Short description
Morrison1989 - Folate Cycle
The model describes the folate cycle kinetics in breast cancer cells.

This model is described in the article:

Morrison PF, Allegra CJ.
J. Biol. Chem. 1989 Jun; 264(18): 10552-10566

Abstract:

A mathematical description of polyglutamated folate kinetics for human breast carcinoma cells (MCF-7) has been formulated based upon experimental folate, methotrexate (MTX), purine, and pyrimidine pool sizes as well as reaction rate parameters obtained from intact MCF-7 cells and their enzyme isolates. The schema accounts for the interconversion of highly polyglutamated tetrahydrofolate, 5-methyl-FH4, 5-10-CH2FH4, dihydrofolate (FH2), 10-formyl-FH4 (FFH4), and 10-formyl-FH2 (FFH2), as well as formation and transport of the MTX polyglutamates. Inhibition mechanisms have been chosen to reproduce all observed non-, un-, and pure competition inhibition patterns. Steady state folate concentrations and thymidylate and purine synthesis rates in drug-free intact cells were used to determine normal folate Vmax values. The resulting average-cell folate model, examined for its ability to predict folate pool behavior following exposure to 1 microM MTX over 21 h, agreed well with the experiment, including a relative preservation of the FFH4 and CH2FH4 pools. The results depend strongly on thymidylate synthase (TS) reaction mechanism, especially the assumption that MTX di- and triglutamates inhibit TS synthesis as greatly in the intact cell as they do with purified enzyme. The effects of cell cycle dependence of TS and dihydrofolate reductase activities were also examined by introducing G- to S-phase activity ratios of these enzymes into the model. For activity ratios down to at least 5%, cell population averaged folate pools were only slightly affected, while CH2FH4 pools in S-phase cells were reduced to as little as 10% of control values. Significantly, these folate pool dynamics were indicated to arise from both direct inhibition by MTX polyglutamates as well as inhibition by elevated levels of polyglutamated FH2 and FFH2.

Note: two flow BCs were converted into two downstream concentration BCs, thus removing the GAR and dUMP state variables. This dropped the number of ODEs from 21 to 19.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Format
SBML (L2V1)
Related Publication
  • Folate cycle kinetics in human breast cancer cells.
  • Morrison PF, Allegra CJ
  • The Journal of biological chemistry , 6/ 1989 , Volume 264 , pages: 10552-10566
  • Division of Research Services, National Institutes of Health, Bethesda, Maryland 20892.
  • A mathematical description of polyglutamated folate kinetics for human breast carcinoma cells (MCF-7) has been formulated based upon experimental folate, methotrexate (MTX), purine, and pyrimidine pool sizes as well as reaction rate parameters obtained from intact MCF-7 cells and their enzyme isolates. The schema accounts for the interconversion of highly polyglutamated tetrahydrofolate, 5-methyl-FH4, 5-10-CH2FH4, dihydrofolate (FH2), 10-formyl-FH4 (FFH4), and 10-formyl-FH2 (FFH2), as well as formation and transport of the MTX polyglutamates. Inhibition mechanisms have been chosen to reproduce all observed non-, un-, and pure competition inhibition patterns. Steady state folate concentrations and thymidylate and purine synthesis rates in drug-free intact cells were used to determine normal folate Vmax values. The resulting average-cell folate model, examined for its ability to predict folate pool behavior following exposure to 1 microM MTX over 21 h, agreed well with the experiment, including a relative preservation of the FFH4 and CH2FH4 pools. The results depend strongly on thymidylate synthase (TS) reaction mechanism, especially the assumption that MTX di- and triglutamates inhibit TS synthesis as greatly in the intact cell as they do with purified enzyme. The effects of cell cycle dependence of TS and dihydrofolate reductase activities were also examined by introducing G- to S-phase activity ratios of these enzymes into the model. For activity ratios down to at least 5%, cell population averaged folate pools were only slightly affected, while CH2FH4 pools in S-phase cells were reduced to as little as 10% of control values. Significantly, these folate pool dynamics were indicated to arise from both direct inhibition by MTX polyglutamates as well as inhibition by elevated levels of polyglutamated FH2 and FFH2.
Contributors
Nicolas Le Novère

Metadata information

is
BioModels Database MODEL6617317313
BioModels Database BIOMD0000000018
isDescribedBy
PubMed 2732237
hasTaxon
Taxonomy Homo sapiens
isVersionOf
hasPart
hasProperty
Human Disease Ontology breast cancer
Curation status
Curated
  • Model originally submitted by : Nicolas Le Novère
  • Submitted: 13-Sep-2005 14:15:44
  • Last Modified: 18-May-2017 11:55:12
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 18-May-2017 11:55:12
    • Submitted by: Nicolas Le Novère
    • With comment: Current version of Morrison1989 - Folate Cycle
  • Version: 1 public model Download this version
    • Submitted on: 13-Sep-2005 14:15:44
    • Submitted by: Nicolas Le Novère
    • With comment: Original import of Morrison1989_FolateCycle