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BIOMD0000000213 - Nijhout2004_Folate_Cycle

 

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Reference Publication
Publication ID: 15496403
Nijhout HF, Reed MC, Budu P, Ulrich CM.
A mathematical model of the folate cycle: new insights into folate homeostasis.
J. Biol. Chem. 2004 Dec; 279(53): 55008-55016
Departments of Biology and Mathematics, Duke University, Durham, NC 27708, USA. hfn@duke.edu  [more]
Model
Original Model: BIOMD0000000213.origin
Submitter: Michal Galdzicki
Submission ID: MODEL4336555445
Submission Date: 01 Jun 2009 17:03:10 UTC
Last Modification Date: 08 Apr 2016 16:02:28 UTC
Creation Date: 25 Mar 2009 13:33:53 UTC
Encoders:  Michal Galdzicki
set #1
bqbiol:hasTaxon Taxonomy Mammalia
bqbiol:isVersionOf Gene Ontology folic acid metabolic process
Notes

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.

Model
Publication ID: 15496403 Submission Date: 01 Jun 2009 17:03:10 UTC Last Modification Date: 08 Apr 2016 16:02:28 UTC Creation Date: 25 Mar 2009 13:33:53 UTC
Mathematical expressions
Reactions
V_NE V_MS V_MTHFR V_FTD
V_FTS V_AICART V_PGT V_TS
V_DHFR V_MTCH V_SHMT V_MTD
Physical entities
Compartments Species
compartment _5mTHF THF DHF
_5_10_CH2THF _5_10_CHTHF _10fTHF
Ser Gly dUMP
GAR AICAR HCOOH
NADPH Hcy  
Global parameters
NE_k1 NE_k2 MS_Vmax MS_Km_5mTHF
MS_Km_Hcy MS_Kd MTHFR_Vmax MTHFR_Km_NADPH
MTHFR_Km_5_10_CH2THF FTD_Vmax FTD_Km_10fTHF FTS_Vmax
FTS_Km_HCOOH FTS_Km_THF AICART_Vmax AICART_Km_AICAR
AICART_Km_10fTHF PGT_Vmax PGT_Km_GAR PGT_Km_10fTHF
TS_Vmax TS_Km_dUMP TS_Km_5_10_CH2THF DHFR_Vmax
DHFR_Km_NADPH DHFR_Km_DHF MTCH_VmaxF MTCH_Km_5_10_CHTHF
MTCH_VmaxR MTCH_Km_10fTHF SHMT_VmaxF SHMT_Km_Ser
SHMT_Km_THF SHMT_VmaxR MTD_VmaxF MTD_Km_5_10_CH2THF
MTD_VmaxR MTD_Km_5_10_CHTHF    
Reactions (12)
 
 V_NE [THF] → [_5_10_CH2THF];   {HCOOH}
 
 V_MS [_5mTHF] → [THF];   {Hcy}
 
 V_MTHFR [_5_10_CH2THF] → [_5mTHF];   {NADPH}
 
 V_FTD [_10fTHF] → [THF];  
 
 V_FTS [THF] → [_10fTHF];   {HCOOH}
 
 V_AICART [_10fTHF] → [THF];   {AICAR}
 
 V_PGT [_10fTHF] → [THF];   {GAR}
 
 V_TS [_5_10_CH2THF] → [DHF];   {dUMP}
 
 V_DHFR [DHF] → [THF];   {NADPH}
 
 V_MTCH [_5_10_CHTHF] → [_10fTHF];  
 
 V_SHMT [THF] → [_5_10_CH2THF];   {Ser} , {Gly}
 
 V_MTD [_5_10_CH2THF] → [_5_10_CHTHF];  
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 _5mTHF
Compartment: compartment
Initial concentration: 5.16
 
 THF
Compartment: compartment
Initial concentration: 6.73
 
 DHF
Compartment: compartment
Initial concentration: 0.027
 
 _5_10_CH2THF
Compartment: compartment
Initial concentration: 0.94
 
 _5_10_CHTHF
Compartment: compartment
Initial concentration: 1.153
 
 _10fTHF
Compartment: compartment
Initial concentration: 5.99
 
 Ser
Compartment: compartment
Initial concentration: 468.0
 
 Gly
Compartment: compartment
Initial concentration: 1850.0
 
 dUMP
Compartment: compartment
Initial concentration: 20.0
 
 GAR
Compartment: compartment
Initial concentration: 10.0
 
 AICAR
Compartment: compartment
Initial concentration: 2.1
 
 HCOOH
Compartment: compartment
Initial concentration: 900.0
 
 NADPH
Compartment: compartment
Initial concentration: 50.0
 
 Hcy
Compartment: compartment
Initial concentration: 1.0
 
Global Parameters (38)
 
   NE_k1
Value: 0.15
Constant
 
   NE_k2
Value: 12.0
Constant
 
   MS_Vmax
Value: 500.0
Constant
 
   MS_Km_5mTHF
Value: 25.0
Constant
 
   MS_Km_Hcy
Value: 0.1
Constant
 
   MS_Kd
Value: 1.0
Constant
 
   MTHFR_Vmax
Value: 6000.0
Constant
 
   MTHFR_Km_NADPH
Value: 16.0
Constant
 
   MTHFR_Km_5_10_CH2THF
Value: 50.0
Constant
 
   FTD_Vmax
Value: 14000.0
Constant
 
   FTD_Km_10fTHF
Value: 20.0
Constant
 
   FTS_Vmax
Value: 2000.0
Constant
 
   FTS_Km_HCOOH
Value: 43.0
Constant
 
   FTS_Km_THF
Value: 3.0
Constant
 
   AICART_Vmax
Value: 45000.0
Constant
 
   AICART_Km_AICAR
Value: 100.0
Constant
 
   AICART_Km_10fTHF
Value: 5.9
Constant
 
   PGT_Vmax
Value: 16200.0
Constant
 
   PGT_Km_GAR
Value: 520.0
Constant
 
   PGT_Km_10fTHF
Value: 4.9
Constant
 
   TS_Vmax
Value: 50.0
Constant
 
   TS_Km_dUMP
Value: 6.3
Constant
 
   TS_Km_5_10_CH2THF
Value: 14.0
Constant
 
   DHFR_Vmax
Value: 50.0
Constant
 
   DHFR_Km_NADPH
Value: 4.0
Constant
 
   DHFR_Km_DHF
Value: 0.5
Constant
 
   MTCH_VmaxF
Value: 800000.0
Constant
 
   MTCH_Km_5_10_CHTHF
Value: 250.0
Constant
 
   MTCH_VmaxR
Value: 20000.0
Constant
 
   MTCH_Km_10fTHF
Value: 100.0
Constant
 
   SHMT_VmaxF
Value: 40000.0
Constant
 
   SHMT_Km_Ser
Value: 600.0
Constant
 
   SHMT_Km_THF
Value: 50.0
Constant
 
   SHMT_VmaxR
Value: 25000.0
Constant
 
   MTD_VmaxF
Value: 200000.0
Constant
 
   MTD_Km_5_10_CH2THF
Value: 2.0
Constant
 
   MTD_VmaxR
Value: 594000.0
Constant
 
   MTD_Km_5_10_CHTHF
Value: 10.0
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000213

Curator's comment: (updated: 01 Jun 2009 18:02:53 BST)

parameter scan performed performed using Copasi 4.4.29

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