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BIOMD0000000018 - Morrison1989 - Folate Cycle

 

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Reference Publication
Publication ID: 2732237
Morrison PF, Allegra CJ.
Folate cycle kinetics in human breast cancer cells.
J. Biol. Chem. 1989 Jun; 264(18): 10552-10566
Division of Research Services, National Institutes of Health, Bethesda, Maryland 20892.  [more]
Model
Original Model: BIOMD0000000018.origin
Submitter: Nicolas Le Novère
Submission ID: MODEL6617317313
Submission Date: 13 Sep 2005 14:15:44 UTC
Last Modification Date: 18 May 2017 11:55:12 UTC
Creation Date: 29 Jun 2005 11:22:41 UTC
Encoders:  Nicolas Le Novère
   Tomas Radivoyevitch
set #1
bqbiol:isVersionOf Gene Ontology folic acid metabolic process
bqbiol:hasPart KEGG Pathway Folate biosynthesis
KEGG Pathway One carbon pool by folate
bqbiol:hasTaxon Taxonomy Homo sapiens
bqbiol:hasProperty Human Disease Ontology breast cancer
Notes
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.

Model
Publication ID: 2732237 Submission Date: 13 Sep 2005 14:15:44 UTC Last Modification Date: 18 May 2017 11:55:12 UTC Creation Date: 29 Jun 2005 11:22:41 UTC
Mathematical expressions
Reactions
SHMT SHMTr HCHOtoCH2FH4 CH2FH4toHCHO
MTHFR MTR HCOOHtoCHOFH4 GARFT
ATIC7 MTHFD TYMS DHFReductase
FFH2syn ATIC12 AICARsyn FPGS12
FPGS23 FPGS34 FPGS45 GGH21
GGH32 GGH43 GGH54 RFC
MTX1export MTX2export MTX3export MTX4export
MTX5export MTX1on MTX2on MTX3on
MTX4on MTX5on MTX1off MTX2off
MTX3off MTX4off MTX5off DHFRfsyn
DHFRdeg FH2bdeg MTX1deg MTX2deg
MTX3deg MTX4deg MTX5deg  
Rules
Assignment Rule (variable: dihydrofolate bound) Assignment Rule (variable: dihydrofolate reductase total)    
Physical entities
Compartments Species
ext EMTX    
cell dihydrofolate free dihydrofolate bound dihydrofolate reductase free
dihydrofolate reductase total tetrahydrofolate 5,10-methylene-tetrahydrofolate
5-methyl-tetrahydrofolate 10-formyl-tetrahydrofolate 10-formyl-dihydrofolate
HCHO FGAR AICAR
MTX1 MTX2 MTX3
MTX4 MTX5 MTX1b
MTX2b MTX3b MTX4b
MTX5b dUMP GAR
serine formate ATP
glutamine glycine NADP
NADPH homocysteine  
Global parameters
Keq      
Reactions (47)
 
 SHMT [tetrahydrofolate] + [serine] → [5,10-methylene-tetrahydrofolate];  
 
 SHMTr [5,10-methylene-tetrahydrofolate] → [tetrahydrofolate];   {glycine}
 
 HCHOtoCH2FH4 [tetrahydrofolate] + [HCHO] → [5,10-methylene-tetrahydrofolate];  
 
 CH2FH4toHCHO [5,10-methylene-tetrahydrofolate] → [tetrahydrofolate] + [HCHO];  
 
 MTHFR [5,10-methylene-tetrahydrofolate] + [NADPH] → [5-methyl-tetrahydrofolate];   {dihydrofolate free} , {MTX1} , {MTX2} , {MTX3} , {MTX4} , {MTX5}
 
 MTR [5-methyl-tetrahydrofolate] + [homocysteine] → [tetrahydrofolate];  
 
 HCOOHtoCHOFH4 [tetrahydrofolate] + [formate] + [ATP] → [10-formyl-tetrahydrofolate];  
 
 GARFT [10-formyl-tetrahydrofolate] + [GAR] → [FGAR] + [tetrahydrofolate];   {dihydrofolate free} , {10-formyl-dihydrofolate} , {MTX1} , {MTX2} , {MTX3} , {MTX4} , {MTX5}
 
 ATIC7 [10-formyl-tetrahydrofolate] + [AICAR] → [tetrahydrofolate];   {dihydrofolate free} , {10-formyl-dihydrofolate} , {MTX1} , {MTX2} , {MTX3} , {MTX4} , {MTX5}
 
 MTHFD [5,10-methylene-tetrahydrofolate] + [NADP] → [10-formyl-tetrahydrofolate];  
 
 TYMS [5,10-methylene-tetrahydrofolate] + [dUMP] → [dihydrofolate free];   {dihydrofolate free} , {10-formyl-dihydrofolate} , {MTX1} , {MTX2} , {MTX3} , {MTX4} , {MTX5}
 
 DHFReductase [dihydrofolate free] → [tetrahydrofolate];   {dihydrofolate bound}
 
 FFH2syn [dihydrofolate free] → [10-formyl-dihydrofolate];  
 
 ATIC12 [10-formyl-dihydrofolate] + [AICAR] → [dihydrofolate free];   {dihydrofolate free} , {MTX1} , {MTX2} , {MTX3} , {MTX4} , {MTX5}
 
 AICARsyn [FGAR] → [AICAR];   {glutamine}
 
 FPGS12 [MTX1] → [MTX2];  
 
 FPGS23 [MTX2] → [MTX3];  
 
 FPGS34 [MTX3] → [MTX4];  
 
 FPGS45 [MTX4] → [MTX5];  
 
 GGH21 [MTX2] → [MTX1];  
 
 GGH32 [MTX3] → [MTX2];  
 
 GGH43 [MTX4] → [MTX3];  
 
 GGH54 [MTX5] → [MTX4];  
 
 RFC [EMTX] → [MTX1];  
 
 MTX1export [MTX1] → ;  
 
 MTX2export [MTX2] → ;  
 
 MTX3export [MTX3] → ;  
 
 MTX4export [MTX4] → ;  
 
 MTX5export [MTX5] → ;  
 
 MTX1on [MTX1] + [dihydrofolate reductase free] → [MTX1b];  
 
 MTX2on [MTX2] + [dihydrofolate reductase free] → [MTX2b];  
 
 MTX3on [MTX3] + [dihydrofolate reductase free] → [MTX3b];  
 
 MTX4on [MTX4] + [dihydrofolate reductase free] → [MTX4b];  
 
 MTX5on [MTX5] + [dihydrofolate reductase free] → [MTX5b];  
 
 MTX1off [MTX1b] → [MTX1] + [dihydrofolate reductase free];  
 
 MTX2off [MTX2b] → [MTX2] + [dihydrofolate reductase free];  
 
 MTX3off [MTX3b] → [MTX3] + [dihydrofolate reductase free];  
 
 MTX4off [MTX4b] → [MTX4] + [dihydrofolate reductase free];  
 
 MTX5off [MTX5b] → [MTX5] + [dihydrofolate reductase free];  
 
 DHFRfsyn  → [dihydrofolate reductase free];   {EMTX}
 
 DHFRdeg [dihydrofolate reductase free] → ;   {dihydrofolate bound}
 
 FH2bdeg  → [dihydrofolate free];   {dihydrofolate bound}
 
 MTX1deg [MTX1b] → [MTX1];  
 
 MTX2deg [MTX2b] → [MTX2];  
 
 MTX3deg [MTX3b] → [MTX3];  
 
 MTX4deg [MTX4b] → [MTX4];  
 
 MTX5deg [MTX5b] → [MTX5];  
 
Rules (2)
 
 Assignment Rule (name: FH2b) dihydrofolate bound = FH2f*DHFRf/Keq
 
 Assignment Rule (name: DHFRtot) dihydrofolate reductase total = FH2b+DHFRf+MTX1b+MTX2b+MTX3b+MTX4b+MTX5b
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 EMTX
Compartment: ext
Initial concentration: 0.0
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 dihydrofolate free
Compartment: cell
Initial concentration: 0.0012
 
  dihydrofolate bound
Compartment: cell
Initial concentration: 0.0024
 
 dihydrofolate reductase free
Compartment: cell
Initial concentration: 0.64
 
  dihydrofolate reductase total
Compartment: cell
Initial concentration: 0.64
 
 tetrahydrofolate
Compartment: cell
Initial concentration: 0.46
 
 5,10-methylene-tetrahydrofolate
Compartment: cell
Initial concentration: 0.26
 
 5-methyl-tetrahydrofolate
Compartment: cell
Initial concentration: 1.63
 
 10-formyl-tetrahydrofolate
Compartment: cell
Initial concentration: 1.0
 
 10-formyl-dihydrofolate
Compartment: cell
Initial concentration: 3.32E-4
 
 HCHO
Compartment: cell
Initial concentration: 0.0074
 
 FGAR
Compartment: cell
Initial concentration: 16.49
 
 AICAR
Compartment: cell
Initial concentration: 3.695
 
 MTX1
Compartment: cell
Initial concentration: 0.0
 
 MTX2
Compartment: cell
Initial concentration: 0.0
 
 MTX3
Compartment: cell
Initial concentration: 0.0
 
 MTX4
Compartment: cell
Initial concentration: 0.0
 
 MTX5
Compartment: cell
Initial concentration: 0.0
 
 MTX1b
Compartment: cell
Initial concentration: 0.0
 
 MTX2b
Compartment: cell
Initial concentration: 0.0
 
 MTX3b
Compartment: cell
Initial concentration: 0.0
 
 MTX4b
Compartment: cell
Initial concentration: 0.0
 
 MTX5b
Compartment: cell
Initial concentration: 0.0
 
 dUMP
Compartment: cell
Initial concentration: 20.76
 
 GAR
Compartment: cell
Initial concentration: 689.6
 
 serine
Compartment: cell
Initial concentration: 123.3
 
 formate
Compartment: cell
Initial concentration: 500.0
 
 ATP
Compartment: cell
Initial concentration: 2980.0
 
 glutamine
Compartment: cell
Initial concentration: 7170.0
 
 glycine
Compartment: cell
Initial concentration: 1600.0
 
 NADP
Compartment: cell
Initial concentration: 6.73
 
 NADPH
Compartment: cell
Initial concentration: 294.0
 
 homocysteine
Compartment: cell
Initial concentration: 10.0
 
Global Parameters (1)
 
   Keq
Value: 0.32
Constant
 
SHMT (3)
 
   Vm
Value: 18330.0
Constant
 
   Km1
Value: 1.7
Constant
 
   Km2
Value: 210.0
Constant
 
SHMTr (3)
 
   Vm
Value: 1.22E7
Constant
 
   Km1
Value: 3200.0
Constant
 
   Km2
Value: 10000.0
Constant
 
HCHOtoCH2FH4 (1)
 
   hp
Value: 23.2
Constant
 
CH2FH4toHCHO (1)
 
   hl
Value: 0.3
Constant
 
MTHFR (9)
 
   Vm
Value: 224.8
Constant
 
   Km1
Value: 50.0
Constant
 
   Km2
Value: 50.0
Constant
 
   Ki1
Value: 0.4
Constant
 
   Ki21
Value: 59.0
Constant
 
   Ki22
Value: 21.3
Constant
 
   Ki23
Value: 7.68
Constant
 
   Ki24
Value: 2.77
Constant
 
   Ki25
Value: 1.0
Constant
 
MTR (3)
 
   Vm
Value: 22600.0
Constant
 
   Km1
Value: 125.0
Constant
 
   Km2
Value: 2900.0
Constant
 
HCOOHtoCHOFH4 (4)
 
   Vm
Value: 3600.0
Constant
 
   Km1
Value: 230.0
Constant
 
   Km2
Value: 56.0
Constant
 
   Km3
Value: 1600.0
Constant
 
GARFT (10)
 
   Vm
Value: 4126.0
Constant
 
   Km1
Value: 4.9
Constant
 
   Km2
Value: 52.0
Constant
 
   Ki1
Value: 5.0
Constant
 
   Ki1f
Value: 1.0
Constant
 
   Ki21
Value: 84.0
Constant
 
   Ki22
Value: 60.0
Constant
 
   Ki23
Value: 43.0
Constant
 
   Ki24
Value: 31.0
Constant
 
   Ki25
Value: 22.0
Constant
 
ATIC7 (10)
 
   Vm
Value: 31675.0
Constant
 
   Km1
Value: 5.5
Constant
 
   Km2
Value: 24.0
Constant
 
   Ki1
Value: 2.89
Constant
 
   Ki1f
Value: 5.3
Constant
 
   Ki21
Value: 40.0
Constant
 
   Ki22
Value: 31.5
Constant
 
   Ki23
Value: 2.33
Constant
 
   Ki24
Value: 3.61
Constant
 
   Ki25
Value: 5.89
Constant
 
MTHFD (3)
 
   Vm
Value: 68500.0
Constant
 
   Km1
Value: 3.0
Constant
 
   Km2
Value: 21.8
Constant
 
TYMS (10)
 
   Vm
Value: 58.0
Constant
 
   Km1
Value: 2.5
Constant
 
   Km2
Value: 1.8
Constant
 
   Ki1
Value: 3.0
Constant
 
   Ki1f
Value: 1.6
Constant
 
   Ki21
Value: 13.0
Constant
 
   Ki22
Value: 0.08
Constant
 
   Ki23
Value: 0.07
Constant
 
   Ki24
Value: 0.065
Constant
 
   Ki25
Value: 0.047
Constant
 
DHFReductase (1)
 
   kter
Value: 2109.4
Constant
 
FFH2syn (1)
 
   Vm
Value: 65.0
Constant
 
ATIC12 (10)
 
   Vm
Value: 9503.0
Constant
 
   Km1
Value: 5.3
Constant
 
   Km2
Value: 24.0
Constant
 
   Ki1
Value: 2.89
Constant
 
   Ki1f
Value: 5.5
Constant
 
   Ki21
Value: 40.0
Constant
 
   Ki22
Value: 31.5
Constant
 
   Ki23
Value: 2.33
Constant
 
   Ki24
Value: 3.61
Constant
 
   Ki25
Value: 5.89
Constant
 
AICARsyn (3)
 
   Vm
Value: 4656.0
Constant
 
   Km1
Value: 100.0
Constant
 
   Km2
Value: 100.0
Constant
 
FPGS12 (1)
 
   Vm
Value: 0.129
Constant
 
FPGS23 (1)
 
   Vm
Value: 0.369
Constant
 
FPGS34 (1)
 
   Vm
Value: 0.118
Constant
 
FPGS45 (1)
 
   Vm
Value: 0.185
Constant
 
GGH21 (1)
 
   Vm
Value: 0.195
Constant
 
GGH32 (1)
 
   Vm
Value: 0.025
Constant
 
GGH43 (1)
 
   Vm
Value: 0.031
Constant
 
GGH54 (1)
 
   Vm
Value: 0.191
Constant
 
RFC (2)
 
   Vm
Value: 82.2
Constant
 
   Km
Value: 8.2
Constant
 
MTX1export (1)
 
   Vm
Value: 4.65
Constant
 
MTX2export (1)
 
   Vm
Constant
 
MTX3export (1)
 
   Vm
Value: 0.063
Constant
 
MTX4export (1)
 
   Vm
Value: 0.063
Constant
 
MTX5export (1)
 
   Vm
Value: 0.063
Constant
 
MTX1on (1)
 
   Vm
Value: 23100.0
Constant
 
MTX2on (1)
 
   Vm
Value: 44300.0
Constant
 
MTX3on (1)
 
   Vm
Value: 85100.0
Constant
 
MTX4on (1)
 
   Vm
Value: 163000.0
Constant
 
MTX5on (1)
 
   Vm
Value: 314000.0
Constant
 
MTX1off (1)
 
   Vm
Value: 0.42
Constant
 
MTX2off (1)
 
   Vm
Value: 0.42
Constant
 
MTX3off (1)
 
   Vm
Value: 0.42
Constant
 
MTX4off (1)
 
   Vm
Value: 0.42
Constant
 
MTX5off (1)
 
   Vm
Value: 0.42
Constant
 
DHFRfsyn (2)
 
   k0
Value: 0.0192
Constant
 
   k1
Value: 0.04416
Constant
 
DHFRdeg (1)
 
   Vm
Value: 0.03
Constant
 
FH2bdeg (1)
 
   Vm
Value: 0.03
Constant
 
MTX1deg (1)
 
   Vm
Value: 0.03
Constant
 
MTX2deg (1)
 
   Vm
Value: 0.03
Constant
 
MTX3deg (1)
 
   Vm
Value: 0.03
Constant
 
MTX4deg (1)
 
   Vm
Value: 0.03
Constant
 
MTX5deg (1)
 
   Vm
Value: 0.03
Constant
 
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