Location: Chen, Popel, 2006 @ 609ef8a095e8 / chen_popel_2006.cellml

Author:
pmr2.import <nobody@models.cellml.org>
Date:
2007-08-30 05:47:21+12:00
Desc:
committing version01 of chen_popel_2006
Permanent Source URI:
https://models.physiomeproject.org/workspace/36b/rawfile/609ef8a095e89e842e0fa2acb57cbf663dfa3263/chen_popel_2006.cellml

<?xml version='1.0' encoding='utf-8'?>
<!--  FILE :  chen_model_2006.xml

CREATED :  30th August 2007

LAST MODIFIED : 30th August 2007

AUTHOR :  Catherine Lloyd
          Bioengineering Institute
          The University of Auckland
          
MODEL STATUS :  This model conforms to the CellML 1.1 Specification.

DESCRIPTION :  This file contains a CellML description of Chen and Popel's 2006 mathematical model of biochemical pathways of nitric oxide release from vascular endothelial cells.

CHANGES:  
  
--><model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqs="http://www.cellml.org/bqs/1.0#" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" cmeta:id="chen_model_2006" name="chen_popel_model_2006_version01">

<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
  <articleinfo>
  <title>Theoretical analysis of biochemical pathways of nitric oxide release from vascular endothelial cells</title>
  <author>
    <firstname>Catherine</firstname>
          <surname>Lloyd</surname>
    <affiliation>
      <shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
    </affiliation>
  </author>
</articleinfo>
  <sect1 id="sec_structure">
  <title>Model Structure</title>

<para>
Nitric oxide (NO) plays an essential role in a diverse range of physiological and pathological processes, including acting as a potent vasodilator.  NO can be synthesised in a reaction catalysed by the enzyme nitric oxide synthase (NOS), of which there are three isoforms: neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3).  The substrates required for NO synthesis include: L-arginine (Arg), oxygen (O2), and nicotinamide adenine dinucleotide phosphate (NADPH).  Once NO is synthesised in the vasculature, it diffuses into the smooth muscle of the blood vessel walls, resulting in muscle relaxation and vasodilation.  As such, NO derived from NOS3 has been considered as the main regulator of vascular tone.  However, despite its physiological importance, there is a general lack of data on NO production and how its distribution changes around arterioles under different oxygen conditions, mainly due to experimental limitations.
</para>

<para>
In the study described here in CellML, Kejing Chen and Aleksander Popel have focused on NO production catalysed by eNOS in particular, and they have developed a mathematical model to capture the characteristics of this biochemical pathway.  A schematic diagram of the reactions included in this model is outlined in the figure below.
</para>

<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
  <imageobject>
    <objectinfo>
      <title>model diagram</title>
    </objectinfo>
    <imagedata fileref="chen_model_2006.gif"/>
  </imageobject>
</mediaobject>
<caption>Schematic diagram of the mathematical model.  Pathway of nitric oxide (NO) synthesis catalysed by endothelial nitric oxide synthase (eNOS, or eNOS3).  The heme iron (Fe) is the main catalysis site and is used to represent the enzyme in this figure and also in the model.  The heme ion of eNOS binds L-arginine (Arg), hydroxyl-L-arginine (NOHA), and oxygen (O2), and undergoes a series of oxygenation and reduction reactions.</caption>
</informalfigure>

<para>
The complete original paper reference is cited below:
</para>

<para>
<ulink url="http://www.sciencedirect.com/science?_ob=ArticleURL&amp;_udi=B6T38-4K0C9J0-1&amp;_user=140507&amp;_coverDate=08%2F15%2F2006&amp;_rdoc=1&amp;_fmt=summary&amp;_orig=search&amp;_cdi=4940&amp;_sort=d&amp;_docanchor=&amp;view=c&amp;_acct=C000011498&amp;_version=1&amp;_urlVersion=0&amp;_userid=140507&amp;md5=bf746bb9f29371129a38807d2671010b">Theoretical analysis of biochemical pathways of nitric oxide release from vascular endothelial cells</ulink>, Kejing Chen and Aleksander S. Popel, 2006, <ulink url="http://www.sciencedirect.com/science/journal/08915849">
            <emphasis>Free Radical Biology and Medicine</emphasis>
          </ulink>, 41, 668-680.  (<ulink url="http://www.sciencedirect.com/science?_ob=ArticleURL&amp;_udi=B6T38-4K0C9J0-1&amp;_user=140507&amp;_coverDate=08%2F15%2F2006&amp;_rdoc=1&amp;_fmt=full&amp;_orig=search&amp;_cdi=4940&amp;_sort=d&amp;_docanchor=&amp;view=c&amp;_acct=C000011498&amp;_version=1&amp;_urlVersion=0&amp;_userid=140507&amp;md5=00a43f25f5dbc6d5b5c0ce55ee10da20">Full text</ulink> and PDF versions of the article are available to journal subscribers on the <emphasis>Free Radical Biology and Medicine</emphasis> website.)  <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&amp;cmd=Retrieve&amp;dopt=AbstractPlus&amp;list_uids=16864000&amp;query_hl=1&amp;itool=pubmed_docsum">PubMed ID: 16864000</ulink>
</para>

</sect1>
</article>
</documentation> 





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            <ci>time</ci>
          </bvar> 
          <ci> Fe2_NOHA </ci> 
        </apply>
        <apply>
          <minus/> 
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> k7 </ci>
              <ci> Fe3_NOHA </ci>
            </apply>
            <apply>
              <times/>
              <ci> k_10 </ci>
              <ci> Fe3_O2_NOHA </ci>
            </apply>
            <apply>
              <times/>
              <ci> k_9 </ci>
              <ci> Fe2 </ci>
              <ci> NOHA </ci>
            </apply>
          </apply>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> k9 </ci>
              <ci> Fe2_NOHA </ci>
            </apply>
            <apply>
              <times/>
              <ci> k10 </ci>
              <ci> Fe2_NOHA </ci>
              <ci> O2 </ci>
            </apply>
          </apply>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="Fe3_O2_NOHA" name="Fe3_O2_NOHA">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="Fe3_O2_NOHA">
        <dc:title>Fe3_O2_NOHA</dc:title>
        <dcterms:alternative>oxidised neuronal nitric oxide synthase (heme iron 3+) bound to hydroxyl-L-arginine</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable units="micromolar" public_interface="out" name="Fe3_O2_NOHA" initial_value="0.0"/>
    
    <variable units="micromolar" public_interface="in" name="Fe2_NOHA"/>
    <variable units="micromolar" public_interface="in" name="O2"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k11"/>
    <variable units="second_order_rate_constant" public_interface="in" name="k10"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k_10"/>
    <variable units="second" public_interface="in" name="time"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="8"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> Fe3_O2_NOHA </ci> 
        </apply>
        <apply>
          <minus/> 
          <apply>
            <times/>
            <ci> k10 </ci>
            <ci> Fe2_NOHA </ci>
            <ci> O2 </ci>
          </apply>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> k11 </ci>
              <ci> Fe3_O2_NOHA </ci>
            </apply>
            <apply>
              <times/>
              <ci> k_10 </ci>
              <ci> Fe3_O2_NOHA </ci>
            </apply>
          </apply>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="Fe3_NO" name="Fe3_NO">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="Fe3_NO">
        <dc:title>Fe3_NO</dc:title>
        <dcterms:alternative>neuronal nitric oxide synthase (heme iron 3+) bound to nitric oxide</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable units="micromolar" public_interface="out" name="Fe3_NO" initial_value="0.0"/>
    
    <variable units="micromolar" public_interface="in" name="Fe3_O2_NOHA"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k12"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k14"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k11"/>
    <variable units="second" public_interface="in" name="time"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="9"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> Fe3_NO </ci> 
        </apply>
        <apply>
          <minus/> 
          <apply>
            <times/>
            <ci> k11 </ci>
            <ci> Fe3_O2_NOHA </ci>
          </apply>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> k14 </ci>
              <ci> Fe3_NO </ci>
            </apply>
            <apply>
              <times/>
              <ci> k12 </ci>
              <ci> Fe3_NO </ci>
            </apply>
          </apply>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="Fe2_NO" name="Fe2_NO">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="Fe2_NO">
        <dc:title>Fe2_NO</dc:title>
        <dcterms:alternative>neuronal nitric oxide synthase (heme iron 2+) bound to nitric oxide</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable units="micromolar" public_interface="out" name="Fe2_NO" initial_value="0.0"/>
    
    <variable units="micromolar" public_interface="in" name="Fe3_NO"/>
    <variable units="micromolar" public_interface="in" name="O2"/>
    <variable units="second_order_rate_constant" public_interface="in" name="k13"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k12"/>
    <variable units="second" public_interface="in" name="time"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="10"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> Fe2_NO </ci> 
        </apply>
        <apply>
          <minus/> 
          <apply>
            <times/>
            <ci> k12 </ci>
            <ci> Fe3_NO </ci>
          </apply>
          <apply>
            <times/>
            <ci> k13 </ci>
            <ci> Fe2_NO </ci>
            <ci> O2 </ci>
          </apply>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="NO" name="NO">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="NO">
        <dc:title>NO</dc:title>
        <dcterms:alternative>nitric oxide</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable units="micromolar" name="NO" initial_value="0.0"/>
    
    <variable units="micromolar" public_interface="in" name="Fe3_NO"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k14"/>
    <variable units="second" public_interface="in" name="time"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="11"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> NO </ci> 
        </apply>
        <apply>
          <times/>
          <ci> k14 </ci>
          <ci> Fe3_NO </ci>
        </apply>
      </apply>
    </math>
  </component>

  <component name="citrulline">  
    <variable units="micromolar" name="citrulline" initial_value="0.0"/>
    
    <variable units="micromolar" public_interface="in" name="Fe3_O2_NOHA"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k11"/>
    <variable units="second" public_interface="in" name="time"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="12"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> citrulline </ci> 
        </apply>
        <apply>
          <times/>
          <ci> k11 </ci>
          <ci> Fe3_O2_NOHA </ci>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="NO3" name="NO3">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="NO3">
        <dc:title>NO3</dc:title>
        <dcterms:alternative>nitrate</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable units="micromolar" name="NO3" initial_value="0.0"/>
    
    <variable units="micromolar" public_interface="in" name="Fe2_NO"/>
    <variable units="micromolar" public_interface="in" name="O2"/>
    <variable units="second_order_rate_constant" public_interface="in" name="k13"/>
    <variable units="second" public_interface="in" name="time"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="13"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> NO3 </ci> 
        </apply>
        <apply>
          <times/>
          <ci> k13 </ci>
          <ci> Fe2_NO </ci>
          <ci> O2 </ci>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="NOHA" name="NOHA">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="NOHA">
        <dc:title>NOHA</dc:title>
        <dcterms:alternative>hydroxyl-L-arginine</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable units="micromolar" public_interface="out" name="NOHA" initial_value="0.0"/>
    
    <variable units="micromolar" public_interface="in" name="Fe2_NOHA"/>
    <variable units="micromolar" public_interface="in" name="Fe2"/>
    <variable units="micromolar" public_interface="in" name="Fe3_NOHA"/>
    <variable units="micromolar" public_interface="in" name="Fe3"/>
    <variable units="second_order_rate_constant" public_interface="in" name="k_8"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k8"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k9"/>
    <variable units="second_order_rate_constant" public_interface="in" name="k_9"/>
    <variable units="second" public_interface="in" name="time"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="14"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> NOHA </ci> 
        </apply>
        <apply>
          <minus/>
          <apply>
            <plus/>  
            <apply>
              <times/>
              <ci> k8 </ci>
              <ci> Fe3_NOHA </ci>
            </apply>
            <apply>
              <times/>
              <ci> k9 </ci>
              <ci> Fe2_NOHA </ci>
            </apply>
          </apply>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> k_8 </ci>
              <ci> Fe3 </ci>
              <ci> NOHA </ci>
            </apply>
            <apply>
              <times/>
              <ci> k_9 </ci>
              <ci> Fe2 </ci>
              <ci> NOHA </ci>
            </apply>
          </apply>
        </apply>
      </apply>
    </math>
  </component>

  <component name="model_constants"> 
    <variable units="micromolar" public_interface="out" name="O2" initial_value="172.0"/>
    <variable units="second_order_rate_constant" public_interface="out" name="k1" initial_value="0.1"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k_1" initial_value="0.1"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k2" initial_value="0.91"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k3" initial_value="0.91"/>
    <variable units="second_order_rate_constant" public_interface="out" name="k4" initial_value="1.89"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k_4" initial_value="11.4"/>
    <variable units="second_order_rate_constant" public_interface="out" name="k5" initial_value="2.58"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k_5" initial_value="98.0"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k6" initial_value="12.6"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k7" initial_value="0.91"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k8" initial_value="0.1"/>
    <variable units="second_order_rate_constant" public_interface="out" name="k_8" initial_value="0.1"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k9" initial_value="11.4"/>
    <variable units="second_order_rate_constant" public_interface="out" name="k_9" initial_value="1.89"/>
    <variable units="second_order_rate_constant" public_interface="out" name="k10" initial_value="3.33"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k_10" initial_value="89.9"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k11" initial_value="29.4"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k12" initial_value="0.91"/>
    <variable units="second_order_rate_constant" public_interface="out" name="k13" initial_value="0.033"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k14" initial_value="53.9"/>
  </component>

  <connection>
    <map_components component_2="environment" component_1="Arg"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="Fe3"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>

  <connection>
    <map_components component_2="environment" component_1="Fe3_Arg"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="Fe2"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>

  <connection>
    <map_components component_2="environment" component_1="Fe2_Arg"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="Fe3_O2_Arg"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>

  <connection>
    <map_components component_2="environment" component_1="Fe3_NOHA"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>

  <connection>
    <map_components component_2="environment" component_1="Fe2_NOHA"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="Fe3_O2_NOHA"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>

  <connection>
    <map_components component_2="environment" component_1="Fe3_NO"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="Fe2_NO"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>

  <connection>
    <map_components component_2="environment" component_1="NO"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>

  <connection>
    <map_components component_2="environment" component_1="citrulline"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>

  <connection>
    <map_components component_2="environment" component_1="NO3"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>

  <connection>
    <map_components component_2="environment" component_1="NOHA"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>

  <connection>
    <map_components component_2="Arg" component_1="Fe3"/>
    <map_variables variable_2="Fe3" variable_1="Fe3"/>
    <map_variables variable_2="Arg" variable_1="Arg"/>
  </connection>

  <connection>
    <map_components component_2="Arg" component_1="Fe2"/>
    <map_variables variable_2="Fe2" variable_1="Fe2"/>
    <map_variables variable_2="Arg" variable_1="Arg"/>
  </connection>

  <connection>
    <map_components component_2="Arg" component_1="Fe3_Arg"/>
    <map_variables variable_2="Fe3_Arg" variable_1="Fe3_Arg"/>
    <map_variables variable_2="Arg" variable_1="Arg"/>
  </connection>

  <connection>
    <map_components component_2="Arg" component_1="Fe2_Arg"/>
    <map_variables variable_2="Fe2_Arg" variable_1="Fe2_Arg"/>
    <map_variables variable_2="Arg" variable_1="Arg"/>
  </connection>

  <connection>
    <map_components component_2="model_constants" component_1="Arg"/>
    <map_variables variable_2="k1" variable_1="k1"/>
    <map_variables variable_2="k_1" variable_1="k_1"/>
    <map_variables variable_2="k4" variable_1="k4"/>
    <map_variables variable_2="k_4" variable_1="k_4"/>
  </connection>  
  
  <connection>
    <map_components component_2="Fe3_Arg" component_1="Fe3"/>
    <map_variables variable_2="Fe3" variable_1="Fe3"/>
    <map_variables variable_2="Fe3_Arg" variable_1="Fe3_Arg"/>
  </connection>

  <connection>
    <map_components component_2="Fe3_NOHA" component_1="Fe3"/>
    <map_variables variable_2="Fe3" variable_1="Fe3"/>
    <map_variables variable_2="Fe3_NOHA" variable_1="Fe3_NOHA"/>
  </connection>

  <connection>
    <map_components component_2="NOHA" component_1="Fe3"/>
    <map_variables variable_2="Fe3" variable_1="Fe3"/>
    <map_variables variable_2="NOHA" variable_1="NOHA"/>
  </connection>  

  <connection>
    <map_components component_2="Fe3_NO" component_1="Fe3"/>
    <map_variables variable_2="Fe3_NO" variable_1="Fe3_NO"/>
  </connection>

  <connection>
    <map_components component_2="Fe2_NO" component_1="Fe3"/>
    <map_variables variable_2="Fe2_NO" variable_1="Fe2_NO"/>
  </connection>

  <connection>
    <map_components component_2="model_constants" component_1="Fe3"/>
    <map_variables variable_2="O2" variable_1="O2"/>
    <map_variables variable_2="k1" variable_1="k1"/>
    <map_variables variable_2="k_1" variable_1="k_1"/>
    <map_variables variable_2="k2" variable_1="k2"/>
    <map_variables variable_2="k8" variable_1="k8"/>
    <map_variables variable_2="k_8" variable_1="k_8"/>
    <map_variables variable_2="k13" variable_1="k13"/>
    <map_variables variable_2="k14" variable_1="k14"/>
  </connection>

  <connection>
    <map_components component_2="model_constants" component_1="Fe3_Arg"/>
    <map_variables variable_2="k1" variable_1="k1"/>
    <map_variables variable_2="k_1" variable_1="k_1"/>
    <map_variables variable_2="k3" variable_1="k3"/>
  </connection>

  <connection>
    <map_components component_2="Fe2_Arg" component_1="Fe2"/>
    <map_variables variable_2="Fe2" variable_1="Fe2"/>
    <map_variables variable_2="Fe2_Arg" variable_1="Fe2_Arg"/>
  </connection> 

  <connection>
    <map_components component_2="Fe3" component_1="Fe2"/>
    <map_variables variable_2="Fe3" variable_1="Fe3"/>
  </connection>

  <connection>
    <map_components component_2="Fe2_NOHA" component_1="Fe2"/>
    <map_variables variable_2="Fe2" variable_1="Fe2"/>
    <map_variables variable_2="Fe2_NOHA" variable_1="Fe2_NOHA"/>
  </connection>

  <connection>
    <map_components component_2="NOHA" component_1="Fe2"/>
    <map_variables variable_2="Fe2" variable_1="Fe2"/>
    <map_variables variable_2="NOHA" variable_1="NOHA"/>
  </connection>  

  <connection>
    <map_components component_2="model_constants" component_1="Fe2"/>
    <map_variables variable_2="k4" variable_1="k4"/>
    <map_variables variable_2="k_4" variable_1="k_4"/>
    <map_variables variable_2="k9" variable_1="k9"/>
    <map_variables variable_2="k_9" variable_1="k_9"/>
    <map_variables variable_2="k2" variable_1="k2"/>
  </connection>

  <connection>
    <map_components component_2="Fe2_Arg" component_1="Fe3_O2_Arg"/>
    <map_variables variable_2="Fe3_O2_Arg" variable_1="Fe3_O2_Arg"/>
    <map_variables variable_2="Fe2_Arg" variable_1="Fe2_Arg"/>
  </connection> 

  <connection>
    <map_components component_2="Fe3_Arg" component_1="Fe2_Arg"/>
    <map_variables variable_2="Fe3_Arg" variable_1="Fe3_Arg"/>
  </connection>

  <connection>
    <map_components component_2="model_constants" component_1="Fe2_Arg"/>
    <map_variables variable_2="O2" variable_1="O2"/>
    <map_variables variable_2="k4" variable_1="k4"/>
    <map_variables variable_2="k_4" variable_1="k_4"/>
    <map_variables variable_2="k5" variable_1="k5"/>
    <map_variables variable_2="k_5" variable_1="k_5"/>
    <map_variables variable_2="k3" variable_1="k3"/>
  </connection>

  <connection>
    <map_components component_2="model_constants" component_1="Fe3_O2_Arg"/>
    <map_variables variable_2="O2" variable_1="O2"/>
    <map_variables variable_2="k5" variable_1="k5"/>
    <map_variables variable_2="k_5" variable_1="k_5"/>
    <map_variables variable_2="k6" variable_1="k6"/>
  </connection>

  <connection>
    <map_components component_2="Fe3_O2_Arg" component_1="Fe3_NOHA"/>
    <map_variables variable_2="Fe3_O2_Arg" variable_1="Fe3_O2_Arg"/>
  </connection>

  <connection>
    <map_components component_2="NOHA" component_1="Fe3_NOHA"/>
    <map_variables variable_2="NOHA" variable_1="NOHA"/>
    <map_variables variable_2="Fe3_NOHA" variable_1="Fe3_NOHA"/>
  </connection> 

  <connection>
    <map_components component_2="model_constants" component_1="Fe3_NOHA"/>
    <map_variables variable_2="k6" variable_1="k6"/>
    <map_variables variable_2="k7" variable_1="k7"/>
    <map_variables variable_2="k8" variable_1="k8"/>
    <map_variables variable_2="k_8" variable_1="k_8"/>
  </connection>

  <connection>
    <map_components component_2="NOHA" component_1="Fe2_NOHA"/>
    <map_variables variable_2="NOHA" variable_1="NOHA"/>
    <map_variables variable_2="Fe2_NOHA" variable_1="Fe2_NOHA"/>
  </connection> 

  <connection>
    <map_components component_2="Fe3_NOHA" component_1="Fe2_NOHA"/>
    <map_variables variable_2="Fe3_NOHA" variable_1="Fe3_NOHA"/>
  </connection>

  <connection>
    <map_components component_2="Fe3_O2_NOHA" component_1="Fe2_NOHA"/>
    <map_variables variable_2="Fe2_NOHA" variable_1="Fe2_NOHA"/>
    <map_variables variable_2="Fe3_O2_NOHA" variable_1="Fe3_O2_NOHA"/>
  </connection>

  <connection>
    <map_components component_2="model_constants" component_1="Fe2_NOHA"/>
    <map_variables variable_2="O2" variable_1="O2"/>
    <map_variables variable_2="k7" variable_1="k7"/>
    <map_variables variable_2="k_10" variable_1="k_10"/>
    <map_variables variable_2="k10" variable_1="k10"/>
    <map_variables variable_2="k9" variable_1="k9"/>
    <map_variables variable_2="k_9" variable_1="k_9"/>
  </connection>

  <connection>
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