<?xml version="1.0" encoding="utf-8"?>
<!--
This CellML file was generated on 22/04/2010 at 1:15:15 at p.m. using:
COR (0.9.31.1371)
Copyright 2002-2010 Dr Alan Garny
http://cor.physiol.ox.ac.uk/ - cor@physiol.ox.ac.uk
CellML 1.0 was used to generate this model
http://www.cellml.org/
-->
<model 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:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" name="reed_2004" cmeta:id="reed_2004" 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#">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>A Mathematical Model of the Methionine Cycle</title>
<author>
<firstname>Catherine</firstname>
<surname>Lloyd</surname>
<affiliation>
<shortaffil>Auckland Bioengineering Institute, The University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<section id="sec_status">
<title>Model Status</title>
<para>
This model runs in COR and OpenCell and the units are consistent throughout. The model recreates the published results (Figures 4A and 4B), and is able to simulate other figures if the Metin and 5mTHF values are varied.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
ABSTRACT: Building on the work of Martinov et al. (2000), a mathematical model is developed for the methionine cycle. A large amount of information is available about the enzymes that catalyse individual reaction steps in the cycle, from methionine to S-adenosylmethionine to S-adenosylhomocysteine to homocysteine, and the removal of mass from the cycle by the conversion of homocysteine to cystathionine. Nevertheless, the behavior of the cycle is very complicated since many substrates alter the activities of the enzymes in the reactions that produce them, and some can also alter the activities of other enzymes in the cycle. The model consists of four differential equations, based on known reaction kinetics, that can be solved to give the time course of the concentrations of the four main substrates in the cycle under various circumstances. We show that the behavior of the model in response to genetic abnormalities and dietary deficiencies is similar to the changes seen in a wide variety of experimental studies. We conduct computational "experiments" that give understanding of the regulatory behavior of the methionine cycle under normal conditions and the behavior in the presence of genetic variation and dietary deficiencies.
</para>
<para>
The original paper reference is cited below:
</para>
<para>
A mathematical model of the methionine cycle, Michael C. Reed, H. Frederik Nijhout, Rachel Sparks, and Cornelia M. Ulrich, 2004, <emphasis>Journal of Theoretical Biology</emphasis>, 226, 33-43. <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14637052&dopt=Abstract">PubMed ID: 14637052</ulink>
</para>
<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>reaction diagram</title>
</objectinfo>
<imagedata fileref="reed_2004.png"/>
</imageobject>
</mediaobject>
<caption>Components of the methionine metabolism modelled by Reed <emphasis>et al.</emphasis>. The main metabolites are shown in blue boxes and the enzymes in red boxes.</caption>
</informalfigure>
<para>
</para>
</sect1>
</article>
</documentation>
<rdf:RDF>
<rdf:Description rdf:about="#Met">
<dc:title>Met</dc:title>
<dcterms:alternative>methionine</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<rdf:RDF>
<rdf:Description rdf:about="#AdoMet">
<dc:title>AdoMet</dc:title>
<dcterms:alternative>S-adenosylmethionine</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<rdf:RDF>
<rdf:Description rdf:about="#AdoHcy">
<dc:title>AdoHcy</dc:title>
<dcterms:alternative>S-adenosylhomocysteine</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<rdf:RDF>
<rdf:Description rdf:about="#Hcy">
<dc:title>Hcy</dc:title>
<dcterms:alternative>homocysteine</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Seq rdf:about="rdf:#2c2c654f-9671-47de-b131-74ad8ec40463">
<rdf:li rdf:resource="rdf:#72cc3bb1-0faf-458c-a445-201d868dd6b7"/>
<rdf:li rdf:resource="rdf:#69109693-1792-46f1-b3b9-2155f95caf62"/>
<rdf:li rdf:resource="rdf:#b488654e-3c5e-4a3c-b4fd-d1dfb10686c7"/>
<rdf:li rdf:resource="rdf:#1e7f6617-c59e-489f-883f-2469052b2d71"/>
</rdf:Seq>
<rdf:Description rdf:about="rdf:#3e4351ce-fbbb-4b3b-b8b6-5b2415a5c5f6">
<vCard:Given>Michael</vCard:Given>
<vCard:Family>Reed</vCard:Family>
<vCard:Other>C</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#2208f684-21d8-4268-b243-b2ca70b91c90">
<vCard:Given>H</vCard:Given>
<vCard:Family>Nijhout</vCard:Family>
<vCard:Other>Frederik</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="">
<dc:publisher>
The University of Auckland, Auckland Bioengineering Institute
</dc:publisher>
<dcterms:created rdf:resource="rdf:#e5ab328d-1fb0-412d-ad97-bb3d77447cc7"/>
<dc:creator rdf:resource="rdf:#2ef4be55-af9c-4d0f-8c96-5bfdd6ef7ea9"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#e5ab328d-1fb0-412d-ad97-bb3d77447cc7">
<dcterms:W3CDTF>2003-11-27</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#69109693-1792-46f1-b3b9-2155f95caf62">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#2208f684-21d8-4268-b243-b2ca70b91c90"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#bd7044bf-5672-4f0f-925d-74c6b29a91c0">
<dc:title>Journal of theoretical biology</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#617d4d46-3faf-4829-89aa-9a3fa7ccfa09">
<vCard:FN>Catherine Lloyd</vCard:FN>
</rdf:Description>
<rdf:Description rdf:about="rdf:#2ef4be55-af9c-4d0f-8c96-5bfdd6ef7ea9">
<vCard:ORG rdf:resource="rdf:#177f08f7-0aa9-455b-a28a-a0cf71fc0f92"/>
<vCard:EMAIL rdf:resource="rdf:#de106423-dd71-4dbb-a8b8-bbcd7e68b112"/>
<vCard:N rdf:resource="rdf:#cd48391e-7dbe-4c9d-898e-b5f8887e7277"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#fb708d99-b8ba-40f5-9975-f54e808b0b96">
<bqs:Pubmed_id>14637052</bqs:Pubmed_id>
<bqs:JournalArticle rdf:resource="rdf:#e34133af-153e-4f43-a99b-89ea0fd41031"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#de106423-dd71-4dbb-a8b8-bbcd7e68b112">
<rdf:type rdf:resource="http://imc.org/vCard/3.0#internet"/>
<rdf:value>c.lloyd@auckland.ac.nz</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="rdf:#d4af9cfa-62f1-4770-95e7-f4de199c046f">
<dc:creator rdf:resource="rdf:#617d4d46-3faf-4829-89aa-9a3fa7ccfa09"/>
<rdf:value>
This is the CellML description of Reed et al.'s mathematical model of
the methionine cycle.
</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="rdf:#b488654e-3c5e-4a3c-b4fd-d1dfb10686c7">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#353789cd-cfb4-4c3a-9fb5-7b9fb7b7b4ac"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#cd48391e-7dbe-4c9d-898e-b5f8887e7277">
<vCard:Given>Catherine</vCard:Given>
<vCard:Family>Lloyd</vCard:Family>
<vCard:Other>May</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#1e7f6617-c59e-489f-883f-2469052b2d71">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#642e45a3-cc46-4279-ac16-e0f490cef2b2"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#353789cd-cfb4-4c3a-9fb5-7b9fb7b7b4ac">
<vCard:Given>Rachel</vCard:Given>
<vCard:Family>Sparks</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#77f5ec57-d29a-469b-abd5-10913a6994b9">
<dc:subject rdf:resource="rdf:#32f502db-5827-4808-bbce-97a2f92c39ec"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#49857add-1ae2-452c-a73f-eef30a0657c3">
<dcterms:W3CDTF>2004-01-07</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#177f08f7-0aa9-455b-a28a-a0cf71fc0f92">
<vCard:Orgname>The University of Auckland</vCard:Orgname>
<vCard:Orgunit>Auckland Bioengineering Institute</vCard:Orgunit>
</rdf:Description>
<rdf:Description rdf:about="rdf:#32f502db-5827-4808-bbce-97a2f92c39ec">
<bqs:subject_type>keyword</bqs:subject_type>
<rdf:value>
<rdf:Bag>
<rdf:li>methionine</rdf:li>
<rdf:li>metabolism</rdf:li>
</rdf:Bag>
</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="rdf:#72cc3bb1-0faf-458c-a445-201d868dd6b7">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#3e4351ce-fbbb-4b3b-b8b6-5b2415a5c5f6"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#642e45a3-cc46-4279-ac16-e0f490cef2b2">
<vCard:Given>Cornelia</vCard:Given>
<vCard:Family>Ulrich</vCard:Family>
<vCard:Other>M</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#e34133af-153e-4f43-a99b-89ea0fd41031">
<dc:creator rdf:resource="rdf:#2c2c654f-9671-47de-b131-74ad8ec40463"/>
<dc:title>
A mathematical model of the methionine cycle
</dc:title>
<bqs:volume>226</bqs:volume>
<bqs:first_page>33</bqs:first_page>
<bqs:Journal rdf:resource="rdf:#bd7044bf-5672-4f0f-925d-74c6b29a91c0"/>
<dcterms:issued rdf:resource="rdf:#49857add-1ae2-452c-a73f-eef30a0657c3"/>
<bqs:last_page>43</bqs:last_page>
</rdf:Description>
<rdf:Description rdf:about="#reed_2004">
<dc:title>
Reed et al.'s mathematical model of the methionine cycle.
</dc:title>
<cmeta:comment xmlns:cmeta="http://www.cellml.org/metadata/1.0#" rdf:resource="rdf:#d4af9cfa-62f1-4770-95e7-f4de199c046f"/>
<bqs:reference rdf:resource="rdf:#77f5ec57-d29a-469b-abd5-10913a6994b9"/>
<bqs:reference rdf:resource="rdf:#fb708d99-b8ba-40f5-9975-f54e808b0b96"/>
</rdf:Description>
</rdf:RDF> <units xmlns="http://www.cellml.org/cellml/1.0#" name="micromolar">
<unit units="mole" prefix="micro"/>
<unit units="litre" exponent="-1"/>
</units>
<units xmlns="http://www.cellml.org/cellml/1.0#" name="per_micromolar">
<unit units="micromolar" exponent="-1"/>
</units>
<units xmlns="http://www.cellml.org/cellml/1.0#" name="hour">
<unit units="second" multiplier="3600"/>
</units>
<units xmlns="http://www.cellml.org/cellml/1.0#" name="flux">
<unit units="micromolar"/>
<unit units="hour" exponent="-1"/>
</units>
<units xmlns="http://www.cellml.org/cellml/1.0#" name="first_order_rate_constant">
<unit units="hour" exponent="-1"/>
</units>
<units xmlns="http://www.cellml.org/cellml/1.0#" name="second_order_rate_constant">
<unit units="micromolar" exponent="-1"/>
<unit units="hour" exponent="-1"/>
</units>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="environment">
<variable name="time" units="hour" public_interface="out"/>
<variable name="Metin" units="flux" public_interface="out"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>Metin</ci>
<piecewise>
<piece>
<cn cellml:units="flux">200</cn>
<apply>
<or/>
<apply>
<lt/>
<ci>time</ci>
<cn cellml:units="hour">2</cn>
</apply>
<apply>
<geq/>
<ci>time</ci>
<cn cellml:units="hour">8</cn>
</apply>
</apply>
</piece>
<piece>
<cn cellml:units="flux">300</cn>
<apply>
<and/>
<apply>
<geq/>
<ci>time</ci>
<cn cellml:units="hour">2</cn>
</apply>
<apply>
<lt/>
<ci>time</ci>
<cn cellml:units="hour">5</cn>
</apply>
</apply>
</piece>
<piece>
<cn cellml:units="flux">100</cn>
<apply>
<and/>
<apply>
<geq/>
<ci>time</ci>
<cn cellml:units="hour">5</cn>
</apply>
<apply>
<lt/>
<ci>time</ci>
<cn cellml:units="hour">8</cn>
</apply>
</apply>
</piece>
<otherwise>
<cn cellml:units="flux">200</cn>
</otherwise>
</piecewise>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="Met">
<variable name="Met" units="micromolar" initial_value="53.5" public_interface="out"/>
<variable name="V_MS" units="flux" public_interface="in"/>
<variable name="V_BHMT" units="flux" public_interface="in"/>
<variable name="V_MATI" units="flux" public_interface="in"/>
<variable name="V_MATIII" units="flux" public_interface="in"/>
<variable name="Metin" units="flux" public_interface="in"/>
<variable name="time" units="hour" public_interface="in"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Met</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>V_MS</ci>
<ci>V_BHMT</ci>
<ci>Metin</ci>
</apply>
<apply>
<plus/>
<ci>V_MATI</ci>
<ci>V_MATIII</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="AdoMet">
<variable name="AdoMet" units="micromolar" initial_value="137.6" public_interface="out"/>
<variable name="V_METH" units="flux" public_interface="in"/>
<variable name="V_GNMT" units="flux" public_interface="in"/>
<variable name="V_MATI" units="flux" public_interface="in"/>
<variable name="V_MATIII" units="flux" public_interface="in"/>
<variable name="time" units="hour" public_interface="in"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>AdoMet</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>V_MATI</ci>
<ci>V_MATIII</ci>
</apply>
<apply>
<plus/>
<ci>V_METH</ci>
<ci>V_GNMT</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="AdoHcy">
<variable name="AdoHcy" units="micromolar" initial_value="13.2" public_interface="out"/>
<variable name="V_METH" units="flux" public_interface="in"/>
<variable name="V_GNMT" units="flux" public_interface="in"/>
<variable name="V_AH" units="flux" public_interface="in"/>
<variable name="time" units="hour" public_interface="in"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>AdoHcy</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>V_METH</ci>
<ci>V_GNMT</ci>
</apply>
<ci>V_AH</ci>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="Hcy">
<variable name="Hcy" units="micromolar" initial_value="0.88" public_interface="out"/>
<variable name="V_AH" units="flux" public_interface="in"/>
<variable name="V_CBS" units="flux" public_interface="in"/>
<variable name="V_MS" units="flux" public_interface="in"/>
<variable name="V_BHMT" units="flux" public_interface="in"/>
<variable name="time" units="hour" public_interface="in"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Hcy</ci>
</apply>
<apply>
<minus/>
<ci>V_AH</ci>
<apply>
<plus/>
<ci>V_CBS</ci>
<ci>V_MS</ci>
<ci>V_BHMT</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="V_MATI">
<variable name="V_MATI" units="flux" public_interface="out"/>
<variable name="Met" units="micromolar" public_interface="in"/>
<variable name="AdoMet" units="micromolar" public_interface="in"/>
<variable name="V_MATImax" units="flux" initial_value="561"/>
<variable name="Km_MATI" units="micromolar" initial_value="41"/>
<variable name="Ki_MATI" units="micromolar" initial_value="50"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>V_MATI</ci>
<apply>
<divide/>
<ci>V_MATImax</ci>
<apply>
<plus/>
<cn cellml:units="dimensionless">1</cn>
<apply>
<times/>
<apply>
<divide/>
<ci>Km_MATI</ci>
<ci>Met</ci>
</apply>
<apply>
<plus/>
<cn cellml:units="dimensionless">1</cn>
<apply>
<divide/>
<ci>AdoMet</ci>
<ci>Ki_MATI</ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="V_MATIII">
<variable name="V_MATIII" units="flux" public_interface="out"/>
<variable name="AdoMet" units="micromolar" public_interface="in"/>
<variable name="Met" units="micromolar" public_interface="in"/>
<variable name="V_MATIIImax" units="flux" initial_value="22870"/>
<variable name="Km1_MATIII" units="micromolar"/>
<variable name="Km2_MATIII" units="micromolar" initial_value="21.1"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>V_MATIII</ci>
<apply>
<divide/>
<ci>V_MATIIImax</ci>
<apply>
<plus/>
<cn cellml:units="dimensionless">1</cn>
<apply>
<divide/>
<apply>
<times/>
<ci>Km1_MATIII</ci>
<ci>Km2_MATIII</ci>
</apply>
<apply>
<plus/>
<apply>
<power/>
<ci>Met</ci>
<cn cellml:units="dimensionless">2</cn>
</apply>
<apply>
<times/>
<ci>Met</ci>
<ci>Km2_MATIII</ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>Km1_MATIII</ci>
<apply>
<divide/>
<cn cellml:units="micromolar">20000</cn>
<apply>
<plus/>
<cn cellml:units="dimensionless">1</cn>
<apply>
<times/>
<cn cellml:units="dimensionless">5.7</cn>
<apply>
<power/>
<apply>
<divide/>
<ci>AdoMet</ci>
<apply>
<plus/>
<ci>AdoMet</ci>
<cn cellml:units="micromolar">600</cn>
</apply>
</apply>
<cn cellml:units="dimensionless">2</cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="V_GNMT">
<variable name="V_GNMT" units="flux" public_interface="out"/>
<variable name="AdoMet" units="micromolar" public_interface="in"/>
<variable name="AdoHcy" units="micromolar" public_interface="in"/>
<variable name="V_GNMTmax" units="flux" initial_value="10600"/>
<variable name="Km_GNMT" units="micromolar" initial_value="4500"/>
<variable name="Ki_GNMT" units="micromolar" initial_value="20"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>V_GNMT</ci>
<apply>
<divide/>
<apply>
<times/>
<apply>
<divide/>
<ci>V_GNMTmax</ci>
<apply>
<plus/>
<cn cellml:units="dimensionless">1</cn>
<apply>
<power/>
<apply>
<divide/>
<ci>Km_GNMT</ci>
<ci>AdoMet</ci>
</apply>
<cn cellml:units="dimensionless">2.3</cn>
</apply>
</apply>
</apply>
<cn cellml:units="dimensionless">1</cn>
</apply>
<apply>
<plus/>
<cn cellml:units="dimensionless">1</cn>
<apply>
<divide/>
<ci>AdoHcy</ci>
<ci>Ki_GNMT</ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="V_METH">
<variable name="V_METH" units="flux" public_interface="out"/>
<variable name="AdoMet" units="micromolar" public_interface="in"/>
<variable name="AdoHcy" units="micromolar" public_interface="in"/>
<variable name="V_METHmax" units="flux" initial_value="4521"/>
<variable name="Km1_METH" units="micromolar"/>
<variable name="Km2_METH_A" units="dimensionless" initial_value="10"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>V_METH</ci>
<apply>
<divide/>
<ci>V_METHmax</ci>
<apply>
<plus/>
<cn cellml:units="dimensionless">1</cn>
<apply>
<divide/>
<ci>Km1_METH</ci>
<ci>AdoMet</ci>
</apply>
<ci>Km2_METH_A</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>Km2_METH_A</ci>
<ci>Km1_METH</ci>
</apply>
<ci>AdoMet</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>Km1_METH</ci>
<apply>
<times/>
<cn cellml:units="micromolar">1</cn>
<apply>
<plus/>
<cn cellml:units="dimensionless">1</cn>
<apply>
<divide/>
<ci>AdoHcy</ci>
<cn cellml:units="micromolar">4</cn>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="V_MS">
<variable name="V_MS" units="flux" public_interface="out"/>
<variable name="five_mTHF" units="micromolar" initial_value="5.2"/>
<variable name="Hcy" units="micromolar" public_interface="in"/>
<variable name="V_MSmax" units="flux" initial_value="500"/>
<variable name="Kd_MS" units="micromolar" initial_value="1"/>
<variable name="Km_Hcy_MS" units="micromolar" initial_value="0.1"/>
<variable name="Km_five_mTHF_MS" units="micromolar" initial_value="25"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>V_MS</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>V_MSmax</ci>
<ci>five_mTHF</ci>
<ci>Hcy</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>Kd_MS</ci>
<ci>Km_Hcy_MS</ci>
</apply>
<apply>
<times/>
<ci>Km_Hcy_MS</ci>
<ci>five_mTHF</ci>
</apply>
<apply>
<times/>
<ci>Km_five_mTHF_MS</ci>
<ci>Hcy</ci>
</apply>
<apply>
<times/>
<ci>five_mTHF</ci>
<ci>Hcy</ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="V_AH">
<variable name="V_AH" units="flux" public_interface="out"/>
<variable name="AdoHcy" units="micromolar" public_interface="in"/>
<variable name="Hcy" units="micromolar" public_interface="in"/>
<variable name="alpha1" units="first_order_rate_constant" initial_value="100"/>
<variable name="alpha2" units="dimensionless" initial_value="10"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>V_AH</ci>
<apply>
<times/>
<ci>alpha1</ci>
<apply>
<minus/>
<ci>AdoHcy</ci>
<apply>
<times/>
<ci>alpha2</ci>
<ci>Hcy</ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="V_CBS">
<variable name="V_CBS" units="flux" public_interface="out"/>
<variable name="AdoHcy" units="micromolar" public_interface="in"/>
<variable name="Hcy" units="micromolar" public_interface="in"/>
<variable name="AdoMet" units="micromolar" public_interface="in"/>
<variable name="beta1" units="second_order_rate_constant" initial_value="1.7"/>
<variable name="beta2" units="first_order_rate_constant" initial_value="30"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>V_CBS</ci>
<apply>
<times/>
<apply>
<minus/>
<apply>
<times/>
<ci>beta1</ci>
<apply>
<plus/>
<ci>AdoMet</ci>
<ci>AdoHcy</ci>
</apply>
</apply>
<ci>beta2</ci>
</apply>
<ci>Hcy</ci>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="V_BHMT">
<variable name="V_BHMT" units="flux" public_interface="out"/>
<variable name="AdoMet" units="micromolar" public_interface="in"/>
<variable name="AdoHcy" units="micromolar" public_interface="in"/>
<variable name="Hcy" units="micromolar" public_interface="in"/>
<variable name="V_BHMTmax" units="flux" initial_value="2500"/>
<variable name="Km_BHMT" units="micromolar" initial_value="12"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>V_BHMT</ci>
<apply>
<divide/>
<apply>
<times/>
<apply>
<minus/>
<cn cellml:units="dimensionless">0.7</cn>
<apply>
<times/>
<cn cellml:units="per_micromolar">0.025</cn>
<apply>
<minus/>
<apply>
<plus/>
<ci>AdoMet</ci>
<ci>AdoHcy</ci>
</apply>
<cn cellml:units="micromolar">150</cn>
</apply>
</apply>
</apply>
<ci>V_BHMTmax</ci>
<ci>Hcy</ci>
</apply>
<apply>
<plus/>
<ci>Km_BHMT</ci>
<ci>Hcy</ci>
</apply>
</apply>
</apply>
</math>
</component>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Met" component_2="V_MATI"/>
<map_variables variable_1="Met" variable_2="Met"/>
<map_variables variable_1="V_MATI" variable_2="V_MATI"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Met" component_2="V_MATIII"/>
<map_variables variable_1="Met" variable_2="Met"/>
<map_variables variable_1="V_MATIII" variable_2="V_MATIII"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Met" component_2="V_MS"/>
<map_variables variable_1="V_MS" variable_2="V_MS"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Met" component_2="V_BHMT"/>
<map_variables variable_1="V_BHMT" variable_2="V_BHMT"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="AdoMet" component_2="V_MATI"/>
<map_variables variable_1="AdoMet" variable_2="AdoMet"/>
<map_variables variable_1="V_MATI" variable_2="V_MATI"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="AdoMet" component_2="V_MATIII"/>
<map_variables variable_1="AdoMet" variable_2="AdoMet"/>
<map_variables variable_1="V_MATIII" variable_2="V_MATIII"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="AdoMet" component_2="V_METH"/>
<map_variables variable_1="AdoMet" variable_2="AdoMet"/>
<map_variables variable_1="V_METH" variable_2="V_METH"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="AdoMet" component_2="V_CBS"/>
<map_variables variable_1="AdoMet" variable_2="AdoMet"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="AdoMet" component_2="V_BHMT"/>
<map_variables variable_1="AdoMet" variable_2="AdoMet"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="AdoMet" component_2="V_GNMT"/>
<map_variables variable_1="AdoMet" variable_2="AdoMet"/>
<map_variables variable_1="V_GNMT" variable_2="V_GNMT"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="AdoHcy" component_2="V_METH"/>
<map_variables variable_1="AdoHcy" variable_2="AdoHcy"/>
<map_variables variable_1="V_METH" variable_2="V_METH"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="AdoHcy" component_2="V_GNMT"/>
<map_variables variable_1="AdoHcy" variable_2="AdoHcy"/>
<map_variables variable_1="V_GNMT" variable_2="V_GNMT"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="AdoHcy" component_2="V_AH"/>
<map_variables variable_1="AdoHcy" variable_2="AdoHcy"/>
<map_variables variable_1="V_AH" variable_2="V_AH"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="AdoHcy" component_2="V_CBS"/>
<map_variables variable_1="AdoHcy" variable_2="AdoHcy"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="AdoHcy" component_2="V_BHMT"/>
<map_variables variable_1="AdoHcy" variable_2="AdoHcy"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Hcy" component_2="V_AH"/>
<map_variables variable_1="Hcy" variable_2="Hcy"/>
<map_variables variable_1="V_AH" variable_2="V_AH"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Hcy" component_2="V_CBS"/>
<map_variables variable_1="Hcy" variable_2="Hcy"/>
<map_variables variable_1="V_CBS" variable_2="V_CBS"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Hcy" component_2="V_MS"/>
<map_variables variable_1="Hcy" variable_2="Hcy"/>
<map_variables variable_1="V_MS" variable_2="V_MS"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Hcy" component_2="V_BHMT"/>
<map_variables variable_1="Hcy" variable_2="Hcy"/>
<map_variables variable_1="V_BHMT" variable_2="V_BHMT"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Met" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
<map_variables variable_1="Metin" variable_2="Metin"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="AdoMet" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="AdoHcy" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Hcy" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
</model>
