelminthic function, which was attributed to their potent inhibitory action on helminthic PFK and hence the glycolytic pathway (14)(15)(16). Phosphofuctokinase from mammalian tissues are considered to be less sensitive to antimony inhibition than that from parasites be- cause IC 50 for rat brain and sheep heart are 4 mM and k1 mM, respectively, while that for Schistosomal Mansoni is 0.02 mM (14,15).…”

Section: Discussionmentioning

confidence: 99%

“…Biochemical studies of antimony compounds were focused on their inhibitory actions of PFK and other glycolytic enzymes of the helminthic parasites (14,15). Mammalian PFK is considered to be much less susceptible to antimony inhibition (15,16). The accumulation of trivalent antimonial compounds in erythrocytes suggested that they may exert an effect on enzymes controlling key metabolic functions.…”

Section: Introductionmentioning

confidence: 99%

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Effects of potassium antimony tartrate on rat erythrocyte phosphofructokinase activity

Poon

Chu

1998

J. Biochem. Mol. Toxicol.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of potassium antimony tartrate on rat erythrocyte phosphofructokinase activity

Poon

Chu

1998

J. Biochem. Mol. Toxicol.

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“…Antimony potassium tartrate was first administered to patients infected with S. haematobium in 1917 (14) and antimonials were the mainstay of schistosomiasis treatment until the introduction of praziquantel in the 1980s. Initially, the antischistosomal activity of antimony potassium tartrate was proposed to be due to the inhibition of phosphofructokinase (55). However, the inhibition of TGR (iC50 = 50 nM) by antimony potassium tartrate is three orders of magnitude lower than that for phosphofructokinase (iC50 = 16 lM), suggesting that its chemotherapeutic action is more likely to occur through inhibition of TGR.…”

Section: Williams Et Almentioning

confidence: 98%

Thioredoxin Glutathione Reductase-Dependent Redox Networks in Platyhelminth Parasites

Williams

Bonilla²,

Gladyshev³

et al. 2013

Antioxidants & Redox Signaling

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Significance: Platyhelminth parasites cause chronic infections that are a major cause of disability, mortality, and economic losses in developing countries. Maintaining redox homeostasis is a major adaptive problem faced by parasites and its disruption can shift the biochemical balance toward the host. Platyhelminth parasites possess a streamlined thiol-based redox system in which a single enzyme, thioredoxin glutathione reductase (TGR), a fusion of a glutaredoxin (Grx) domain to canonical thioredoxin reductase (TR) domains, supplies electrons to oxidized glutathione (GSSG) and thioredoxin (Trx). TGR has been validated as a drug target for schistosomiasis. Recent Advances: In addition to glutathione (GSH) and Trx reduction, TGR supports GSH-independent deglutathionylation conferring an additional advantage to the TGR redox array. Biochemical and structural studies have shown that the TR activity does not require the Grx domain, while the glutathione reductase and deglutathionylase activities depend on the Grx domain, which receives electrons from the TR domains. The search for TGR inhibitors has identified promising drug leads, notably oxadiazole N-oxides. Critical Issues: A conspicuous feature of platyhelminth TGRs is that their Grx-dependent activities are temporarily inhibited at high GSSG concentrations. The mechanism underlying the phenomenon and its biological relevance are not completely understood. Future Directions: The functional diversity of Trxs and Grxs encoded in platyhelminth genomes remains to be further assessed to thoroughly understand the TGR-dependent redox network. Optimization of TGR inhibitors and identification of compounds targeting other parasite redox enzymes are good options to clinically develop relevant drugs for these neglected, but important diseases. Antioxid. Redox Signal. 19,[735][736][737][738][739][740][741][742][743][744][745]

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“…These trivalent organic antimonials (e.g. Stibophen, Scheme 1) target the glycolytic enzyme phosphofructokinase (PFK, EC 2.7.1.11) [41,42]. A similar mechanism, combined with inhibition of a second enzyme, aldolase occurs in filarial worms [43].…”

Section: The Potentials and Pitfalls Of Targeting Metabolic Enzymesmentioning

confidence: 99%

Metabolic enzymes of helminth parasites: potential as drug targets

Timson¹

2015

CPPS

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Metabolic pathways which extract energy from carbon compounds are essential for an organism's survival. Therefore, inhibition of enzymes in these pathways represents a potential therapeutic strategy to combat parasitic infections. However, the high degree of similarity between host and parasite enzymes makes this strategy potentially difficult. Nevertheless, several existing drugs to treat infections by parasitic helminths (worms) target metabolic enzymes. These include the trivalent antimonials which target phosphofructokinase and Clorsulon which targets phosphoglycerate mutase and phosphoglycerate kinase. Glycolytic enzymes from a variety of helminths have been characterised biochemically, and some inhibitors identified. To date none of these inhibitors have been developed into therapies. Many of these enzymes are externalised from the parasite and so are also of interest in the development of potential vaccines. Less work has been done on tricarboxylic acid cycle enzymes and oxidative phosphorylation complexes. Again, while some inhibitors have been identified none have been developed into drug-like molecules. Barriers to the development of novel drugs targeting metabolic enzymes include the lack of experimentally determined structures of helminth enzymes, lack of direct proof that the enzymes are vital in the parasites and lack of cell culture systems for many helminth species. Nevertheless, the success of Clorsulon (which discriminates between highly similar host and parasite enzymes) should inspire us to consider making serious efforts to discover novel anthelminthics which target metabolic enzymes.

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Purification, kinetics and inhibition by antimonials of recombinant phosphofructokinase from Schistosoma mansoni

Cited by 19 publications

References 10 publications

Effects of potassium antimony tartrate on rat erythrocyte phosphofructokinase activity

Effects of potassium antimony tartrate on rat erythrocyte phosphofructokinase activity

Thioredoxin Glutathione Reductase-Dependent Redox Networks in Platyhelminth Parasites

Metabolic enzymes of helminth parasites: potential as drug targets

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