Kinetic properties of phosphofructokinase (and fructose bisphosphatase) of the liver fluke, Fasciola hepatica

Lloyd, Geoffrey M.

doi:10.1016/s0020-7519(83)80011-3

Cited by 11 publications

(8 citation statements)

References 24 publications

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“…Phosphofructokinase from F. hepatica shows some similar kinetics to the enzyme from mammalian sources. Fructose-6-phosphate substrate curves are typically sigmoidal in nature and conform well to the allosteric model proposed by Monod, Changeux & Jacob (1963) and Lloyd (1983a). When present at above optimal levels the second substrate of the reaction, ATP, acts as an inhibitor of the liver fluke enzyme at low fructose-6-phosphate concentrations, whereas increased fructose-6-phosphate levels relieve this inhibition.…”

Section: H E P H O S P H O F R T J C T O K I N a S E / F R U C T O S supporting

confidence: 75%

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Energy metabolism and its regulation in the adult liver flukeFasciola hepatica

Lloyd

1986

Parasitology

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SUMMARYThe adult liver fluke, Fasciola hepatica, inhabits the bile duct of its final host, usually cattle or sheep. The veterinary aspects of infection with F. hepatica can represent a major problem and consequently fascioliasis can have serious economic effects. As recently as 1972 the loss in revenue due to liver fluke infestations in the UK was estimated at an incredible £50 million per annum (Coles, 1975). Not only can F. hepatica infect cattle and sheep, but also outbreaks of human disease have been reported. The last serious outbreak in Britain was in 1968 when at least 49 cases were identified (Ashton, Boardman, D'Sa, Everall & Houghton, 1970; Hardman, Jones & Davies, 1970).

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Section: H E P H O S P H O F R T J C T O K I N a S E / F R U C T O S supporting

confidence: 75%

“…A high rate of cycling is energetically unfavourable owing to the utilization of one molecule of ATP/cycle. As a consequence of this (and from kinetic studies) the cycle as such is not thought to operate in F. hepatica (Lloyd, 1983a).…”

Section: H E P H O S P H O F R T J C T O K I N a S E / F R U C T O S mentioning

confidence: 98%

Energy metabolism and its regulation in the adult liver flukeFasciola hepatica

Lloyd

1986

Parasitology

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“…At higher ATP concentration, a lowering of catalyzed rate was observed (inhibition by excess ATP). The enzyme from other mammalian [39] and parasite sources [18] required more ATP for optimal activity. The corresponding optimum ATP concentrations for the monkey liver [40] and rat small intestine enzymes [41] were found to be 0.4 and 1.0 mM, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphofructokinase (ATP: D-fructose-6-phosphotrans-ferase, EC 2.7.1.11, PFK) is an enzyme of prime importance in the regulation of glycolytic flux in both the mammalian [1–5] and parasites [6–8], for example nematodes such as filarial worms Setaria cervi [9–13] and Dirofilaria immitis [14], Ascaris suum [15], malaria parasite Plasmodium berghei [16], intestinal parasite Entamoeba histolytica [17], liver fluke Fasciola hepatica [18], and a few others including Toxoplasma gondii [19], Trypanosoma cruzi [20], and Trypanosoma brucei [21]. The filarial worms studied so far employ predominantly anaerobic metabolism of carbohydrate (glycogen and/glucose) as a major source of energy [22].…”

Section: Introductionmentioning

confidence: 99%

Kinetic Characterisation of Phosphofructokinase Purified fromSetaria cervi: A Bovine Filarial Parasite

Sharma

2011

Enzyme Research

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Phosphofructokinase (PFK), a regulatory enzyme in glycolytic pathway, has been purified to electrophoretic homogeneity from adult female Setaria cervi and partially characterized. For this enzyme, the Lineweaver-Burk's double reciprocal plots of initial rates and D-fructose-6-phosphate (F-6-P) or Mg-ATP concentrations for varying values of cosubstrate concentration gave intersecting lines indicating that K m values for F-6-P (1.05 mM) and ATP (3 μM) were independent of each other. S. cervi PFK, when assayed at inhibitory concentration of ATP (>0.1 mM), exhibited sigmoidal behavior towards binding with F-6-P with a Hill coefficient (n) value equal to 1.8 and 1.7 at 1.0 and 0.33 mM ATP, respectively. D-fructose-1,6-diphosphate (FDP) competitively inhibited the filarial enzyme: K i and Hill coefficient values being 0.18 μM and 2.0, respectively. Phosphoenolpyruvate (PEP) also inhibited the enzyme competitively with the K i value equal to 0.8 mM. The Hill coefficient values (>1.5) for F-6-P (at inhibitory concentration of ATP) and FDP suggested its positive cooperative kinetics towards F-6-P and FDP, showing presence of more than one binding sites for these molecules in enzyme protein and allosteric nature of the filarial enzyme. The product inhibition studies gave us the only compatible mechanism of random addition process with a probable orientation of substrates and products on the enzyme surface.

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“…In the filarial parasite Setaria cervi, the enzyme may act as a secondary target for the anthelminthic suramin (Scheme 3) [101]. The enzyme has been characterised from a number of other species, including the nematodes Teladorsagia circumcincta [102] and A. suum [103,104], the trematode F. hepatica [105][106][107] and the cestode Hymenolepis diminuta [108]. To date, no compounds have been identified which mimic the worm clearing effectiveness of the trivalent antimonials but lack the side-effects.…”

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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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Kinetic properties of phosphofructokinase (and fructose bisphosphatase) of the liver fluke, Fasciola hepatica

Cited by 11 publications

References 24 publications

Energy metabolism and its regulation in the adult liver flukeFasciola hepatica

Energy metabolism and its regulation in the adult liver flukeFasciola hepatica

Kinetic Characterisation of Phosphofructokinase Purified fromSetaria cervi: A Bovine Filarial Parasite

Metabolic enzymes of helminth parasites: potential as drug targets

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