BioModels

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A model of glycolysis in the causative agent of human African trypanosomiasis, Trypanosoma brucei, has already shown the utility of this approach. Here we add the pentose phosphate pathway (PPP) of T. brucei to the glycolytic model. The PPP is localized to both the cytosol and the glycosome and adding it to the glycolytic model without further adjustments leads to a draining of the essential bound-phosphate moiety within the glycosome. This phosphate "leak" must be resolved for the model to be a reasonable representation of parasite physiology. Two main types of theoretical solution to the problem could be identified: (i) including additional enzymatic reactions in the glycosome, or (ii) adding a mechanism to transfer bound phosphates between cytosol and glycosome. One example of the first type of solution would be the presence of a glycosomal ribokinase to regenerate ATP from ribose 5-phosphate and ADP. Experimental characterization of ribokinase in T. brucei showed that very low enzyme levels are sufficient for parasite survival, indicating that other mechanisms are required in controlling the phosphate leak. Examples of the second type would involve the presence of an ATP:ADP exchanger or recently described permeability pores in the glycosomal membrane, although the current absence of identified genes encoding such molecules impedes experimental testing by genetic manipulation. Confronted with this uncertainty, we present a modeling strategy that identifies robust predictions in the context of incomplete system characterization. We illustrate this strategy by exploring the mechanism underlying the essential function of one of the PPP enzymes, and validate it by confirming the model predictions experimentally.. 12, 9. Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation and Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom ; Systems and Synthetic Biology Group, Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.viji@ebi.ac.ukEMBL-EBIBIOMD0000000516Dynamic models of metabolism can be useful in identifying potential drug targets, especially in unicellular organisms. A model of glycolysis in the causative agent of human African trypanosomiasis, Trypanosoma brucei, has already shown the utility of this approach. Here we add the pentose phosphate pathway (PPP) of T. brucei to the glycolytic model. The PPP is localized to both the cytosol and the glycosome and adding it to the glycolytic model without further adjustments leads to a draining of the essential bound-phosphate moiety within the glycosome. This phosphate "leak" must be resolved for the model to be a reasonable representation of parasite physiology. Two main types of theoretical solution to the problem could be identified: (i) including additional enzymatic reactions in the glycosome, or (ii) adding a mechanism to transfer bound phosphates between cytosol and glycosome. One example of the first type of solution would be the presence of a glycosomal ribokinase to regenerate ATP from ribose 5-phosphate and ADP. Experimental characterization of ribokinase in T. brucei showed that very low enzyme levels are sufficient for parasite survival, indicating that other mechanisms are required in controlling the phosphate leak. Examples of the second type would involve the presence of an ATP:ADP exchanger or recently described permeability pores in the glycosomal membrane, although the current absence of identified genes encoding such molecules impedes experimental testing by genetic manipulation. Confronted with this uncertainty, we present a modeling strategy that identifies robust predictions in the context of incomplete system characterization. We illustrate this strategy by exploring the mechanism underlying the essential function of one of the PPP enzymes, and validate it by confirming the model predictions experimentally.Handling uncertainty in dynamic models: the pentose phosphate pathway in Trypanosoma brucei.Kerkhoven Eduard J EJ, Achcar Fiona F, Alibu Vincent P VP, Burchmore Richard J RJ, Gilbert Ian H IH, Trybiło Maciej M, Driessen Nicole N NN, Gilbert David D, Breitling Rainer R, Bakker Barbara M BM, Barrett Michael P MPribose phosphate, Striadyne, Materials, DCAF9, Product, Metabolic Concepts, A4, Embden-Meyerhof, Pentose, Pentose Phosphate Shunt, (D-ribofuranose)-isomer, 1B1, countertransporter activity, anon-EST:Posey9, solute:solute exchange, Hexose Monophosphate Shunts, Metabolism Concept, study treatment, Transfer, Bind, Theory, catabolism, D-ribokinase, Tissue, coding, Pathways, metabolic process resulting in cell growth, Mechanism Device, Application Context, medicine, CrATP, Cr(H2O)4 ATP, s, Study Agent, 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Preparation, Model, CG34197, Controlled, Pentosephosphate Shunt, DRUG, membrane, Controlling, Encoded, Embden Meyerhof Pathway, Microbody, drug, Magnesium Chloride, enzyme activity, Resolved, Adenosine 5'-(tetrahydrogen triphosphate), Magnesium, Cistrons, LGMD2C, Testing, Metabolic Phenomena, ribose 5-phosphate, Metabolism Concepts, count in organism, Atriphos, Pharmacologic Agent, ML-1, survival, GLI3-190, Manipulate, pustular psoriasis of the palms and/or soles, Phenomena, whole membrane, Dmel_CG34197, Africam sleeping sickness, connected anatomical system, human African trypanosomiasis, Resolution, transmembrane, Manganese Adenosine Triphosphate, biodegradation, Metabolic, BiologicEntity, adducin, Required, Pentose Shunt, GDC Therapeutic Agent Terminology, Membrane, Embden-Meyerhof-Parnas pathway, Drug, Preparations, single-organism metabolic process, ATPIB, SCARMD2, Inclusive, Additional, Manipulation, EST D, Limit, Revised International Prognostic Scoring System for 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Levulosa Ife, CaATP, Adenosine, Pentose-Phosphate, glycolysis, adipose, Pentosephosphate Pathway, ATPIB, MgATP, Levulosa Ibys, Embden-Meyerhof Pathways, Levulosa Braun, Levulosado Bieffe Medit, Calcium SaltModeling System, Pathway, Trypanosoma brucei subgroup, Model System, Trypanosoma brucei bruceus, Trypanosoma bruceus, Pentose Phosphate Shunts, Pentose Phosphate Pathways, Pentosephosphate Shunts, Pathways, Trypanosoma (Trypanozoon) brucei, Pentose Shunt, Pentose, pentose phosphate shunt, model, Pentose Shunts, Pentose Phosphate Shunt, Trypanosoma brucei., Hexose Monophosphate, Trypanosoma brucei, Pentosephosphate, Shunts, hexose monophosphate pathway, Trypanosoma, Shunt, Pentose-Phosphate, Hexose Monophosphate Shunts, Pentosephosphate Pathways, pentose-phosphate pathway, brucei brucei, Pentosephosphate Pathway, pentose phosphate pathway, Pentose-Phosphate Pathways, bruceus, Pentose Phosphate, Hexose Monophosphate Shunt, Model, Models, Pentose-Phosphate Pathway, brucei, Handling, Pentosephosphate Shuntextent, dec, ribose phosphate, Striadyne, Materials, Public Sectors, DCAF9, Product, Metabolic Concepts, A4, Embden-Meyerhof, Pentose, E-Cadherin, Pentose Phosphate Shunt, (D-ribofuranose)-isomer, 1B1, countertransporter activity, anon-EST:Posey9, solute:solute exchange, Levulosa Mein, Hexose Monophosphate Shunts, TEP1, Metabolism Concept, Public Enterprise, dec1, arabino-Hexulose, fs(1)14-963, catabolism, DCAD2, DCad2, D-ribokinase, Tissue, Pathways, metabolic process resulting in cell growth, Fruchtzucker, DECad, D17Mit170, CG3722, DE Cad, CrATP, medicine, Cr(H2O)4 ATP, s, fs(1)M1021, DEcad, fs(1)12-3907, Inorganic, HtsF, sleeping sickness, Add, ATPsyn-&bgr, DE, ADD, Levulose, Pathway, Levulosa, ATPsyn-b, Trypanosoma brucei bruceus, completeness, Diphosphate, African sleeping sickness, ADP, Glucose transporter type 5, metabolism resulting in cell growth, familial, anaerobic glycolysis, Shg, integral to membrane, Embden-Meyerhof-Parnas, Tl3, Dmel_CG9325, Tl2, Levulosado Braun, fs(1)12-1873, add, DmelCG5124, Embden-Meyerhof-Parnas Pathway, htsRC, PTEN1, ECadh, Public Domain, adp, CG43443, Domains, Magnesium Salt, secretion, Pyrophosphate, Adenosine Pyrophosphate, ADENOSINE-5'-TRIPHOSPHATE, HTS, Hts, D E-cad, death rate, Levulosa Baxter, Adenosine 5'-(trihydrogen diphosphate), GLI3FL, E-cadherin, 5'-Pyrophosphate, Trypanosoma bruceus, Pentose Phosphate Shunts, Pdn, solute:solute antiporter activity, Trypanosoma brucei, gp150, Fc, Adenosine triphosphate, experimental procedures, Adenosine, Pentose-Phosphate, Sector, glycolysis, Material, brucei brucei, Cytosols, monobarium salt, CT12481, Embden-Meyerhof Pathways, Levulosado Bieffe Medit, DCad, ECad2, MgADP, ADD-87, Sectors, localised, Fru, Fleboplast, Magnesium Adenosine Triphosphate, DE Cadh, GLM2, Processes, Biocatalysts, Plast Apyr Levulosa Mein, fs(1)14A-114, Ovhts, Palmoplantar Pustulosis, number, ATP-MgCl2, Trypanosoma (Trypanozoon) brucei, HtsRC, Copyrights, pentose phosphate shunt, IB, Metabolic Processes, body system, Adenylpyrophosphate, African trypanosomiasis, DmelCG2175, l(2)k03401, pentose-phosphate pathway, pentose phosphate pathway, Fleboplast Levulosa, localised pustular psoriasis, l(2)k14523, system, Ovhts-RC, Hexose Monophosphate Shunt, MAM, Pentose-Phosphate Pathway, Enterprises, CadE, Ecad, anatomical systems, cadh, Tissues, absent from organism, beta-ATPase, Pentose Phosphate Pathways, Metabolic Concept, Fcp7C, Public Enterprises, Solution, Shunts, Fructose transporter, ECAD, ECad, drugs, Enzyme, ATPasebeta, D-cad, MnATP, ATPase beta, Enterprise, constitutitional genetic, ATPB, CADH, Pharmaceuticals, DmelCG43443, [PO4](3-), Products, Hts-RC, (D-ribose)-isomer, dec[[1]], cou, degradation, Magnesium ADP, CG2175, function, Cadh, porter, Concept, ATP-syn-B, localized pustular psoriasis, fs(1)C1, fs(1)12-403, N-cad, Lr, Apir, African Trypanosomiasis, Public, CWS1, brucei, metabolism, Bph, Metabolic Phenomenon, Inorganic Phosphate, multicellular organism metabolic process, DMDA1, Pharmaceutic Preparations, antiport, Adenosine 5' Pyrophosphate, Glycosomes, Hexose Monophosphate, E-cad, D-ribose 5-phosphate, adipose, Pentosephosphate Pathway, Bra, palmoplantar pustulosis, fs(1)13-453, deoxyribokinase, Attention Deficit Hyperactivity Disorder, phosphates, Pharmaceutical Products, hereditary, Calcium Salt, E-CAD, E-Cad, l(2)k10220, Anabolism, biochemical pathways, fs(1)A384, Metabolic Process, Trypanosoma brucei subgroup, AU023367, Adenosine Triphosphate, ribose 5-monophosphate, CG5124, Pi, Pentose Shunts, ribose-5-phosphoric acid, Embden Meyerhof Parnas Pathway, Pentosephosphate, Trypanosoma, Membrane Tissues, fs(1)A257, Pharmaceutical Product, Concepts, Embden-Meyerhof Pathway, anon-WO0196371.27, fs(1)5, exchanger, Phenomenon, small intestine, H4atp, fs(1)M102, Chromium Adenosine Triphosphate, me75, Orthophosphate, reference sample, enzymes, fs(1)11-549, PHOSPHATE ION, membrane region, Public Domains, PPP, Fruktose, Phosphate, T1, genetic, ATPsyn b, DE-CAD2, dEcad, Pharmaceutical, biotransformation, DECadh, l(2)01103, Glycosome, Catabolism, HAT, ATP, Chromium Ammonium Salt, Membrane Tissue, Papers, Levulosado Vitulia, Process, exchange transporter activity, incomplete, DE-Cad2, membranous organ component, hexose monophosphate pathway, DE-cadh, fs(1)1501, abolished, fs(1)12-365, Shunt, DE-Cadherin, Pentose-Phosphate Pathways, Manganese Salt, DE-cadherin, Genetic Materials, Pentose Phosphate, Pharmaceutic, Adenosine 5'-triphosphate, D-ribose-5-phosphoric acid, anon-WO0196371.1, anon-WO0196371.3, Genetic Material, Domain, CG11154, Phosphates, shg/DE-Cad, membrane of organ, absence, l(2)k06121, PO4(3-), MMAC1, AI854843, add-like, Embden-Meyerhof pathway, monosodium salt, Permeabilities, organ system, CaATP, Adducin, DMDA, phosphate, Parasite, DmelCG3722, phosphate ions, MgATP, Biocatalyst, Cistron, inherited genetic, Fc1, BZS, com5, Levulosa Braun, fs(1)12-2514, experimental, fs(1)384, Pentosephosphate Shunts, Gene, Gm695, CG9325, Xt, presence, TYPE, l(2)10469, DAGA4, MHAM, Apir Levulosa, Add-hts, Metabolism, integral component of membrane, ATP-synbeta, modified Embden-Meyerhof pathway, l(2)00634, Adenosine 5'-Pyrophosphate, Low, Metabolism Phenomena, SCG3, Drugs, acropustulosis, HTS-R1, methods, localized, Genetic, DmelCG11154, LPP, experimental section, ATP MgCl2, Inorganic Phosphates, Levulosa Grifols, HTS-RC, ion antiporter activity, fs(1)12-3512, Abstract, Chromium Salt, Pentosephosphate Pathways, time of survival, bruceus, region of membrane, Preparation, CG34197, Controlled, Pentosephosphate Shunt, DE[cyto], membrane, Controlling, Embden Meyerhof Pathway, fs(1)13C-73, Microbody, drug, DE-cad, GLUT-5, Magnesium Chloride, enzyme activity, Adenosine 5'-(tetrahydrogen triphosphate), Magnesium, Cistrons, LGMD2C, Metabolic Phenomena, ribose 5-phosphate, Metabolism Concepts, count in organism, Atriphos, ML-1, Cad, survival, GLI3-190, fs(1)12-4860, pustular psoriasis of the palms and/or soles, Phenomena, whole membrane, DE-CAD, DE-Cad, Dmel_CG34197, fs(1)14E19, Africam sleeping sickness, connected anatomical system, human African trypanosomiasis, Data Base, transmembrane, Manganese Adenosine Triphosphate, cad, 10q23del, biodegradation, Metabolic, adducin, Pentose Shunt, Membrane, Embden-Meyerhof-Parnas pathway, Levulosa Ife, Drug, DEC, Preparations, single-organism metabolic process, ATPIB, SCARMD2, fs(1)13C-57, Public., EST D, Levulosa Ibys, e-cad, pustulosis of palm and sole, Pharmaceutical PreparationfalseKerkhoven2013 - Glycolysis and Pentose Phosphate Pathway in T.brucei - MODEL D in fructose medium (with ATP:ADP antiporter) Kerkhoven2013 - Glycolysis and Pentose Phosphate Pathway in T.brucei - MODEL D in fructose medium (with ATP:ADP antiporter) There are six models (Model A, B, C, C-fruc, D, D-fruc) described in the paper. Model A ( BIOMD0000000513 ) is the model developed originally by Achar et al. (2012) ( BIOMD0000000428 ), which describes glycolysis in T.brucei. This glycolysis model is extended to include pentose phosphate pathway (PPP), which is Model B (( BIOMD0000000514 ). Model B is further extended to include glycosomal ribokinase, leading to Model C ( BIOMD0000000510 ). Model D ( BIOMD0000000511 ) is again an extension of Model B, which includes an ATP:ADP antiporter. Model C-fruc ( BIOMD0000000515 ) and Model D-fruc ( BIOMD0000000516 ) are extensions of Model C and D, respectively, which includes fructose transporter and its subsequent utilizing reactions. This model correspond to Model D-fruc of the paper. This model is described in the article: Handling uncertainty in dynamic models: the pentose phosphate pathway in Trypanosoma brucei. Kerkhoven EJ, Achcar F, Alibu VP, Burchmore RJ, Gilbert IH, Trybiło M, Driessen NN, Gilbert D, Breitling R, Bakker BM, Barrett MP. PLoS Comput Biol. 2013 Dec;9(12):e1003371. Abstract: Dynamic models of metabolism can be useful in identifying potential drug targets, especially in unicellular organisms. A model of glycolysis in the causative agent of human African trypanosomiasis, Trypanosoma brucei, has already shown the utility of this approach. Here we add the pentose phosphate pathway (PPP) of T. brucei to the glycolytic model. The PPP is localized to both the cytosol and the glycosome and adding it to the glycolytic model without further adjustments leads to a draining of the essential bound-phosphate moiety within the glycosome. This phosphate "leak" must be resolved for the model to be a reasonable representation of parasite physiology. Two main types of theoretical solution to the problem could be identified: (i) including additional enzymatic reactions in the glycosome, or (ii) adding a mechanism to transfer bound phosphates between cytosol and glycosome. One example of the first type of solution would be the presence of a glycosomal ribokinase to regenerate ATP from ribose 5-phosphate and ADP. Experimental characterization of ribokinase in T. brucei showed that very low enzyme levels are sufficient for parasite survival, indicating that other mechanisms are required in controlling the phosphate leak. Examples of the second type would involve the presence of an ATP:ADP exchanger or recently described permeability pores in the glycosomal membrane, although the current absence of identified genes encoding such molecules impedes experimental testing by genetic manipulation. Confronted with this uncertainty, we present a modeling strategy that identifies robust predictions in the context of incomplete system characterization. We illustrate this strategy by exploring the mechanism underlying the essential function of one of the PPP enzymes, and validate it by confirming the model predictions experimentally. This model is hosted on BioModels Database and identified by: BIOMD0000000516 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. 2024-08-212024-09-022014-01-31BIOMD000000051624339766CHEBI:28757CHEBI:57642CHEBI:15422CHEBI:16761CHEBI:4170CHEBI:17794CHEBI:28874CHEBI:15379CHEBI:18009CHEBI:48928CHEBI:16526CHEBI:58121CHEBI:58273CHEBI:17234CHEBI:16474CHEBI:15361CHEBI:13389CHEBI:40595CHEBI:17138CHEBI:17754CHEBI:35490CHEBI:14336CHEBI:17842CHEBI:18021CHEBI:16027CHEBI:16908MODEL1401310003BIOMD000000051659444848683GO:0006096GO:0006098GO:0005829GO:0020015GO:00056235691BTO:0035490Q9GRG6