<?xml version="1.0" encoding="UTF-8"?>
<!--This biomodel was generated in VCML Version 0.4-->
<vcml xmlns="http://sourceforge.net/projects/vcell/vcml" Version="0.4">
   <BioModel Name="Kholodenko2000_MAPK_feedback">
      <Model Name="Kholodenko2000_MAPK_feedback">
         <Compound Name="MKKK">
            <Annotation>MKKK</Annotation>
         </Compound>
         <Compound Name="MKKK_P">
            <Annotation>MKKK_P</Annotation>
         </Compound>
         <Compound Name="MKK">
            <Annotation>MKK</Annotation>
         </Compound>
         <Compound Name="MKK_P">
            <Annotation>MKK_P</Annotation>
         </Compound>
         <Compound Name="MKK_PP">
            <Annotation>MKK_PP</Annotation>
         </Compound>
         <Compound Name="MAPK">
            <Annotation>MAPK</Annotation>
         </Compound>
         <Compound Name="MAPK_P">
            <Annotation>MAPK_P</Annotation>
         </Compound>
         <Compound Name="MAPK_PP">
            <Annotation>MAPK_PP</Annotation>
         </Compound>
         <Feature Name="uVol" />
         <LocalizedCompound Name="MKKK" CompoundRef="MKKK" Structure="uVol" OverrideName="true" />
         <LocalizedCompound Name="MKKK_P" CompoundRef="MKKK_P" Structure="uVol" OverrideName="true" />
         <LocalizedCompound Name="MKK" CompoundRef="MKK" Structure="uVol" OverrideName="true" />
         <LocalizedCompound Name="MKK_P" CompoundRef="MKK_P" Structure="uVol" OverrideName="true" />
         <LocalizedCompound Name="MKK_PP" CompoundRef="MKK_PP" Structure="uVol" OverrideName="true" />
         <LocalizedCompound Name="MAPK" CompoundRef="MAPK" Structure="uVol" OverrideName="true" />
         <LocalizedCompound Name="MAPK_P" CompoundRef="MAPK_P" Structure="uVol" OverrideName="true" />
         <LocalizedCompound Name="MAPK_PP" CompoundRef="MAPK_PP" Structure="uVol" OverrideName="true" />
         <SimpleReaction Structure="uVol" Name="J0" FluxCarrierValence="0" FluxOption="MolecularOnly">
            <Reactant LocalizedCompoundRef="MKKK" Stoichiometry="1" />
            <Product LocalizedCompoundRef="MKKK_P" Stoichiometry="1" />
            <Modifier LocalizedCompoundRef="MAPK_PP" />
            <Kinetics KineticsType="GeneralKinetics">
               <Parameter Name="J" Role="reaction rate" Unit="uM.s-1">(sbmlRateFactor * V1 * MKKK * MKKK_ConcFactor / ((1.0 + pow((MAPK_PP * MAPK_PP_ConcFactor / Ki),n)) * (K1 + (MKKK * MKKK_ConcFactor))))</Parameter>
               <Parameter Name="V1" Role="user defined" Unit="1.0E-6 m-3.mol.s-1">2.5</Parameter>
               <Parameter Name="Ki" Role="user defined" Unit="1.0E-6 m-3.mol">9.0</Parameter>
               <Parameter Name="n" Role="user defined" Unit="1">1.0</Parameter>
               <Parameter Name="K1" Role="user defined" Unit="1.0E-6 m-3.mol">10.0</Parameter>
               <Parameter Name="sbmlRateFactor" Role="user defined" Unit="1000.0 ">9.999999999999998E-4</Parameter>
               <Parameter Name="MKKK_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
               <Parameter Name="MAPK_PP_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
            </Kinetics>
         </SimpleReaction>
         <SimpleReaction Structure="uVol" Name="J1" FluxCarrierValence="0" FluxOption="MolecularOnly">
            <Reactant LocalizedCompoundRef="MKKK_P" Stoichiometry="1" />
            <Product LocalizedCompoundRef="MKKK" Stoichiometry="1" />
            <Kinetics KineticsType="GeneralKinetics">
               <Parameter Name="J" Role="reaction rate" Unit="uM.s-1">(sbmlRateFactor * V2 * MKKK_P * MKKK_P_ConcFactor / (KK2 + (MKKK_P * MKKK_P_ConcFactor)))</Parameter>
               <Parameter Name="V2" Role="user defined" Unit="1.0E-6 m-3.mol.s-1">0.25</Parameter>
               <Parameter Name="KK2" Role="user defined" Unit="1.0E-6 m-3.mol">8.0</Parameter>
               <Parameter Name="sbmlRateFactor" Role="user defined" Unit="1000.0 ">9.999999999999998E-4</Parameter>
               <Parameter Name="MKKK_P_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
            </Kinetics>
         </SimpleReaction>
         <SimpleReaction Structure="uVol" Name="J2" FluxCarrierValence="0" FluxOption="MolecularOnly">
            <Reactant LocalizedCompoundRef="MKK" Stoichiometry="1" />
            <Product LocalizedCompoundRef="MKK_P" Stoichiometry="1" />
            <Modifier LocalizedCompoundRef="MKKK_P" />
            <Kinetics KineticsType="GeneralKinetics">
               <Parameter Name="J" Role="reaction rate" Unit="uM.s-1">(sbmlRateFactor * k3 * MKKK_P * MKKK_P_ConcFactor * MKK * MKK_ConcFactor / (KK3 + (MKK * MKK_ConcFactor)))</Parameter>
               <Parameter Name="k3" Role="user defined" Unit="s-1">0.025</Parameter>
               <Parameter Name="KK3" Role="user defined" Unit="1.0E-6 m-3.mol">15.0</Parameter>
               <Parameter Name="sbmlRateFactor" Role="user defined" Unit="1000.0 ">9.999999999999998E-4</Parameter>
               <Parameter Name="MKKK_P_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
               <Parameter Name="MKK_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
            </Kinetics>
         </SimpleReaction>
         <SimpleReaction Structure="uVol" Name="J3" FluxCarrierValence="0" FluxOption="MolecularOnly">
            <Reactant LocalizedCompoundRef="MKK_P" Stoichiometry="1" />
            <Product LocalizedCompoundRef="MKK_PP" Stoichiometry="1" />
            <Modifier LocalizedCompoundRef="MKKK_P" />
            <Kinetics KineticsType="GeneralKinetics">
               <Parameter Name="J" Role="reaction rate" Unit="uM.s-1">(sbmlRateFactor * k4 * MKKK_P * MKKK_P_ConcFactor * MKK_P * MKK_P_ConcFactor / (KK4 + (MKK_P * MKK_P_ConcFactor)))</Parameter>
               <Parameter Name="k4" Role="user defined" Unit="s-1">0.025</Parameter>
               <Parameter Name="KK4" Role="user defined" Unit="1.0E-6 m-3.mol">15.0</Parameter>
               <Parameter Name="sbmlRateFactor" Role="user defined" Unit="1000.0 ">9.999999999999998E-4</Parameter>
               <Parameter Name="MKKK_P_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
               <Parameter Name="MKK_P_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
            </Kinetics>
         </SimpleReaction>
         <SimpleReaction Structure="uVol" Name="J4" FluxCarrierValence="0" FluxOption="MolecularOnly">
            <Reactant LocalizedCompoundRef="MKK_PP" Stoichiometry="1" />
            <Product LocalizedCompoundRef="MKK_P" Stoichiometry="1" />
            <Kinetics KineticsType="GeneralKinetics">
               <Parameter Name="J" Role="reaction rate" Unit="uM.s-1">(sbmlRateFactor * V5 * MKK_PP * MKK_PP_ConcFactor / (KK5 + (MKK_PP * MKK_PP_ConcFactor)))</Parameter>
               <Parameter Name="V5" Role="user defined" Unit="1.0E-6 m-3.mol.s-1">0.75</Parameter>
               <Parameter Name="KK5" Role="user defined" Unit="1.0E-6 m-3.mol">15.0</Parameter>
               <Parameter Name="sbmlRateFactor" Role="user defined" Unit="1000.0 ">9.999999999999998E-4</Parameter>
               <Parameter Name="MKK_PP_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
            </Kinetics>
         </SimpleReaction>
         <SimpleReaction Structure="uVol" Name="J5" FluxCarrierValence="0" FluxOption="MolecularOnly">
            <Reactant LocalizedCompoundRef="MKK_P" Stoichiometry="1" />
            <Product LocalizedCompoundRef="MKK" Stoichiometry="1" />
            <Kinetics KineticsType="GeneralKinetics">
               <Parameter Name="J" Role="reaction rate" Unit="uM.s-1">(sbmlRateFactor * V6 * MKK_P * MKK_P_ConcFactor / (KK6 + (MKK_P * MKK_P_ConcFactor)))</Parameter>
               <Parameter Name="V6" Role="user defined" Unit="1.0E-6 m-3.mol.s-1">0.75</Parameter>
               <Parameter Name="KK6" Role="user defined" Unit="1.0E-6 m-3.mol">15.0</Parameter>
               <Parameter Name="sbmlRateFactor" Role="user defined" Unit="1000.0 ">9.999999999999998E-4</Parameter>
               <Parameter Name="MKK_P_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
            </Kinetics>
         </SimpleReaction>
         <SimpleReaction Structure="uVol" Name="J6" FluxCarrierValence="0" FluxOption="MolecularOnly">
            <Reactant LocalizedCompoundRef="MAPK" Stoichiometry="1" />
            <Product LocalizedCompoundRef="MAPK_P" Stoichiometry="1" />
            <Modifier LocalizedCompoundRef="MKK_PP" />
            <Kinetics KineticsType="GeneralKinetics">
               <Parameter Name="J" Role="reaction rate" Unit="uM.s-1">(sbmlRateFactor * k7 * MKK_PP * MKK_PP_ConcFactor * MAPK * MAPK_ConcFactor / (KK7 + (MAPK * MAPK_ConcFactor)))</Parameter>
               <Parameter Name="k7" Role="user defined" Unit="s-1">0.025</Parameter>
               <Parameter Name="KK7" Role="user defined" Unit="1.0E-6 m-3.mol">15.0</Parameter>
               <Parameter Name="sbmlRateFactor" Role="user defined" Unit="1000.0 ">9.999999999999998E-4</Parameter>
               <Parameter Name="MKK_PP_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
               <Parameter Name="MAPK_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
            </Kinetics>
         </SimpleReaction>
         <SimpleReaction Structure="uVol" Name="J7" FluxCarrierValence="0" FluxOption="MolecularOnly">
            <Reactant LocalizedCompoundRef="MAPK_P" Stoichiometry="1" />
            <Product LocalizedCompoundRef="MAPK_PP" Stoichiometry="1" />
            <Modifier LocalizedCompoundRef="MKK_PP" />
            <Kinetics KineticsType="GeneralKinetics">
               <Parameter Name="J" Role="reaction rate" Unit="uM.s-1">(sbmlRateFactor * k8 * MKK_PP * MKK_PP_ConcFactor * MAPK_P * MAPK_P_ConcFactor / (KK8 + (MAPK_P * MAPK_P_ConcFactor)))</Parameter>
               <Parameter Name="k8" Role="user defined" Unit="s-1">0.025</Parameter>
               <Parameter Name="KK8" Role="user defined" Unit="1.0E-6 m-3.mol">15.0</Parameter>
               <Parameter Name="sbmlRateFactor" Role="user defined" Unit="1000.0 ">9.999999999999998E-4</Parameter>
               <Parameter Name="MKK_PP_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
               <Parameter Name="MAPK_P_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
            </Kinetics>
         </SimpleReaction>
         <SimpleReaction Structure="uVol" Name="J8" FluxCarrierValence="0" FluxOption="MolecularOnly">
            <Reactant LocalizedCompoundRef="MAPK_PP" Stoichiometry="1" />
            <Product LocalizedCompoundRef="MAPK_P" Stoichiometry="1" />
            <Kinetics KineticsType="GeneralKinetics">
               <Parameter Name="J" Role="reaction rate" Unit="uM.s-1">(sbmlRateFactor * V9 * MAPK_PP * MAPK_PP_ConcFactor / (KK9 + (MAPK_PP * MAPK_PP_ConcFactor)))</Parameter>
               <Parameter Name="V9" Role="user defined" Unit="1.0E-6 m-3.mol.s-1">0.5</Parameter>
               <Parameter Name="KK9" Role="user defined" Unit="1.0E-6 m-3.mol">15.0</Parameter>
               <Parameter Name="sbmlRateFactor" Role="user defined" Unit="1000.0 ">9.999999999999998E-4</Parameter>
               <Parameter Name="MAPK_PP_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
            </Kinetics>
         </SimpleReaction>
         <SimpleReaction Structure="uVol" Name="J9" FluxCarrierValence="0" FluxOption="MolecularOnly">
            <Reactant LocalizedCompoundRef="MAPK_P" Stoichiometry="1" />
            <Product LocalizedCompoundRef="MAPK" Stoichiometry="1" />
            <Kinetics KineticsType="GeneralKinetics">
               <Parameter Name="J" Role="reaction rate" Unit="uM.s-1">(sbmlRateFactor * V10 * MAPK_P * MAPK_P_ConcFactor / (KK10 + (MAPK_P * MAPK_P_ConcFactor)))</Parameter>
               <Parameter Name="V10" Role="user defined" Unit="1.0E-6 m-3.mol.s-1">0.5</Parameter>
               <Parameter Name="KK10" Role="user defined" Unit="1.0E-6 m-3.mol">15.0</Parameter>
               <Parameter Name="sbmlRateFactor" Role="user defined" Unit="1000.0 ">9.999999999999998E-4</Parameter>
               <Parameter Name="MAPK_P_ConcFactor" Role="user defined" Unit="0.0010 ">1000.0000000000001</Parameter>
            </Kinetics>
         </SimpleReaction>
         <Diagram Name="uVol" Structure="uVol" />
      </Model>
      <SimulationSpec Name="Kholodenko2000_MAPK_feedback_Compartmental" Stochastic="false" UseConcentration="true">
         <Geometry Name="Compartmental" Dimension="0">
            <Extent X="10.0" Y="10.0" Z="10.0" />
            <Origin X="0.0" Y="0.0" Z="0.0" />
            <SubVolume Name="Compartment" Handle="0" Type="Compartmental" />
         </Geometry>
         <GeometryContext>
            <FeatureMapping Feature="uVol" SubVolume="Compartment" Resolved="false" Size="1.0000000000000001E15">
               <BoundariesTypes Xm="Flux" Xp="Flux" Ym="Flux" Yp="Flux" Zm="Flux" Zp="Flux" />
            </FeatureMapping>
         </GeometryContext>
         <ReactionContext>
            <LocalizedCompoundSpec LocalizedCompoundRef="MKKK" ForceConstant="false" EnableDiffusion="true">
               <InitialConcentration>0.08999999999999998</InitialConcentration>
               <Diffusion>0.0</Diffusion>
            </LocalizedCompoundSpec>
            <LocalizedCompoundSpec LocalizedCompoundRef="MKKK_P" ForceConstant="false" EnableDiffusion="true">
               <InitialConcentration>0.009999999999999998</InitialConcentration>
               <Diffusion>0.0</Diffusion>
            </LocalizedCompoundSpec>
            <LocalizedCompoundSpec LocalizedCompoundRef="MKK" ForceConstant="false" EnableDiffusion="true">
               <InitialConcentration>0.27999999999999997</InitialConcentration>
               <Diffusion>0.0</Diffusion>
            </LocalizedCompoundSpec>
            <LocalizedCompoundSpec LocalizedCompoundRef="MKK_P" ForceConstant="false" EnableDiffusion="true">
               <InitialConcentration>0.009999999999999998</InitialConcentration>
               <Diffusion>0.0</Diffusion>
            </LocalizedCompoundSpec>
            <LocalizedCompoundSpec LocalizedCompoundRef="MKK_PP" ForceConstant="false" EnableDiffusion="true">
               <InitialConcentration>0.009999999999999998</InitialConcentration>
               <Diffusion>0.0</Diffusion>
            </LocalizedCompoundSpec>
            <LocalizedCompoundSpec LocalizedCompoundRef="MAPK" ForceConstant="false" EnableDiffusion="true">
               <InitialConcentration>0.27999999999999997</InitialConcentration>
               <Diffusion>0.0</Diffusion>
            </LocalizedCompoundSpec>
            <LocalizedCompoundSpec LocalizedCompoundRef="MAPK_P" ForceConstant="false" EnableDiffusion="true">
               <InitialConcentration>0.009999999999999998</InitialConcentration>
               <Diffusion>0.0</Diffusion>
            </LocalizedCompoundSpec>
            <LocalizedCompoundSpec LocalizedCompoundRef="MAPK_PP" ForceConstant="false" EnableDiffusion="true">
               <InitialConcentration>0.009999999999999998</InitialConcentration>
               <Diffusion>0.0</Diffusion>
            </LocalizedCompoundSpec>
            <ReactionSpec ReactionStepRef="J0" ReactionMapping="included" />
            <ReactionSpec ReactionStepRef="J1" ReactionMapping="included" />
            <ReactionSpec ReactionStepRef="J2" ReactionMapping="included" />
            <ReactionSpec ReactionStepRef="J3" ReactionMapping="included" />
            <ReactionSpec ReactionStepRef="J4" ReactionMapping="included" />
            <ReactionSpec ReactionStepRef="J5" ReactionMapping="included" />
            <ReactionSpec ReactionStepRef="J6" ReactionMapping="included" />
            <ReactionSpec ReactionStepRef="J7" ReactionMapping="included" />
            <ReactionSpec ReactionStepRef="J8" ReactionMapping="included" />
            <ReactionSpec ReactionStepRef="J9" ReactionMapping="included" />
         </ReactionContext>
      </SimulationSpec>
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