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BIOMD0000000247 - Ralser2007_Carbohydrate_Rerouting_ROS

 

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Reference Publication
Publication ID: 18154684
Ralser M, Wamelink MM, Kowald A, Gerisch B, Heeren G, Struys EA, Klipp E, Jakobs C, Breitenbach M, Lehrach H, Krobitsch S.
Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress.
J. Biol. 2007; 6(4): 10
Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany. ralser@molgen.mpg.de  [more]
Model
Original Model: BIOMD0000000247.xml.origin
Submitter: Kieran Smallbone
Submission ID: MODEL1003300000
Submission Date: 30 Mar 2010 16:24:21 UTC
Last Modification Date: 14 Feb 2014 14:48:25 UTC
Creation Date: 11 Apr 2007 11:09:00 UTC
Encoders:  Jacky L Snoep
   Kieran Smallbone
set #1
bqbiol:occursIn Taxonomy Saccharomyces cerevisiae
bqbiol:isVersionOf Gene Ontology cellular response to oxidative stress
bqbiol:hasVersion Gene Ontology NADP metabolic process
Gene Ontology pentose-phosphate shunt
Gene Ontology glycolytic process
set #2
bqbiol:hasVersion KEGG Pathway sce00010
KEGG Pathway sce00030
set #3
bqmodel:isDerivedFrom BioModels Database Teusink2000_Glycolysis
Notes

This is the model with unfitted parameters described in the article
Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress
Markus Ralser, Mirjam M Wamelink, Axel Kowald, Birgit Gerisch, Gino Heeren, Eduard A Struys, Edda Klipp, Cornelis Jakobs, Michael Breitenbach, Hans Lehrach and Sylvia Krobitsch, J Biol 2007 6(4):10; PMID: 18154684 , doi: 10.1186/jbiol61
Abstract:
BACKGROUND: Eukaryotic cells have evolved various response mechanisms to counteract the deleterious consequences of oxidative stress. Among these processes, metabolic alterations seem to play an important role.
RESULTS: We recently discovered that yeast cells with reduced activity of the key glycolytic enzyme triosephosphate isomerase exhibit an increased resistance to the thiol-oxidizing reagent diamide. Here we show that this phenotype is conserved in Caenorhabditis elegans and that the underlying mechanism is based on a redirection of the metabolic flux from glycolysis to the pentose phosphate pathway, altering the redox equilibrium of the cytoplasmic NADP(H) pool. Remarkably, another key glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), is known to be inactivated in response to various oxidant treatments, and we show that this provokes a similar redirection of the metabolic flux.
CONCLUSION: The naturally occurring inactivation of GAPDH functions as a metabolic switch for rerouting the carbohydrate flux to counteract oxidative stress. As a consequence, altering the homoeostasis of cytoplasmic metabolites is a fundamental mechanism for balancing the redox state of eukaryotic cells under stress conditions.

Different realtive enzyme velocities can be simulated by varying the parameters k_rel_TPI and k_rel_GAPDH .

This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2010 The BioModels Team.
For more information see the terms of use .
To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.

Model
Publication ID: 18154684 Submission Date: 30 Mar 2010 16:24:21 UTC Last Modification Date: 14 Feb 2014 14:48:25 UTC Creation Date: 11 Apr 2007 11:09:00 UTC
Mathematical expressions
Reactions
Hexokinase Glucose-6-phosphate isomerase Phosphofructokinase Aldolase
Glycerol 3-phosphate dehydrogenase Glyceraldehyde 3-phosphate dehydrogenase Phosphoglycerate kinase Phosphoglycerate mutase
Enolase Pyruvate kinase Pyruvate decarboxylase Succinate synthesis
Alcohol dehydrogenase ATPase activity vTPI vG6PDH
v6PGL vGluDH vPPI vTransk1
vR5PI vTransald vTransk2 vNADPH
Glucose transport      
Rules
Assignment Rule (variable: ratio_NADPH_NADP)      
Physical entities
Compartments Species
extracellular CO2 Ethanol Succinate
Glycerol Extracellular Glucose  
cytoplasm High energy phosphates Glucose 6 Phosphate Fructose 6 Phosphate
Fructose-1,6 bisphosphate NADH NAD
1,3-bisphosphoglycerate 3-phosphoglycerate 2-phosphoglycerate
Phosphoenolpyruvate Pyruvate Acetaldehyde
X glyceraldehyde 3-phosphate dihydroxyacetone phosphate
D-6-phosphoglucono-delta-lactone 6-phosphogluconate NADP+
NADPH ribulose 5-phosphate ribose 5-phosphate
xylulose 5-phosphate sedoheptulose 7-phosphate erythrose 4-phosphate
Glucose in Cytosol F2,6P  
Global parameters
k_rel_TPI k_rel_GAPDH ratio_NADPH_NADP sum of AXP conc
Reactions (25)
 
 Hexokinase [Glucose in Cytosol] + [High energy phosphates] ↔ [Glucose 6 Phosphate];  
 
 Glucose-6-phosphate isomerase [Glucose 6 Phosphate] ↔ [Fructose 6 Phosphate];  
 
 Phosphofructokinase [Fructose 6 Phosphate] + [High energy phosphates] ↔ [Fructose-1,6 bisphosphate];   {F2,6P}
 
 Aldolase [Fructose-1,6 bisphosphate] ↔ [dihydroxyacetone phosphate] + [glyceraldehyde 3-phosphate];  
 
 Glycerol 3-phosphate dehydrogenase [dihydroxyacetone phosphate] + [NADH] ↔ [Glycerol] + [NAD];  
 
 Glyceraldehyde 3-phosphate dehydrogenase [glyceraldehyde 3-phosphate] + [NAD] ↔ [1,3-bisphosphoglycerate] + [NADH];  
 
 Phosphoglycerate kinase [1,3-bisphosphoglycerate] ↔ [3-phosphoglycerate] + [High energy phosphates];  
 
 Phosphoglycerate mutase [3-phosphoglycerate] ↔ [2-phosphoglycerate];  
 
 Enolase [2-phosphoglycerate] ↔ [Phosphoenolpyruvate];  
 
 Pyruvate kinase [Phosphoenolpyruvate] ↔ [Pyruvate] + [High energy phosphates];  
 
 Pyruvate decarboxylase [Pyruvate] ↔ [Acetaldehyde] + [CO2];  
 
 Succinate synthesis 2.0 × [Acetaldehyde] + 3.0 × [NAD] ↔ 3.0 × [NADH] + [Succinate];  
 
 Alcohol dehydrogenase [Acetaldehyde] + [NADH] ↔ [Ethanol] + [NAD];  
 
 ATPase activity [High energy phosphates] ↔ [X];  
 
 vTPI [glyceraldehyde 3-phosphate] ↔ [dihydroxyacetone phosphate];  
 
 vG6PDH [Glucose 6 Phosphate] + [NADP+] → [D-6-phosphoglucono-delta-lactone] + [NADPH];   {NADPH}
 
 v6PGL [D-6-phosphoglucono-delta-lactone] → [6-phosphogluconate];  
 
 vGluDH [6-phosphogluconate] + [NADP+] → [ribulose 5-phosphate] + [NADPH];   {NADPH}
 
 vPPI [ribulose 5-phosphate] ↔ [ribose 5-phosphate];  
 
 vTransk1 [ribose 5-phosphate] + [xylulose 5-phosphate] ↔ [glyceraldehyde 3-phosphate] + [sedoheptulose 7-phosphate];  
 
 vR5PI [ribulose 5-phosphate] ↔ [xylulose 5-phosphate];  
 
 vTransald [sedoheptulose 7-phosphate] + [glyceraldehyde 3-phosphate] ↔ [Fructose 6 Phosphate] + [erythrose 4-phosphate];  
 
 vTransk2 [xylulose 5-phosphate] + [erythrose 4-phosphate] ↔ [glyceraldehyde 3-phosphate] + [Fructose 6 Phosphate];  
 
 vNADPH [NADPH] → [NADP+];  
 
 Glucose transport [Extracellular Glucose] ↔ [Glucose in Cytosol];  
 
Rules (1)
 
 Assignment Rule (name: ratio_NADPH_NADP) ratio_NADPH_NADP = NADPH/NADP
 
 extracellular Spatial dimensions: 3.0  Compartment size: 1.0
 
 CO2
Compartment: extracellular
Initial concentration: 1.0
 
 Ethanol
Compartment: extracellular
Initial concentration: 50.0
 
 Succinate
Compartment: extracellular
Initial concentration: 0.1
 
 Glycerol
Compartment: extracellular
Initial concentration: 0.15
 
 Extracellular Glucose
Compartment: extracellular
Initial concentration: 50.0
 
 cytoplasm Spatial dimensions: 3.0  Compartment size: 1.0
 
 High energy phosphates
Compartment: cytoplasm
Initial concentration: 5.0
 
 Glucose 6 Phosphate
Compartment: cytoplasm
Initial concentration: 1.39
 
 Fructose 6 Phosphate
Compartment: cytoplasm
Initial concentration: 0.28
 
 Fructose-1,6 bisphosphate
Compartment: cytoplasm
Initial concentration: 0.1
 
 NADH
Compartment: cytoplasm
Initial concentration: 0.39
 
 NAD
Compartment: cytoplasm
Initial concentration: 1.2
 
 1,3-bisphosphoglycerate
Compartment: cytoplasm
Initial concentration: 0.1
 
 3-phosphoglycerate
Compartment: cytoplasm
Initial concentration: 0.1
 
 2-phosphoglycerate
Compartment: cytoplasm
Initial concentration: 0.1
 
 Phosphoenolpyruvate
Compartment: cytoplasm
Initial concentration: 0.1
 
 Pyruvate
Compartment: cytoplasm
Initial concentration: 3.36
 
 Acetaldehyde
Compartment: cytoplasm
Initial concentration: 0.04
 
 X
Compartment: cytoplasm
Initial concentration: 0.1
 
 glyceraldehyde 3-phosphate
Compartment: cytoplasm
Initial concentration: 0.05
 
 dihydroxyacetone phosphate
Compartment: cytoplasm
Initial concentration: 1.0
 
 D-6-phosphoglucono-delta-lactone
Compartment: cytoplasm
Initial concentration: 0.1
 
 6-phosphogluconate
Compartment: cytoplasm
Initial concentration: 0.1
 
 NADP+
Compartment: cytoplasm
Initial concentration: 0.4
 
 NADPH
Compartment: cytoplasm
Initial concentration: 1.6
 
 ribulose 5-phosphate
Compartment: cytoplasm
Initial concentration: 0.1
 
 ribose 5-phosphate
Compartment: cytoplasm
Initial concentration: 0.1
 
 xylulose 5-phosphate
Compartment: cytoplasm
Initial concentration: 0.1
 
 sedoheptulose 7-phosphate
Compartment: cytoplasm
Initial concentration: 0.1
 
 erythrose 4-phosphate
Compartment: cytoplasm
Initial concentration: 0.0
 
 Glucose in Cytosol
Compartment: cytoplasm
Initial concentration: 0.087
 
 F2,6P
Compartment: cytoplasm
Initial concentration: 0.02
 
Global Parameters (4)
 
   k_rel_TPI
Value: 1.0   (Units: dimensionless)
Constant
 
   k_rel_GAPDH
Value: 1.0   (Units: dimensionless)
Constant
 
   ratio_NADPH_NADP
Value: NaN   (Units: dimensionless)
 
 sum of AXP conc
Value: 4.1
Constant
 
Hexokinase (7)
 
   VmGLK
Value: 226.452   (Units: mMpermin)
Constant
 
   KeqAK
Value: 0.45   (Units: dimensionless)
Constant
 
   KeqGLK
Value: 3800.0   (Units: dimensionless)
Constant
 
   KmGLKATP
Value: 0.15   (Units: mM)
Constant
 
   KmGLKGLCi
Value: 0.08   (Units: mM)
Constant
 
   KmGLKG6P
Value: 30.0   (Units: mM)
Constant
 
   KmGLKADP
Value: 0.23   (Units: mM)
Constant
 
Glucose-6-phosphate isomerase (4)
 
   VmPGI
Value: 339.677   (Units: mMpermin)
Constant
 
   KmPGIG6P
Value: 1.4   (Units: mM)
Constant
 
   KeqPGI
Value: 0.314   (Units: dimensionless)
Constant
 
   KmPGIF6P
Value: 0.3   (Units: mM)
Constant
 
Phosphofructokinase (15)
 
   gR
Value: 5.12   (Units: dimensionless)
Constant
 
   VmPFK
Value: 182.903   (Units: mMpermin)
Constant
 
   KeqAK
Value: 0.45   (Units: dimensionless)
Constant
 
   KmPFKF6P
Value: 0.1   (Units: mM)
Constant
 
   KmPFKATP
Value: 0.71   (Units: mM)
Constant
 
   L0
Value: 0.66   (Units: dimensionless)
Constant
 
   CPFKF26BP
Value: 0.0174   (Units: dimensionless)
Constant
 
   KPFKF26BP
Value: 6.82E-4   (Units: mM)
Constant
 
   CPFKF16BP
Value: 0.397   (Units: dimensionless)
Constant
 
   KPFKF16BP
Value: 0.111   (Units: mM)
Constant
 
   CPFKAMP
Value: 0.0845   (Units: dimensionless)
Constant
 
   KPFKAMP
Value: 0.0995   (Units: mM)
Constant
 
   CiPFKATP
Value: 100.0   (Units: dimensionless)
Constant
 
   KiPFKATP
Value: 0.65   (Units: mM)
Constant
 
   CPFKATP
Value: 3.0   (Units: dimensionless)
Constant
 
Aldolase (7)
 
   VmALD
Value: 322.258   (Units: mMpermin)
Constant
 
   KeqTPI
Value: 0.045   (Units: dimensionless)
Constant
 
   KeqALD
Value: 0.069   (Units: dimensionless)
Constant
 
   KmALDF16P
Value: 0.3   (Units: mM)
Constant
 
   KmALDDHAP
Value: 2.4   (Units: mM)
Constant
 
   KmALDGAP
Value: 2.0   (Units: mM)
Constant
 
   KmALDGAPi
Value: 10.0   (Units: mM)
Constant
 
Glycerol 3-phosphate dehydrogenase (7)
 
   VmG3PDH
Value: 70.15   (Units: mMpermin)
Constant
 
   KeqG3PDH
Value: 4300.0   (Units: dimensionless)
Constant
 
   KeqTPI
Value: 0.045   (Units: dimensionless)
Constant
 
   KmG3PDHDHAP
Value: 0.4   (Units: mM)
Constant
 
   KmG3PDHNADH
Value: 0.023   (Units: mM)
Constant
 
   KmG3PDHNAD
Value: 0.93   (Units: mM)
Constant
 
   KmG3PDHGLY
Value: 1.0   (Units: mM)
Constant
 
Glyceraldehyde 3-phosphate dehydrogenase (8)
 
   VmGAPDHr
Value: 6549.68   (Units: mMpermin)
Constant
 
   KmGAPDHBPG
Value: 0.0098   (Units: mM)
Constant
 
   KmGAPDHNADH
Value: 0.06   (Units: mM)
Constant
 
   KeqTPI
Value: 0.045   (Units: dimensionless)
Constant
 
   VmGAPDHf
Value: 1184.52   (Units: mMpermin)
Constant
 
   KmGAPDHGAP
Value: 0.21   (Units: mM)
Constant
 
   KmGAPDHNAD
Value: 0.09   (Units: mM)
Constant
 
   KeqGAPDH
Value: 0.0050   (Units: dimensionless)
Constant
 
Phosphoglycerate kinase (7)
 
   VmPGK
Value: 1306.45   (Units: mMpermin)
Constant
 
   KeqPGK
Value: 3200.0   (Units: dimensionless)
Constant
 
   KeqAK
Value: 0.45   (Units: dimensionless)
Constant
 
   KmPGKATP
Value: 0.3   (Units: mM)
Constant
 
   KmPGKP3G
Value: 0.53   (Units: mM)
Constant
 
   KmPGKADP
Value: 0.2   (Units: mM)
Constant
 
   KmPGKBPG
Value: 0.0030   (Units: mM)
Constant
 
Phosphoglycerate mutase (4)
 
   VmPGM
Value: 2525.81   (Units: mMpermin)
Constant
 
   KmPGMP3G
Value: 1.2   (Units: mM)
Constant
 
   KeqPGM
Value: 0.19   (Units: dimensionless)
Constant
 
   KmPGMP2G
Value: 0.08   (Units: mM)
Constant
 
Enolase (4)
 
   VmENO
Value: 365.806   (Units: mMpermin)
Constant
 
   KmENOP2G
Value: 0.04   (Units: mM)
Constant
 
   KeqENO
Value: 6.7   (Units: dimensionless)
Constant
 
   KmENOPEP
Value: 0.5   (Units: mM)
Constant
 
Pyruvate kinase (7)
 
   VmPYK
Value: 1088.71   (Units: mMpermin)
Constant
 
   KmPYKPEP
Value: 0.14   (Units: mM)
Constant
 
   KmPYKADP
Value: 0.53   (Units: mM)
Constant
 
   KeqAK
Value: 0.45   (Units: dimensionless)
Constant
 
   KeqPYK
Value: 6500.0   (Units: dimensionless)
Constant
 
   KmPYKPYR
Value: 21.0   (Units: mM)
Constant
 
   KmPYKATP
Value: 1.5   (Units: mM)
Constant
 
Pyruvate decarboxylase (3)
 
   VmPDC
Value: 174.194   (Units: mMpermin)
Constant
 
   nPDC
Value: 1.9   (Units: dimensionless)
Constant
 
   KmPDCPYR
Value: 4.33   (Units: mM)
Constant
 
Succinate synthesis (1)
 
   KSUCC
Value: 21.4   (Units: permin)
Constant
 
Alcohol dehydrogenase (10)
 
   VmADH
Value: 810.0   (Units: mMpermin)
Constant
 
   KiADHNAD
Value: 0.92   (Units: mM)
Constant
 
   KmADHETOH
Value: 17.0   (Units: mM)
Constant
 
   KeqADH
Value: 6.9E-5   (Units: dimensionless)
Constant
 
   KmADHNAD
Value: 0.17   (Units: mM)
Constant
 
   KmADHNADH
Value: 0.11   (Units: mM)
Constant
 
   KiADHNADH
Value: 0.031   (Units: mM)
Constant
 
   KmADHACE
Value: 1.11   (Units: mM)
Constant
 
   KiADHACE
Value: 1.1   (Units: mM)
Constant
 
   KiADHETOH
Value: 90.0   (Units: mM)
Constant
 
ATPase activity (2)
 
   KATPASE
Value: 39.5   (Units: permin)
Constant
 
   KeqAK
Value: 0.45   (Units: dimensionless)
Constant
 
vTPI (4)
 
   KmGA3P
Value: 1.27   (Units: mM)
Constant
 
   KmDHAP
Value: 1.23   (Units: mM)
Constant
 
   VmDHAP
Value: 10900.0   (Units: mMpermin)
Constant
 
   VmGA3P
Value: 555.0   (Units: mMpermin)
Constant
 
vG6PDH (4)
 
   VmG6PDH
Value: 4.0   (Units: mMpermin)
Constant
 
   KmG6P
Value: 0.04   (Units: mM)
Constant
 
   KmNADP
Value: 0.02   (Units: mM)
Constant
 
   KiNADPH
Value: 0.017   (Units: mM)
Constant
 
v6PGL (2)
 
   Vm6PGL
Value: 4.0   (Units: mMpermin)
Constant
 
   Km6PGL
Value: 0.8   (Units: mM)
Constant
 
vGluDH (4)
 
   VmGluDH
Value: 4.0   (Units: mMpermin)
Constant
 
   KmGluconate
Value: 0.02   (Units: mM)
Constant
 
   KmNADP
Value: 0.03   (Units: mM)
Constant
 
   KiNADPH
Value: 0.03   (Units: mM)
Constant
 
vPPI (4)
 
   VmPPIf
Value: 3458.0   (Units: mMpermin)
Constant
 
   VmPPIr
Value: 3458.0   (Units: mMpermin)
Constant
 
   KmRibu5P
Value: 1.6   (Units: mM)
Constant
 
   KmRibo5P
Value: 1.6   (Units: mM)
Constant
 
vTransk1 (6)
 
   VmTransk1f
Value: 4.0   (Units: mMpermin)
Constant
 
   VmTransk1r
Value: 2.0   (Units: mMpermin)
Constant
 
   KmRibose5P
Value: 0.1   (Units: mM)
Constant
 
   KmXyl5P
Value: 0.15   (Units: mM)
Constant
 
   KmGA3P
Value: 0.1   (Units: mM)
Constant
 
   KmSeduhept
Value: 0.15   (Units: mM)
Constant
 
vR5PI (4)
 
   VmR5PIf
Value: 1039.0   (Units: mMpermin)
Constant
 
   VmR5PIr
Value: 1039.0   (Units: mMpermin)
Constant
 
   KmRibu5P
Value: 1.5   (Units: mM)
Constant
 
   KmXyl
Value: 1.5   (Units: mM)
Constant
 
vTransald (6)
 
   VmTransaldf
Value: 55.0   (Units: mMpermin)
Constant
 
   VmTransaldr
Value: 10.0   (Units: mMpermin)
Constant
 
   KmGA3P
Value: 0.22   (Units: mM)
Constant
 
   KmSeduhept
Value: 0.18   (Units: mM)
Constant
 
   KmF6P
Value: 0.32   (Units: mM)
Constant
 
   KmEry4P
Value: 0.018   (Units: mM)
Constant
 
vTransk2 (6)
 
   VmTransk2F
Value: 3.2   (Units: mMpermin)
Constant
 
   VmTransk2r
Value: 43.0   (Units: mMpermin)
Constant
 
   KmXyl5P
Value: 0.16   (Units: mM)
Constant
 
   KmEry4P
Value: 0.09   (Units: mM)
Constant
 
   KmF6P
Value: 1.1   (Units: mM)
Constant
 
   KmGA3P
Value: 2.1   (Units: mM)
Constant
 
vNADPH (1)
 
   kNADPH
Value: 2.0   (Units: permin)
Constant
 
Glucose transport (4)
 
   VmGLT
Value: 97.264   (Units: mMpermin)
Constant
 
   KeqGLT
Value: 1.0   (Units: mM)
Constant
 
   KmGLTGLCo
Value: 1.1918   (Units: mM)
Constant
 
   KmGLTGLCi
Value: 1.1918   (Units: mM)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000247

Curator's comment: (updated: 13 Apr 2010 02:29:17 BST)

Reproduction of figure 5 a of the original publication.

Parameter scans over k_rel_TPI and k_rel_GAPDH with a subsequent steady state analysis were performed using Copasi 4.5.31.

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