Dataset Information

Nijhout2004_Folate_Cycle

ABSTRACT: This is an SBML version of the folate cycle model model from: A mathematical model of the folate cycle: new insights into folate homeostasis. Nijhout HF, Reed MC, Budu P, Ulrich CM J. Biol. Chem.,2004, 279 (53),55008-16 pubmedID: 15496403 Abstract: A mathematical model is developed for the folate cycle based on standard biochemical kinetics. We use the model to provide new insights into several different mechanisms of folate homeostasis. The model reproduces the known pool sizes of folate substrates and the fluxes through each of the loops of the folate cycle and has the qualitative behavior observed in a variety of experimental studies. Vitamin B(12) deficiency, modeled as a reduction in the V(max) of the methionine synthase reaction, results in a secondary folate deficiency via the accumulation of folate as 5-methyltetrahydrofolate (the "methyl trap"). One form of homeostasis is revealed by the fact that a 100-fold up-regulation of thymidylate synthase and dihydrofolate reductase (known to occur at the G(1)/S transition) dramatically increases pyrimidine production without affecting the other reactions of the folate cycle. The model also predicts that an almost total inhibition of dihydrofolate reductase is required to significantly inhibit the thymidylate synthase reaction, consistent with experimental and clinical studies on the effects of methotrexate. Sensitivity to variation in enzymatic parameters tends to be local in the cycle and inversely proportional to the number of reactions that interconvert two folate substrates. Another form of homeostasis is a consequence of the nonenzymatic binding of folate substrates to folate enzymes. Without folate binding, the velocities of the reactions decrease approximately linearly as total folate is decreased. In the presence of folate binding and allosteric inhibition, the velocities show a remarkable constancy as total folate is decreased. This model was encoded by Michal Galdzicki from a MatLab file send to him by Prof. Michael Reed. There some differences in this model compared to the one described in the article, possible due to typos in the publication: 1) reaction NE (THF + H2CO 5,10-CH2-THF) in the article has H2C=O as a reactant and is mentioned to display pseudo first order mass action kinetics, while in the matlab file formic acid, also used in reaction FTS, is included in the rate law for the forward reaction. 2) the reaction MS is modeled after Reed et al. 2004, which is not explicitly mentioned in the article, although Kd and the parameters from Reed et al. 2004 are given. 3) in the kinetic law of the SHTM reaction (THF + Ser 5,10-CH2-THF + Gly), there are separate values given for Km,Gly and Km,5,10-CH2-THF in the article. in the matlab file and the SBML model Km,Ser and Km,THF are used instead of Km,Gly and Km,5,10-CH2-THF for the backwards reaction. 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. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not. 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.

SUBMITTER: Michal Galdzicki

PROVIDER: BIOMD0000000213 | BioModels | 2024-09-02

REPOSITORIES: BioModels

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	BIOMD0000000213?filename=BIOMD0000000213-biopax2.owl	Owl
	BIOMD0000000213?filename=BIOMD0000000213-biopax3.owl	Owl
	BIOMD0000000213?filename=BIOMD0000000213-matlab.m	Other
	BIOMD0000000213?filename=BIOMD0000000213-octave.m	Other
	BIOMD0000000213?filename=BIOMD0000000213.m	Other

Items per page:

1 - 5 of 17

Publications

A mathematical model of the folate cycle: new insights into folate homeostasis.

Nijhout H Frederik HF Reed Michael C MC Budu Paula P Ulrich Cornelia M CM

The Journal of biological chemistry 20041020 53

A mathematical model is developed for the folate cycle based on standard biochemical kinetics. We use the model to provide new insights into several different mechanisms of folate homeostasis. The model reproduces the known pool sizes of folate substrates and the fluxes through each of the loops of the folate cycle and has the qualitative behavior observed in a variety of experimental studies. Vitamin B(12) deficiency, modeled as a reduction in the V(max) of the methionine synthase reaction, res ...[more]

PMID: 15496403

Similar Datasets

Project description:This is an SBML version of the folate cycle model model from: A mathematical model of the folate cycle: new insights into folate homeostasis. Nijhout HF, Reed MC, Budu P, Ulrich CM J. Biol. Chem.,2004, 279 (53),55008-16 Reference publication: 15496403 Abstract: A mathematical model is developed for the folate cycle based on standard biochemical kinetics. We use the model to provide new insights into several different mechanisms of folate homeostasis. The model reproduces the known pool sizes of folate substrates and the fluxes through each of the loops of the folate cycle and has the qualitative behavior observed in a variety of experimental studies. Vitamin B(12) deficiency, modeled as a reduction in the V(max) of the methionine synthase reaction, results in a secondary folate deficiency via the accumulation of folate as 5-methyltetrahydrofolate (the "methyl trap"). One form of homeostasis is revealed by the fact that a 100-fold up-regulation of thymidylate synthase and dihydrofolate reductase (known to occur at the G(1)/S transition) dramatically increases pyrimidine production without affecting the other reactions of the folate cycle. The model also predicts that an almost total inhibition of dihydrofolate reductase is required to significantly inhibit the thymidylate synthase reaction, consistent with experimental and clinical studies on the effects of methotrexate. Sensitivity to variation in enzymatic parameters tends to be local in the cycle and inversely proportional to the number of reactions that interconvert two folate substrates. Another form of homeostasis is a consequence of the nonenzymatic binding of folate substrates to folate enzymes. Without folate binding, the velocities of the reactions decrease approximately linearly as total folate is decreased. In the presence of folate binding and allosteric inhibition, the velocities show a remarkable constancy as total folate is decreased. A curated version of this model is available: BIOMD0000000213 . This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2012 The BioModels.net Team. For more information see the terms of use . 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.

Project description:Morrison1989 - Folate Cycle The model describes the folate cycle kinetics in breast cancer cells. This model is described in the article: Folate cycle kinetics in human breast cancer cells. 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. This model is hosted on BioModels Database and identified by: BIOMD0000000018. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. 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.

Project description:Reed2004 - Methionine Cycle This model is described in the article: A mathematical model of the methionine cycle. Reed MC, Nijhout HF, Sparks R, Ulrich CM. J. Theor. Biol. 2004 Jan; 226(1): 33-43 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. This model is hosted on BioModels Database and identified by: BIOMD0000000698. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. 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.