<?xml version="1.0"?>

<!--  FILE :  cholesterol_biosynthesis_model.xml

CREATED :  14th June 2002

LAST MODIFIED : 22nd July 2002

AUTHOR :  Catherine Lloyd
          The Bioengineering Institute
          The University of Auckland
          
MODEL STATUS :  This model conforms to the CellML 1.0 Specification released on
                10th August 2001, and the 16/01/2002 CellML Metadata 1.0
                Specification.

DESCRIPTION :  This file contains a CellML description of a generic model of
               cholesterol biosynthesis.

CHANGES:  
   22/07/2002 - CML - Added more metadata.
-->

<model name="cholesterol_biosynthesis_model" pathway_editor:rendering_config_file="cholesterol_biosynthesis_CellMLrender.xml" xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" xmlns:pathway_editor="http://www.physiome.com/pathway_editor/1.0#">
  <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqs="http://www.cellml.org/bqs/1.0#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
    <!--
      The following RDF block contains metadata that applies to this document
      as a whole, as indicated by the empty about attribute on the 
      <rdf:Description> element.
    -->
    <rdf:Description rdf:about="">
      <!--
        The Model Builder Metadata.  The Dublin Core "creator" element is used  
        to indicate the person who translated the model into CellML.
      -->
      <dc:creator rdf:parseType="Resource">
        <vCard:N rdf:parseType="Resource">
          <vCard:Family>Lloyd</vCard:Family>
          <vCard:Given>Catherine</vCard:Given>
          <vCard:Other>May</vCard:Other>
        </vCard:N>
        <vCard:EMAIL rdf:parseType="Resource">
          <rdf:value>c.lloyd@auckland.ac.nz</rdf:value>
          <rdf:type rdf:resource="http://imc.org/vCard/3.0#internet" />
        </vCard:EMAIL>
        <vCard:ORG rdf:parseType="Resource">
          <vCard:Orgname>The University of Auckland</vCard:Orgname>
          <vCard:Orgunit>The Bioengineering Institute</vCard:Orgunit>
        </vCard:ORG>
      </dc:creator>
      
      <!--
        The Creation Date metadata. This is the date on which the model
        was translated into CellML.
      -->
      <dcterms:created rdf:parseType="Resource">
        <dcterms:W3CDTF>2002-06-14</dcterms:W3CDTF>
      </dcterms:created>
      
      <!--
        The Last Modified Date metadata. This is the date on which
        the model was last changed.
      -->
      <cmeta:modification rdf:parseType="Resource">
        <rdf:value>
          Added more metadata.
        </rdf:value>
        <cmeta:modifier rdf:parseType="Resource">
          <vCard:N rdf:parseType="Resource">
            <vCard:Family>Lloyd</vCard:Family>
            <vCard:Given>Catherine</vCard:Given>
            <vCard:Other>May</vCard:Other>
          </vCard:N>
        </cmeta:modifier>
        <dcterms:modified rdf:parseType="Resource"> 
          <dcterms:W3CDTF>2002-07-22</dcterms:W3CDTF>
        </dcterms:modified>
      </cmeta:modification>
      
      <!-- The Publisher metadata. -->
      <dc:publisher>
        The University of Auckland, Bioengineering Institute
      </dc:publisher>
    </rdf:Description>
    
    <!--
      The following metadata refers to the model itself, as indicated by the
      reference to the ID "cholesterol_biosynthesis_mode1", which is declared on 
      the <model> element.
    -->
    <rdf:Description rdf:about="#cholesterol_biosynthesis_mode1">
      <!-- A human readable name for the model. -->
      <dc:title>A Generic Model Of Cholesterol Synthesis</dc:title>
      
      <!-- A comment regarding the model. -->
      <cmeta:comment rdf:parseType="Resource">
        <rdf:value>
          Below is a CellML description of a general model of cholesterol 
          synthesis.  It is not based on a specific published mathematical 
          model, but instead it is based on a textbook defined pathway.  The 
          general sequential structure and all the reactant, product and enzyme 
          components are included.  Michaelis-Menten enzyme kinetics are 
          assumed.
          
          The purpose of this description is to illustrate how CellML can be
          used to model a general metabolic pathway.
        </rdf:value>
        <!-- The creator of the comment. -->
        <dc:creator>
          <vCard:FN>Catherine Lloyd</vCard:FN>
        </dc:creator>
      </cmeta:comment>
      
      <cmeta:species>Homo sapiens</cmeta:species>
      
      <!--  Keyword(s) -->
      <bqs:reference rdf:parseType="Resource">
        <dc:subject rdf:parseType="Resource">
          <bqs:subject_type>keyword</bqs:subject_type>
          <rdf:value>metabolism</rdf:value>
        </dc:subject>
      </bqs:reference>
      
      <bqs:Book rdf:parseType="Resource">
        <dc:creator rdf:parseType="Resource">
          <bqs:Person rdf:parseType="Resource">
            <vCard:N rdf:parseType="Resource">
              <vCard:Family>Bronk</vCard:Family>
              <vCard:Given>J</vCard:Given>
              <vCard:Other>Ramsey</vCard:Other>
            </vCard:N>
          </bqs:Person>
        </dc:creator>
        <dc:title>Human Metabolism</dc:title>
        <dcterms:issued rdf:parseType="Resource">
          <dcterms:W3CDTF>1999</dcterms:W3CDTF>
        </dcterms:issued>
        <dc:publisher rdf:parseType="Resource">
          <bqs:Organisation>Addison Wesley Longman Limited</bqs:Organisation>
          <bqs:Property rdf:parseType="Resource">
            <bqs:property_type>location</bqs:property_type>
            <rdf:value>England</rdf:value>
          </bqs:Property>
        </dc:publisher>
      </bqs:Book>
    </rdf:Description>
  </rdf:RDF>
  
  <!--
    We start the model definition with a definition of some named
    sets of units for use throughout the model.
  -->

  <units name="micromolar">
    <unit prefix="micro" units="mole" />
    <unit units="litre" exponent="-1" />
  </units>

  <units name="flux">
     <unit units="micromolar" />
     <unit units="second" exponent="-1" />
  </units>

  <units name="first_order_rate_constant">
    <unit units="second" exponent="-1" />
  </units>

  <units name="second_order_rate_constant">
    <unit units="micromolar" exponent="-1" />
    <unit units="second" exponent="-1" />
  </units>

  <units name="third_order_rate_constant">
    <unit units="micromolar" exponent="-2" />
    <unit units="second" exponent="-1" />
  </units>

  <units name="forth_order_rate_constant">
    <unit units="micromolar" exponent="-3" />
    <unit units="second" exponent="-1" />
  </units>

  <units name="fifth_order_rate_constant">
    <unit units="micromolar" exponent="-4" />
    <unit units="second" exponent="-1" />
  </units>

 <!--  
   The following component is defined for modelling convenience.  It contains 
   all the universal variables, in this case, only time.
 -->
  <component name="global_variables">
    <variable name="time" public_interface="out" units="second" />
  </component>

 <!--  
   The following components describe all the metabolites - both reactants and 
   products - involved in cholesterol synthesis.
  -->

  <component name="Acetyl_CoA" cmeta:id="Acetyl_CoA">
    <variable name="Acetyl_CoA" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_Acetyl_CoA_rxn0" public_interface="in" units="flux" />
    <variable name="delta_Acetyl_CoA_rxn1" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>Acetyl_CoA</ci>
        </apply>
        <apply><plus />
          <ci>delta_Acetyl_CoA_rxn0</ci>
          <ci>delta_Acetyl_CoA_rxn1</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="CoA_SH" cmeta:id="CoA_SH">
    <variable name="CoA_SH" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_CoA_SH_rxn0" public_interface="in" units="flux" />
    <variable name="delta_CoA_SH_rxn1" public_interface="in" units="flux" />
    <variable name="delta_CoA_SH_rxn2" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>CoA_SH</ci>
        </apply>
        <apply><plus />
          <ci>delta_CoA_SH_rxn0</ci>
          <ci>delta_CoA_SH_rxn1</ci>
          <ci>delta_CoA_SH_rxn2</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="Acetoacetyl_CoA" cmeta:id="Acetoacetyl_CoA">
    <variable name="Acetoacetyl_CoA" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_Acetoacetyl_CoA_rxn0" public_interface="in" units="flux" />
    <variable name="delta_Acetoacetyl_CoA_rxn1" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>Acetoacetyl_CoA</ci>
        </apply>
        <apply><plus />
          <ci>delta_Acetoacetyl_CoA_rxn0</ci>
          <ci>delta_Acetoacetyl_CoA_rxn1</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="Hydroxymethylglutaryl_CoA" cmeta:id="Hydroxymethylglutaryl_CoA">
    <variable name="Hydroxymethylglutaryl_CoA" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_Hydroxymethylglutaryl_CoA_rxn1" public_interface="in" units="flux" />
    <variable name="delta_Hydroxymethylglutaryl_CoA_rxn2" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>Hydroxymethylglutaryl_CoA</ci>
        </apply>
        <apply><plus />
          <ci>delta_Hydroxymethylglutaryl_CoA_rxn1</ci>
          <ci>delta_Hydroxymethylglutaryl_CoA_rxn2</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="Mevalonate" cmeta:id="Mevalonate">
    <variable name="Mevalonate" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_Mevalonate_rxn2" public_interface="in" units="flux" />
    <variable name="delta_Mevalonate_rxn3" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>Mevalonate</ci>
        </apply>
        <apply><plus />
          <ci>delta_Mevalonate_rxn2</ci>
          <ci>delta_Mevalonate_rxn3</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="Phosphomevalonate_5" cmeta:id="Phosphomevalonate_5">
    <variable name="Phosphomevalonate_5" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_Phosphomevalonate_5_rxn3" public_interface="in" units="flux" />
    <variable name="delta_Phosphomevalonate_5_rxn4" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>Phosphomevalonate_5</ci>
        </apply>
        <apply><plus />
          <ci>delta_Phosphomevalonate_5_rxn3</ci>
          <ci>delta_Phosphomevalonate_5_rxn4</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="Pyrophosphomevalonate_5" cmeta:id="Pyrophosphomevalonate_5">
    <variable name="Pyrophosphomevalonate_5" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_Pyrophosphomevalonate_5_rxn4" public_interface="in" units="flux" />
    <variable name="delta_Pyrophosphomevalonate_5_rxn5" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>Pyrophosphomevalonate_5</ci>
        </apply>
        <apply><plus />
          <ci>delta_Pyrophosphomevalonate_5_rxn4</ci>
          <ci>delta_Pyrophosphomevalonate_5_rxn5</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="Isopentenyl_pyrophosphate" cmeta:id="Isopentenyl_pyrophosphate">
    <variable name="Isopentenyl_pyrophosphate" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_Isopentenyl_pyrophosphate_rxn5" public_interface="in" units="flux" />
    <variable name="delta_Isopentenyl_pyrophosphate_rxn6" public_interface="in" units="flux" />
    <variable name="delta_Isopentenyl_pyrophosphate_rxn7" public_interface="in" units="flux" />
    <variable name="delta_Isopentenyl_pyrophosphate_rxn8" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>Isopentenyl_pyrophosphate</ci>
        </apply>
        <apply><plus />
          <ci>delta_Isopentenyl_pyrophosphate_rxn5</ci>
          <ci>delta_Isopentenyl_pyrophosphate_rxn6</ci>
          <ci>delta_Isopentenyl_pyrophosphate_rxn7</ci>
          <ci>delta_Isopentenyl_pyrophosphate_rxn8</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="Dimethylallyl_pyrophosphate" cmeta:id="Dimethylallyl_pyrophosphate">
    <variable name="Dimethylallyl_pyrophosphate" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_Dimethylallyl_pyrophosphate_rxn6" public_interface="in" units="flux" />
    <variable name="delta_Dimethylallyl_pyrophosphate_rxn7" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>Dimethylallyl_pyrophosphate</ci>
        </apply>
        <apply><plus />
          <ci>delta_Dimethylallyl_pyrophosphate_rxn6</ci>
          <ci>delta_Dimethylallyl_pyrophosphate_rxn7</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="NADPH" cmeta:id="NADPH">
    <variable name="NADPH" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_NADPH_rxn2" public_interface="in" units="flux" />
    <variable name="delta_NADPH_rxn9" public_interface="in" units="flux" />
    <variable name="delta_NADPH_rxn10" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>NADPH</ci>
        </apply>
        <apply><plus />
          <ci>delta_NADPH_rxn2</ci>
          <ci>delta_NADPH_rxn9</ci>
          <ci>delta_NADPH_rxn10</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="NADP" cmeta:id="NADP">
    <variable name="NADP" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_NADP_rxn2" public_interface="in" units="flux" />
    <variable name="delta_NADP_rxn9" public_interface="in" units="flux" />
    <variable name="delta_NADP_rxn10" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>NADP</ci>
        </apply>
        <apply><plus />
          <ci>delta_NADP_rxn2</ci>
          <ci>delta_NADP_rxn9</ci>
          <ci>delta_NADP_rxn10</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="H" cmeta:id="H">
    <variable name="H" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_H_rxn2" public_interface="in" units="flux" />
    <variable name="delta_H_rxn9" public_interface="in" units="flux" />
    <variable name="delta_H_rxn10" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>H</ci>
        </apply>
        <apply><plus />
          <ci>delta_H_rxn2</ci>
          <ci>delta_H_rxn9</ci>
          <ci>delta_H_rxn10</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="ATP" cmeta:id="ATP">
    <variable name="ATP" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_ATP_rxn3" public_interface="in" units="flux" />
    <variable name="delta_ATP_rxn4" public_interface="in" units="flux" />
    <variable name="delta_ATP_rxn5" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>ATP</ci>
        </apply>
        <apply><plus />
          <ci>delta_ATP_rxn3</ci>
          <ci>delta_ATP_rxn4</ci>
          <ci>delta_ATP_rxn5</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="ADP" cmeta:id="ADP">
    <variable name="ADP" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_ADP_rxn3" public_interface="in" units="flux" />
    <variable name="delta_ADP_rxn4" public_interface="in" units="flux" />
    <variable name="delta_ADP_rxn5" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>ADP</ci>
        </apply>
        <apply><plus />
          <ci>delta_ADP_rxn3</ci>
          <ci>delta_ADP_rxn4</ci>
          <ci>delta_ADP_rxn5</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="Pi" cmeta:id="Pi">
    <variable name="Pi" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_Pi_rxn5" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>Pi</ci>
        </apply>
        <ci>delta_Pi_rxn5</ci>
      </apply>
    </math>
  </component>

  <component name="CO2" cmeta:id="CO2">
    <variable name="CO2" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_CO2_rxn5" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>CO2</ci>
        </apply>
        <ci>delta_CO2_rxn5</ci>
      </apply>
    </math>
  </component>

  <component name="Geranyl_pyrophosphate" cmeta:id="Geranyl_pyrophosphate">
    <variable name="Geranyl_pyrophosphate" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_Geranyl_pyrophosphate_rxn7" public_interface="in" units="flux" />
    <variable name="delta_Geranyl_pyrophosphate_rxn8" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>Geranyl_pyrophosphate</ci>
        </apply>
        <apply><plus />
          <ci>delta_Geranyl_pyrophosphate_rxn7</ci>
          <ci>delta_Geranyl_pyrophosphate_rxn8</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="Farnesyl_pyrophosphate" cmeta:id="Farnesyl_pyrophosphate">
    <variable name="Farnesyl_pyrophosphate" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_Farnesyl_pyrophosphate_rxn8" public_interface="in" units="flux" />
    <variable name="delta_Farnesyl_pyrophosphate_rxn9" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply><eq />
        <apply><diff />
          <bvar>
            <ci>time</ci>
          </bvar>
          <ci>Farnesyl_pyrophosphate</ci>
        </apply>
        <apply><plus />
          <ci>delta_Farnesyl_pyrophosphate_rxn8</ci>
          <ci>delta_Farnesyl_pyrophosphate_rxn9</ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="PPi" cmeta:id="PPi">
    <variable name="PPi" public_interface="out" initial_value="1.0" units="micromolar" />
    <variable name="delta_PPi_rxn7" public_interface="in" units="flux" />
    <variable name="delta_PPi_rxn8" public_interface="in" units="flux" />
    <variable name="delta_PPi_rxn9" public_interface="in" units="flux" />
    <variable name="time" public_interface="in" units="second" />
    <math xmlns="