Nijhout2006_Hepatic_Folate_Metab

  public model
Model Identifier
MODEL1007200000
Short description

This is the model described in the article:
In silico experimentation with a model of hepatic mitochondrial folate metabolism.
H. Frederik Nijhout, Michael C Reed, Shi-Ling Lam, Barry Shane, Jesse F Gregory and Cornelia M Ulrich, Theor Biol Med Model 2006,3:40; PubmedID: 17150100 ; DOI: 10.1186/1742-4682-3-40 ;
Abstract:
BACKGROUND: In eukaryotes, folate metabolism is compartmentalized and occurs in both the cytosol and the mitochondria. The function of this compartmentalization and the great changes that occur in the mitochondrial compartment during embryonic development and in rapidly growing cancer cells are gradually becoming understood, though many aspects remain puzzling and controversial.
APPROACH: We explore the properties of cytosolic and mitochondrial folate metabolism by experimenting with a mathematical model of hepatic one-carbon metabolism. The model is based on known biochemical properties of mitochondrial and cytosolic enzymes. We use the model to study questions about the relative roles of the cytosolic and mitochondrial folate cycles posed in the experimental literature. We investigate: the control of the direction of the mitochondrial and cytosolic serine hydroxymethyltransferase (SHMT) reactions, the role of the mitochondrial bifunctional enzyme, the role of the glycine cleavage system, the effects of variations in serine and glycine inputs, and the effects of methionine and protein loading.
CONCLUSION: The model reproduces many experimental findings and gives new insights into the underlying properties of mitochondrial folate metabolism. Particularly interesting is the remarkable stability of formate production in the mitochondria in the face of large changes in serine and glycine input. The model shows that in the presence of the bifunctional enzyme (as in embryonic tissues and cancer cells), the mitochondria primarily support cytosolic purine and pyrimidine synthesis via the export of formate, while in adult tissues the mitochondria produce serine for gluconeogenesis.

This model does not reproduce the results in the article completely, but most steady state concentrations are in a range of 10% around the published values. Also parameterscans give nearly identical results as shown in the article.

In the SBML version model the volumes of the mitochondrion, the cytoplasm and the cell were all set to one to obtain the same equations as described in the supplemental materials of the article. The total folate is equally split between the cytosol and the mitochondrion and divided by 3/4 for the cytosol and 1/4 for the mitochondrion, respectively. To obtain an SBML model in which the volumes of the compartments, cytosol and mito , are used, the model needs to be altered as follows:
for the initial distribution of folate the terms 3/4 and 1/4 have to be replaced by volumes of cytosol and mitochondria respectively
in the transport reactions between mitochondrion and cytosol the stoichiometry of the mitochondrial reactants has to be set from 3 to 1 and in the first part of the according rate laws the factor mito/3 should simply be replaced with mito .
the stoichiometries of src and dmg have to be changed to cell/mito for mitchondrial and cell/cytosol for cytosolic reactions involving these two species.
While the concentrations stay the same after these alteration, the reaction fluxes change by a factor of cytosol and mito for cytosolic and mitchondrial reactions, respectively.

Originally created by libAntimony v1.3 (using libSBML 3.4.1)

This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
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To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Format
SBML (L2V4)
Related Publication
  • In silico experimentation with a model of hepatic mitochondrial folate metabolism.
  • Nijhout HF, Reed MC, Lam SL, Shane B, Gregory JF 3rd, Ulrich CM
  • Theoretical biology & medical modelling , 12/ 2006 , Volume 3 , pages: 40 , PubMed ID: 17150100
  • Department of Biology, Duke University, Durham, NC 27708, USA. hfn@duke.edu
  • In eukaryotes, folate metabolism is compartmentalized and occurs in both the cytosol and the mitochondria. The function of this compartmentalization and the great changes that occur in the mitochondrial compartment during embryonic development and in rapidly growing cancer cells are gradually becoming understood, though many aspects remain puzzling and controversial.We explore the properties of cytosolic and mitochondrial folate metabolism by experimenting with a mathematical model of hepatic one-carbon metabolism. The model is based on known biochemical properties of mitochondrial and cytosolic enzymes. We use the model to study questions about the relative roles of the cytosolic and mitochondrial folate cycles posed in the experimental literature. We investigate: the control of the direction of the mitochondrial and cytosolic serine hydroxymethyltransferase (SHMT) reactions, the role of the mitochondrial bifunctional enzyme, the role of the glycine cleavage system, the effects of variations in serine and glycine inputs, and the effects of methionine and protein loading.The model reproduces many experimental findings and gives new insights into the underlying properties of mitochondrial folate metabolism. Particularly interesting is the remarkable stability of formate production in the mitochondria in the face of large changes in serine and glycine input. The model shows that in the presence of the bifunctional enzyme (as in embryonic tissues and cancer cells), the mitochondria primarily support cytosolic purine and pyrimidine synthesis via the export of formate, while in adult tissues the mitochondria produce serine for gluconeogenesis.
Contributors
Lukas Endler

Metadata information

is
BioModels Database MODEL1007200000
isDescribedBy
PubMed 17150100
hasTaxon
Taxonomy Homo sapiens
hasProperty
Mathematical Modelling Ontology Ordinary differential equation model
isVersionOf

Curation status
Non-curated


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  • Model originally submitted by : Lukas Endler
  • Submitted: 20-Jul-2010 14:58:01
  • Last Modified: 24-Sep-2010 15:59:26
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 24-Sep-2010 15:59:26
    • Submitted by: Lukas Endler
    • With comment: Current version of Nijhout2006_Hepatic_Folate_Metab
  • Version: 1 public model Download this version
    • Submitted on: 20-Jul-2010 14:58:01
    • Submitted by: Lukas Endler
    • With comment: Original import of Nijhout2006_Hepatic_Folate_Metab

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