THE RELATIONSHIP BETWEEN INHIBITION OF PHOSPHOFRUCTOKINASE ACTIVITY AND THE MODE OF ACTION OF TRIVALENT ORGANIC ANTIMONIALS ON <i>SCHISTOSOMA MANSONI</i>

Bueding, Ernest; Mansour, Joan M.

doi:10.1111/j.1476-5381.1957.tb00114.x

Cited by 57 publications

(23 citation statements)

References 13 publications

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“…Although the primary treatment for schistosomiasis currently is praziquantel, until relatively recently an important treatment option for schistosome infection involved the use of trivalent antimonials, such as PAT (36–39). The cytosolic enzymes phosphofructokinase and thioredoxin glutathione reductase have both been shown to be targets of these antischistosome agents (37, 39, 40). How the drugs enter the schistosomes to effect this inhibition of intracellular enzymes is not known.…”

Section: Discussionmentioning

confidence: 99%

The role of tegumental aquaporin from the human parasitic worm,Schistosoma monsoni, in osmoregulation and drug uptake

Faghiri

Skelly

2009

FASEB j.

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Schistosomes are parasitic platyhelminths that constitute an important public health problem globally. Infection is characterized by the presence of adult worms within the vasculature of their hosts, where they can reside for many years. The worms are covered by an unusual dual lipid bilayer through which they import nutrients. How the parasites import other vital molecules, such as water, is not known. Recent proteomic analysis of the schistosome tegumental membranes revealed the presence of an aquaporin homologue at the host-interactive surface whose cDNA we have cloned and characterized. The cDNA encodes a predicted 304-aa protein (SmAQP) that is found largely in the parasite tegument by immunolocalization and is most highly expressed in the intravascular life stages. Treatment of parasites with short interfering RNAs targeting the SmAQP gene results in potent (>90%) suppression. These suppressed parasites resist swelling when placed in hypotonic medium, unlike their control counterparts, which rapidly double in volume. In addition, SmAQP-suppressed parasites, unlike controls, resist shrinkage when incubated in hyperosmotic solution. While suppressed parasites exhibit lower viability in culture relative to controls and exhibit a stunted appearance following prolonged suppression, they are nonetheless more resistant to killing by the drug potassium antimonyl tartrate (PAT). This is likely because SmAQP acts as a conduit for this drug, as is the case for aquaporins in other systems. These experiments reveal a heretofore unrecognized role of the schistosome tegument in controlling water and drug movement into the parasites and highlight the importance of the tegument in parasite osmoregulation and drug uptake.

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Section: Discussionmentioning

confidence: 99%

The role of tegumental aquaporin from the human parasitic worm,Schistosoma monsoni, in osmoregulation and drug uptake

Faghiri

Skelly

2009

FASEB j.

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“…The first clue on the mode of action of trivalent antimony (SbIII) was provided by Bueding and Mansour (1957) when demonstrating that SbIII inhibit Schistosoma mansoni phosphofructokinase enzymatic activity. Antimony drastically affects glucose metabolism, fatty acid betaoxidation, and ATP formation (Berman et al 1987;1989).…”

Section: Introductionmentioning

confidence: 99%

Leishmania antimony resistance: what we know what we can learn from the field

et al. 2011

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Leishmania is the causative agent of various forms of leishmaniasis, a significant cause of morbidity and mortality. The clinical manifestations of the disease range from self-healing cutaneous and mucocutaneous skin ulcers to a fatal visceral form named visceral leishmaniasis or kala-azar. In the absence of any effective vaccine, the only means to treat and control leishmaniasis is affordable medication. The treatment choice is essentially directed by economic considerations; therefore, for a large majority of countries, chemotherapy relies only on the use of cheaper antimonial compounds. The emergence of antimonial therapy failure in India linked to proven parasite resistance has stressed questions about selective factors as well as transmission risk of drug resistance. Unfortunately, in most parts of the world, the frequency of parasite antimony resistance linked to treatment failure is unknown because of a lack of information on Leishmania antimony susceptibility. This information is crucial for addressing the risk of selection and transmission of drug-resistant parasites, particularly in areas where antimony is the only chemotherapeutic alternative. However, the poor knowledge about factors that favor selection of resistant parasites, the multiplicity of the agents that can play a role in the in vivo antileishmanial activity of antimony, and the lack of a standard protocol to diagnose and survey parasite resistance all contribute to insufficient monitoring of antimony resistance. In this review, we discuss on the factors potentially involved in the selection of antimony resistance in the field and discuss on the methods available for its diagnosis.

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“…Bueding and Mansour found that 10-4 to 1O-3 M (approximately 30 to 300 ,ug/ml) potassium antimony tartrate inhibited Schistosoma mansoni survival and schistosomal phosphofructokinase activity by 50% but poorly inhibited mammalian phosphofructokinase (3,11). Since the product of the phosphofructokinase reaction is the substrate for aldolase and aldolase is the rate-limiting enzyme in S. mansoni glycolysis, the authors reasoned that the mechanisms by which trivalent Sb inhibited schistosomal glycolysis had been elucidated.…”

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confidence: 99%

Biochemical mechanisms of the antileishmanial activity of sodium stibogluconate

Berman¹,

Waddell²,

Hanson³

1985

Antimicrob Agents Chemother

109

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Pentavalent antimonial agents such as sodium stibogluconate (Pentostam; Burroughs Welicome Co., London, United Kingdom) are the drugs of choice for the treatment of leishmaniasis, but their biochemical mechanisms of action are virtually unknown. The viability of Leishmania mexicana (WR 227) promastigotes and amastigotes was decreased 40 to 61% by a 4-h exposure to 500 ji.g of Sb (in the form of stibogluconate) per ml. Such exposure also resulted in a 51 to 65% decrease in incorporation of label into DNA, RNA, and protein; a 56 to 65% decrease in incorporation of label into purine nucleoside triphosphate; and a 34 to 60% increase in incorporation of label into purine nucleoside monophosphate and diphosphate. It is postulated that the apparent decrease in ATP and GTP synthesis from ADP and GDP contributes to decreased macromolecular synthesis and to decreased Leishmania viability. Further experiments suggested that inhibition of glycolysis and the citric acid cycle may partially explain the inability to phosphorylate ADP.Leishmaniasis is initiated when sand flies inject the extracellular promastigote form of the parasite into the skin. Promastigotes are rapidly phagocytized, after which they transform into the intracellular amastigote form. Promastigotes are not seen in clinical lesions; the multiplication of amastigotes within macrophages leads to clinical disease.Pentavalent antimonial agents in the form of sodium stibogluconate (Pentostam; Burroughs Wellcome Co., London, United Kingdom) or meglumine antimonate (Glucantime; Specia, Paris, France) are the primary therapeutic agents for all forms of leishmaniasis (1, 10). Although some form of antimony may have been in use for leishmaniasis since the days of the ancient Greeks (16) and the present formulations were developed in the 1940s, the biochemical mechanisms of the antileishmanial activity of antimony are virtually uninvestigated.Until recently, trivalent antimonial agents were used clinically for schistosomiasis. Bueding and Mansour found that 10-4 to 1O-3 M (approximately 30 to 300 ,ug/ml) potassium antimony tartrate inhibited Schistosoma mansoni survival and schistosomal phosphofructokinase activity by 50% but poorly inhibited mammalian phosphofructokinase (3,11). Since the product of the phosphofructokinase reaction is the substrate for aldolase and aldolase is the rate-limiting enzyme in S. mansoni glycolysis, the authors reasoned that the mechanisms by which trivalent Sb inhibited schistosomal glycolysis had been elucidated. They also hypothesized that such inhibition of glycolysis might be the mechanism for the antischistosomal activity of the drug and for the greater toxicity of Sb to schistosoma than to mammalian cells.We are not aware of a systematic evaluation of the effect of antimonial agents on leishmanial energy metabolism or on other leishmanial biochemical pathways. We report here the effect of antileishmanial concentrations of stibogluconate on macromolecular synthesis, purine nucleotide synthesis, and energy metabolism of Leishmania mexic...

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THE RELATIONSHIP BETWEEN INHIBITION OF PHOSPHOFRUCTOKINASE ACTIVITY AND THE MODE OF ACTION OF TRIVALENT ORGANIC ANTIMONIALS ON SCHISTOSOMA MANSONI

Cited by 57 publications

References 13 publications

The role of tegumental aquaporin from the human parasitic worm,Schistosoma monsoni, in osmoregulation and drug uptake

The role of tegumental aquaporin from the human parasitic worm,Schistosoma monsoni, in osmoregulation and drug uptake

Leishmania antimony resistance: what we know what we can learn from the field

Biochemical mechanisms of the antileishmanial activity of sodium stibogluconate

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