Compartmentation protects trypanosomes from the dangerous design of glycolysis

Bakker, Barbara M.; Mensonides, F.I.C.; Teusink, Bas; Hoek, Pim van; Michels, Paul A.M.; Westerhoff, Hans V.

doi:10.1073/pnas.030539197

Cited by 164 publications

(149 citation statements)

References 45 publications

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“…Furthermore, hexokinase and phosphofructokinase, typically key regulators of glycolysis, are not subject to regulation in trypanosomes (42). Indeed, mathematical modeling suggests that loss of compartmentation of glycolysis would allow these enzymes to mediate toxic effects in bloodstream forms (43). We could not test whether the lethality of PEX14 RNAi is mediated by glycolytic substrates in the bloodstream stage, as the parasites cannot survive in their absence.…”

Section: Discussionmentioning

confidence: 99%

Glucose is toxic to glycosome-deficient trypanosomes

Furuya

Kessler²,

Jardim³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

114

121

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Trypanosomatids, the etiologic agents of sleeping sickness, leishmaniasis, and Chagas' disease, compartmentalize glycolysis within glycosomes, metabolic organelles related to peroxisomes. Here, we identify a trypanosome homologue of PEX14, one of the components of the peroxisomal protein import docking complex. We have used double-stranded RNA interference to target the PEX14 transcript for degradation. Glycosomal matrix protein import was compromised, and both glycolytic bloodstream stage parasites and mitochondrially respiring procyclic stage parasites were killed. Thus, unlike peroxisomes, glycosomes are essential organelles. Surprisingly, procyclic forms, which can grow in the absence of glucose, were killed by PEX14 RNA interference only when simple sugars were present. Thus, interference with glycosome protein import makes glucose toxic to trypanosomes.

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Section: Discussionmentioning

confidence: 99%

Glucose is toxic to glycosome-deficient trypanosomes

Furuya

Kessler²,

Jardim³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

114

121

View full text Add to dashboard Cite

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“…Secondly, in silico experiments can be carried out on the model to test the effects of perturbations on the system and to identify the processes that control the system. These experiments may either be only feasible using a computer, or are faster and cheaper than laboratory experiments (Bakker et al 2000). Such 'dry' experiments may generate new hypotheses about the system, which can then be tested experimentally.…”

Section: Creating a Modelmentioning

confidence: 99%

Systems biology tools for toxicology

et al. 2012

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An important goal of toxicology is to understand and predict the adverse effects of drugs and other xenobiotics. For pharmaceuticals, such effects often emerge unexpectedly in man even when absent from trials in vitro and in animals. Although drugs and xenobiotics act on molecules, it is their perturbation of intracellular networks that matters. The tremendous complexity of these networks makes it difficult to understand the effects of xenobiotics on their ability to function. Because systems biology integrates data concerning molecules and their interactions into an understanding of network behaviour, it should be able to assist toxicology in this respect. This review identifies how in silico systems biology tools, such as kinetic modelling, and metabolic control, robustness and flux analyse, may indeed help understanding network-mediated toxicity. It also shows how these approaches function by implementing them vis-à-vis the glutathione network, which is important for the detoxification of reactive drug metabolites. The tools enable the appreciation of the steady state concept for the detoxification network and make it possible to simulate and then understand effects of perturbations of the macromolecules in the pathway that are counterintuitive. We review how a glutathione model has been used to explain the impact of perturbation of the pathway at various molecular sites, as would be the effect of single-nucleotide polymorphisms. We focus on how the mutations impact the levels of glutathione and of two candidate biomarkers of hepatic glutathione status. We conclude this review by sketching how the various systems biology tools may help in the various phases of drug development in the pharmaceutical industry.

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“…The K M for hexokinase with respect to ATP is 120 µM. 45 Motility Assays and Microscopy. The motility assays were performed in 100 µm high, 1.5 cm wide flowcells.…”

mentioning

confidence: 99%

Herding Nanotransporters: Localized Activation via Release and Sequestration of Control Molecules

2007

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A challenge for nanotechnology is the dynamic and specific control of nanomachines by the user. Molecular shuttles, consisting of cargobinding microtubules propelled by surface-immobilized kinesin motor proteins, are an example of a nanoscale system that ideally can be selectively activated at programmable locations and times. Here we discuss a biomimetic solution where activating molecules are delivered locally via photolysis of a caged compound and subsequently sequestered in an enzymatic network. The controlled sequestration of the activator not only creates a rapid deactivation when the stimulus is removed but also sharpens the concentration profile of the rapidly diffusing activator. This improvement comes at the expense of a reduced efficiency in the utilization of the activator molecules, suggesting that these nanosystems are most efficiently addressed as a swarm rather than as individuals. Our work represents a step toward transferring the cellular control strategies of molecular activation to bionanotechnology.Bionanotechnology is concerned with the utilization of biological components in nanotechnology, 1 which to a varying degree necessitates the use of biological engineering approaches in a wider sense, for example, in the use of selfassembly to create extended structures. However, a striking accomplishment of nature is not only to create nanomachines and weave them into larger structures, but also to control their spatial and temporal activation via specific signals. This controlled activation is often achieved through the delivery of small molecules, whose spatial and temporal distribution is shaped by the actions of multiple enzymes releasing or sequestering the activating species. Examples include intracellular signaling via calcium, 2,3 NAD(P)H, 4 or cAMP. 5In contrast, the dynamic and controlled activation of specific nanomachines has been addressed in a technological context primarily by making light-activation an integral part of the design as in the light-driven synthetic motors based on rotaxanes or catenanes 6 or by designing devices that can be individually activated with a highly specific fuel molecule. 7 A new, chemical approach is to exploit reactiondiffusion systems to locally change buffer conditions and activate enzymes. 8 Here, we present a biomimetic approach to dynamically control motor protein-driven bionanodevices 9 in particular kinesin-driven molecular shuttles. 10 Molecular shuttles consist of a surface patterned with stationary kinesin motors and cargo-binding microtubules transported by the motors. Localized release and enzymatic sequestration of the substrate ATP creates a spatially and temporally well-defined concentration profile, which in turn leads to controlled activation of a small number of molecular shuttles, as shown in Figure 1. This approach significantly expands the scope of previous work, 11 which demonstrated that repeated, stepwise activation of kinesin-driven molecular shuttles can be achieved by A nearly cylindrical cone of UV light is produced ...

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Compartmentation protects trypanosomes from the dangerous design of glycolysis

Cited by 164 publications

References 45 publications

Glucose is toxic to glycosome-deficient trypanosomes

Glucose is toxic to glycosome-deficient trypanosomes

Systems biology tools for toxicology

Herding Nanotransporters: Localized Activation via Release and Sequestration of Control Molecules

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