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BIOMD0000000426 - Mosca2012 - Central Carbon Metabolism Regulated by AKT

 

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Reference Publication
Publication ID: 23181020
Mosca E, Alfieri R, Maj C, Bevilacqua A, Canti G, Milanesi L.
Computational modeling of the metabolic States regulated by the kinase akt.
Front Physiol 2012; 3: 418
Institute for Biomedical Technologies, Consiglio Nazionale delle Ricerche Segrate Milano, Italy.  [more]
Model
Original Model: BIOMD0000000426.xml.origin
Submitter: Ettore Mosca
Submission ID: MODEL1210150000
Submission Date: 15 Oct 2012 09:07:51 UTC
Last Modification Date: 09 Oct 2014 17:31:01 UTC
Creation Date: 03 Sep 2012 15:27:35 UTC
Encoders:  Vijayalakshmi Chelliah
   Ettore Mosca
   Roberta Alfieri
set #1
bqbiol:occursIn Taxonomy Homo sapiens
Brenda Tissue Ontology HeLa cell
bqbiol:isVersionOf Gene Ontology protein kinase B signaling
Gene Ontology regulation of metabolic process
set #2
bqbiol:hasProperty Human Disease Ontology cancer
Notes
Mosca2012 - Central Carbon Metabolism Regulated by AKT

The role of the PI3K/Akt/PKB signalling pathway in oncogenesis has been extensively investigated and altered expression or mutations of many components of this pathway have been implicated in human cancers. Indeed, expression of constitutively active forms of Akt/PKB can prevent cell death upon growth factor withdrawal. PI3K/Akt/mTOR-mediated survival relies on a profound metabolic adaptation, including aerobic glycolysis. Here, the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis has been modelled, considering two states - high and low PI3K/Akt/mTOR activity. The high PI3K/Akt/mTOR activity represents cancer cell line where PI3K/Akt/mTOR promotes a high rate of glucose metabolism (condition H) and the low PI3K/Akt/mTOR activity is characterised by a lower glycolytic rate due to a reduced PI3K/Akt/mTOR signal (condition L). This model corresponds to the high PI3K/Akt/mTOR signal (condition H).

This model is described in the article:

Mosca E, Alfieri R, Maj C, Bevilacqua A, Canti G, Milanesi L.
Frontiers in Systems Biology. 2012 Oct 13

Abstract:

Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modelled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis. We used a computational model in order to compare two metabolic states generated by the specific variation of the metabolic fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One of the two states represented the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis, while the other state represented the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism, as reported in literature in relation to the activity of the PI3K/Akt/mTOR. Some steps that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism.

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: 23181020 Submission Date: 15 Oct 2012 09:07:51 UTC Last Modification Date: 09 Oct 2014 17:31:01 UTC Creation Date: 03 Sep 2012 15:27:35 UTC
Mathematical expressions
Reactions
GLUT HK PGI G6PDH
PGDH RUPE R5PI TKL
TKL2 TAL PRPPS PGLM
GPa FBA TPI GAPDH
PGK GPb GS PFK
PGYM ENO PK LDH
AK DHase DPHase MPM
ATPase      
Rules
Assignment Rule (variable: TKL_Vf) Assignment Rule (variable: TKL2_Vf) Assignment Rule (variable: PGK_Vf) Assignment Rule (variable: PK_Vf)
Assignment Rule (variable: GLUT_Vf) Assignment Rule (variable: PFK_Vf) Assignment Rule (variable: PGK_Vr) Assignment Rule (variable: MPM_Vf)
Assignment Rule (variable: PGDH_Vf) Assignment Rule (variable: ENO_Vf) Assignment Rule (variable: ENO_Vr) Assignment Rule (variable: PGLM_Vmr)
Assignment Rule (variable: DPHase_Vf) Assignment Rule (variable: NADP) Assignment Rule (variable: ADP) Assignment Rule (variable: NADH)
Assignment Rule (variable: GPa_Vr) Assignment Rule (variable: GPb_Vr) Assignment Rule (variable: FBA_Vf) Assignment Rule (variable: FBA_Vr)
Assignment Rule (variable: TPI_Vf) Assignment Rule (variable: TPI_Vr) Assignment Rule (variable: GAPDH_Vf) Assignment Rule (variable: GAPDH_Vr)
Assignment Rule (variable: GS_Vf) Assignment Rule (variable: DHase_Vf) Assignment Rule (variable: PGYM_Vr) Assignment Rule (variable: HK_Vf)
Assignment Rule (variable: G6PDH_Vf) Assignment Rule (variable: PGI_Vmf) Assignment Rule (variable: PGI_Vmr) Assignment Rule (variable: AMP)
Assignment Rule (variable: LDH_Vf) Assignment Rule (variable: LDH_Vr)    
Physical entities
Compartments Species
compartment GLC G6P ADP
ATP F6P F16P
E4P PGN GLC_e
NADP NADPH BPG
RU5P X5P R5P
GAP S7P NADH
NAD AMP PRPP
G1P Pi GLY
CIT F26P DHAP
PG3 PG2 PEP
PYR LAC CO2
O2    
Global parameters
Atot NPtot Ntot GPa_Vr
GPa_Keq GPb_Keq GPb_Vr FBA_Vr
TPI_Vr GAPDH_Vr PGK_Vr FBA_Keq
PGI_Vmr PGI_Keq PGLM_Vmr PGLM_Keq
scale1e3 TPI_Keq GAPDH_Keq PGK_Keq
PGYM_Keq PGYM_Vr ENO_Keq ENO_Vr
LDH_Keq LDH_Vr AMP AKT
AKT_MPM GLUT_Vf HK_Vf PGI_Vmf
G6PDH_Vf PGDH_Vf TKL_Vf TKL2_Vf
FBA_Vf TPI_Vf GAPDH_Vf PGK_Vf
GS_Vf PFK_Vf ENO_Vf PK_Vf
LDH_Vf DHase_Vf DPHase_Vf MPM_Vf
PGK_Kp PGK_Kq PGK_Ka PGK_Kb
ENO_Kmp ENO_Kms PGLM_Vmaxf PGLM_KG6P
PGLM_KG1P GPa_Vmaxf GPa_KiGLYb GPa_KiG1P
GPa_KiGLYf GPa_KPi GPb_Vmaxf GPb_KiGLYb
GPb_KG1P GPb_KiGLYf GPb_KiPi FBA_Kdhap
FBA_Kg3p FBA_Kfbp TPI_Kmp TPI_Kms
GAPDH_Kdpg GAPDH_Knadh GAPDH_Kg3p GAPDH_Knad
GAPDH_Kp PGYM_Vmf PGYM_Kmp PGYM_Kms
PGI_Kf6p PGI_Kg6p LDH_Kp LDH_Kq
LDH_Ka LDH_Kb    
Reactions (29)
 
 GLUT [GLC_e] ↔ [GLC];   {GLC_e} , {GLC}
 
 HK [GLC] + [ATP] ↔ [G6P] + [ADP];   {GLC} , {ATP} , {G6P} , {ADP}
 
 PGI [G6P] ↔ [F6P];   {E4P} , {F16P} , {PGN} , {G6P} , {F6P} , {E4P} , {F16P} , {PGN}
 
 G6PDH [G6P] + [NADP] ↔ [PGN] + [NADPH];   {ATP} , {BPG} , {G6P} , {NADP} , {PGN} , {NADPH} , {ATP} , {BPG}
 
 PGDH [PGN] + [NADP] ↔ [RU5P] + [NADPH];   {BPG} , {ATP} , {PGN} , {NADP} , {RU5P} , {NADPH} , {BPG} , {ATP}
 
 RUPE [RU5P] ↔ [X5P];   {RU5P} , {X5P}
 
 R5PI [RU5P] ↔ [R5P];   {RU5P} , {R5P}
 
 TKL [R5P] + [X5P] ↔ [GAP] + [S7P];   {R5P} , {X5P} , {GAP} , {S7P}
 
 TKL2 [X5P] + [E4P] ↔ [GAP] + [F6P];   {E4P} , {X5P} , {GAP} , {F6P}
 
 TAL [S7P] + [GAP] ↔ [F6P] + [E4P];   {S7P} , {GAP} , {E4P} , {F6P}
 
 PRPPS [R5P] + [ATP] ↔ [AMP] + [PRPP];   {R5P} , {ATP} , {PRPP} , {AMP}
 
 PGLM [G1P] ↔ [G6P];   {G1P} , {G6P}
 
 GPa [GLY] + [Pi] ↔ [GLY] + [G1P];   {GLY} , {Pi} , {G1P}
 
 FBA [F16P] ↔ [GAP] + [DHAP];   {F16P} , {DHAP} , {GAP}
 
 TPI [GAP] ↔ [DHAP];   {GAP} , {DHAP}
 
 GAPDH [GAP] + [NAD] + [Pi] ↔ [BPG] + [NADH];   {NAD} , {GAP} , {Pi} , {BPG} , {NADH}
 
 PGK [BPG] + [ADP] ↔ [PG3] + [ATP];   {BPG} , {ADP} , {PG3} , {ATP}
 
 GPb [GLY] + [Pi] ↔ [GLY] + [G1P];   {GLY} , {Pi} , {G1P}
 
 GS [G1P] + [ATP] ↔ [GLY] + [ADP] + 2.0 × [Pi];   {G1P} , {ATP} , {GLY} , {Pi} , {ADP}
 
 PFK [F6P] + [ATP] ↔ [F16P] + [ADP];   {F26P} , {CIT} , {ATP} , {F26P} , {F6P} , {CIT} , {ADP} , {F16P}
 
 PGYM [PG3] ↔ [PG2];   {PG3} , {PG2}
 
 ENO [PG2] ↔ [PEP];   {PG2} , {PEP}
 
 PK [PEP] + [ADP] ↔ [PYR] + [ATP];   {F16P} , {ADP} , {PEP} , {ATP} , {F16P} , {PYR}
 
 LDH [PYR] + [NADH] ↔ [LAC] + [NAD];   {NADH} , {PYR} , {LAC} , {NAD}
 
 AK 2.0 × [ADP] ↔ [ATP] + [AMP];   {ADP} , {ATP} , {AMP}
 
 DHase [NADH] ↔ [NAD];   {NADH} , {NAD}
 
 DPHase [NADPH] ↔ [NADP];   {NADPH} , {NADP}
 
 MPM 0.08 × [PYR] + 0.2 × [O2] + [Pi] + [ADP] ↔ 0.24 × [CO2] + [ATP];   {PYR} , {Pi} , {ADP} , {O2} , {ATP} , {CO2}
 
 ATPase [ATP] → [ADP] + [Pi];   {ATP}
 
Rules (34)
 
 Assignment Rule (name: parameter_35) TKL_Vf = 1056*parameter_28
 
 Assignment Rule (name: parameter_36) TKL2_Vf = 0.1761*parameter_28
 
 Assignment Rule (name: parameter_40) PGK_Vf = 73.41*parameter_28
 
 Assignment Rule (name: parameter_44) PK_Vf = 27.81*parameter_28
 
 Assignment Rule (name: parameter_30) GLUT_Vf = 23.03*parameter_28
 
 Assignment Rule (name: parameter_42) PFK_Vf = 107.6*parameter_28
 
 Assignment Rule (name: parameter_11) PGK_Vr = parameter_40*parameter_49*parameter_50/(parameter_51*parameter_52*parameter_20)
 
 Assignment Rule (name: parameter_48) MPM_Vf = 9801000*parameter_29
 
 Assignment Rule (name: parameter_34) PGDH_Vf = 31.02*parameter_28
 
 Assignment Rule (name: parameter_43) ENO_Vf = 160.9*parameter_28
 
 Assignment Rule (name: parameter_24) ENO_Vr = parameter_43*parameter_53/(parameter_54*parameter_23)
 
 Assignment Rule (name: parameter_15) PGLM_Vmr = parameter_55*parameter_56/(parameter_57*parameter_16)
 
 Assignment Rule (name: parameter_47) DPHase_Vf = 127800*parameter_28
 
 Assignment Rule (name: species_10) NADP = parameter_2-species_11
 
 Assignment Rule (name: species_3) ADP = parameter_1-species_4
 
 Assignment Rule (name: species_18) NADH = parameter_3-species_19
 
 Assignment Rule (name: parameter_4) GPa_Vr = parameter_58*parameter_59*parameter_60/(parameter_61*parameter_62*parameter_5)
 
 Assignment Rule (name: parameter_7) GPb_Vr = parameter_63*parameter_64*parameter_65/(parameter_66*parameter_67*parameter_6)
 
 Assignment Rule (name: parameter_37) FBA_Vf = 14.63*parameter_28
 
 Assignment Rule (name: parameter_8) FBA_Vr = parameter_37*parameter_68*parameter_69/(parameter_12*parameter_70)
 
 Assignment Rule (name: parameter_38) TPI_Vf = 5.976*parameter_28
 
 Assignment Rule (name: parameter_9) TPI_Vr = parameter_38*parameter_71/(parameter_72*parameter_18)
 
 Assignment Rule (name: parameter_39) GAPDH_Vf = 109.1*parameter_28
 
 Assignment Rule (name: parameter_10) GAPDH_Vr = parameter_39*parameter_73*parameter_74/(parameter_75*parameter_76*parameter_77*parameter_19)
 
 Assignment Rule (name: parameter_41) GS_Vf = 32040*parameter_28
 
 Assignment Rule (name: parameter_46) DHase_Vf = 4982000*parameter_28
 
 Assignment Rule (name: parameter_22) PGYM_Vr = parameter_78*parameter_79/(parameter_80*parameter_21)
 
 Assignment Rule (name: parameter_31) HK_Vf = 86.85*parameter_28
 
 Assignment Rule (name: parameter_33) G6PDH_Vf = 1.008*parameter_28
 
 Assignment Rule (name: parameter_32) PGI_Vmf = 7778*parameter_28
 
 Assignment Rule (name: parameter_13) PGI_Vmr = parameter_32*parameter_81/(parameter_82*parameter_14)
 
 Assignment Rule (name: parameter_27) AMP = species_20
 
 Assignment Rule (name: parameter_45) LDH_Vf = 340.3*parameter_28
 
 Assignment Rule (name: parameter_26) LDH_Vr = parameter_45*parameter_83*parameter_84/(parameter_85*parameter_86*parameter_25)
 
Functions (28)
 
 RUPE lambda(Vmax, RU5P, X5P, Keq_RUPE, KRu5P, KX5P, Vmax*(RU5P-X5P/Keq_RUPE)/(RU5P+KRu5P*(1+X5P/KX5P)))
 
 PGDH lambda(Vmax, K6PG1, KNADP, PGN, NADP, RU5P, NADPH, Kapp, BPG, KPGA23, ATP, KATP, K6PG2, KNADPH, Vmax/K6PG1/KNADP*(PGN*NADP-RU5P*NADPH/Kapp)/((1+NADP/KNADP)*(1+PGN/K6PG1+BPG/KPGA23)+ATP/KATP+NADPH*(1+PGN/K6PG2)/KNADPH))
 
 G6PDH lambda(Vmax, KG6P, KNADP, G6P, NADP, PGN, NADPH, Kapp, ATP, KATP, KNADPH, BPG, KPGA23, Vmax/KG6P/KNADP*(G6P*NADP-PGN*NADPH/Kapp)/(1+NADP*(1+G6P/KG6P)/KNADP+ATP/KATP+NADPH/KNADPH+BPG/KPGA23))
 
 TKL lambda(Vmax, R5P, X5P, GAP, S7P, Keq_TKL, K1, K2, K6, K3, K5, K4, K7, Vmax*(R5P*X5P-GAP*S7P/Keq_TKL)/((K1+R5P)*X5P+(K2+K6*S7P)*R5P+(K3+K5*S7P)*GAP+K4*S7P+K7*X5P*GAP))
 
 PGI lambda(Vmf, A, Kg6p, Vmr, P, Kf6p, E4P, Kery4p, F16P, Kfbp, PGN, Kpg, (Vmf*A/Kg6p-Vmr*P/Kf6p)/(1+A/Kg6p+P/Kf6p+E4P/Kery4p+F16P/Kfbp+PGN/Kpg))
 
 TKL2 lambda(Vmax, E4P, X5P, GAP, F6P, Keq_TKL2, K1, K2, K6, K3, K5, K4, K7, Vmax*(E4P*X5P-GAP*F6P/Keq_TKL2)/((K1+E4P)*X5P+(K2+K6*F6P)*E4P+(K3+K5*F6P)*GAP+K4*F6P+K7*X5P*GAP))
 
 HK lambda(Vmf, Ka, Kb, A, B, P, Q, Kapp, Kp, Kq, Vmf/(Ka*Kb)*(A*B-P*Q/Kapp)/(1+A/Ka+B/Kb+A*B/(Ka*Kb)+P/Kp+Q/Kq+P*Q/(Kp*Kq)+A*Q/(Ka*Kq)+P*B/(Kp*Kb)))
 
 R5PI lambda(Vmax, RU5P, R5P, Keq_R5PI, KRu5P, KR5P, Vmax*(RU5P-R5P/Keq_R5PI)/(RU5P+KRu5P*(1+R5P/KR5P)))
 
 GLUT lambda(Vmaxf, GLC_e, GLC, keq, KGlc_e, KGlc, Vmaxf*(GLC_e-GLC/keq)/(KGlc_e*(1+GLC/KGlc)+GLC_e))
 
 TAL lambda(Vmax, S7P, GAP, E4P, F6P, Keq_TAL, K1, K2, K6, K3, K5, K4, K7, Vmax*(S7P*GAP-E4P*F6P/Keq_TAL)/((K1+GAP)*S7P+(K2+K6*F6P)*GAP+(K3+K5*F6P)*E4P+K4*F6P+K7*S7P*E4P))
 
 PGLM lambda(Vmaxf, G1P, KG1P, Vmaxr, G6P, KG6P, (Vmaxf*G1P/KG1P-Vmaxr*G6P/KG6P)/(1+G1P/KG1P+G6P/KG6P))
 
 PRPPS lambda(Vmax, R5P, ATP, PRPP, AMP, Kapp, KATP, KR5P, Vmax*(R5P*ATP-PRPP*AMP/Kapp)/((KATP+ATP)*(KR5P+R5P)))
 
 GPa lambda(Vmaxf, GLY, Pi, KiGLYf, KPi, Vmaxr, G1P, KGLYb, KiG1P, KiPi, KiGLYb, (Vmaxf*GLY*Pi/(KiGLYf*KPi)-Vmaxr*GLY*G1P/(KGLYb*KiG1P))/(1+GLY/KiGLYf+Pi/KiPi+GLY/KiGLYb+G1P/KiG1P+GLY*Pi/(KiGLYf*KiPi)+GLY*G1P/(KiGLYb*KiG1P)))
 
 GPb lambda(Vmaxf, GLY, Pi, KiGLYf, KPi, Vmaxr, G1P, KiGLYb, KG1P, KiPi, KiG1P, AMP, nH, Kamp, (Vmaxf*GLY*Pi/(KiGLYf*KPi)-Vmaxr*GLY*G1P/(KiGLYb*KG1P))/(1+GLY/KiGLYf+Pi/KiPi+GLY/KiGLYb+G1P/KiG1P+GLY*Pi/(KiGLYf*KPi)+GLY*G1P/(KiGLYb*KG1P))*AMP^nH/Kamp/(1+AMP^nH/Kamp))
 
 FBA lambda(Vmf, A, Kfbp, Vmr, P, Q, Kdhap, Kg3p, (Vmf*A/Kfbp-Vmr*P*Q/(Kdhap*Kg3p))/(1+A/Kfbp+P/Kdhap+Q/Kg3p+P*Q/(Kdhap*Kg3p)))
 
 TPI lambda(Vf, GAP, Kms, Vr, DHAP, Kmp, (Vf*GAP/Kms-Vr*DHAP/Kmp)/(1+GAP/Kms+DHAP/Kmp))
 
 GAPDH lambda(Vmf, A, B, C, Knad, Kg3p, Kp, Vmr, P, Q, Kdpg, Knadh, (Vmf*A*B*C/(Knad*Kg3p*Kp)-Vmr*P*Q/(Kdpg*Knadh))/(1+A/Knad+A*B/(Knad*Kg3p)+A*B*C/(Knad*Kg3p*Kp)+P*Q/(Kdpg*Knadh)+Q/Knadh))
 
 PGK lambda(Vmf, A, B, alfa, Ka, Kb, Vmr, P, Q, beta, Kp, Kq, (Vmf*A*B/(alfa*Ka*Kb)-Vmr*P*Q/(beta*Kp*Kq))/(1+A/Ka+B/Kb+A*B/(alfa*Ka*Kb)+P*Q/(beta*Kp*Kq)+P/Kp+Q/Kq))
 
 PFK lambda(Vm, a, B, Katp, beta, F26P, alfa, Kf26bp, A, Kf6p, L, CIT, Kcit, Kiatp, Q, P, Kadp, Kfbp, Kapp, Vm*a*B/Katp/(1+a*B/Katp)*(1+beta*a*F26P/(alfa*Kf26bp))/(1+a*F26P/(alfa*Kf26bp))*(a*A*(1+a*F26P/(alfa*Kf26bp))/(Kf6p*(1+a*F26P/Kf26bp))*(1+a*A*(1+a*F26P/(alfa*Kf26bp))/(Kf6p*(1+a*F26P/Kf26bp)))^3/(L*(1+a*CIT/Kcit)^4*(1+a*B/Kiatp)^4/(1+a*F26P/Kf26bp)^4+(1+a*A*(1+a*F26P/(alfa*Kf26bp))/(Kf6p*(1+a*F26P/Kf26bp)))^4)-a*Q*a*P/(Kadp*Kfbp*Kapp)/(a*Q/Kadp+a*P/Kfbp+a*Q*a*P/(Kadp*Kfbp)+1)))
 
 PGYM [1] lambda(Vmf, PG3, Kms, Vmr, PG2, Kmp, (Vmf*PG3/Kms-Vmr*PG2/Kmp)/(1+PG3/Kms+PG2/Kmp))
 
 GS lambda(Vmaxf, Kf, a, G1P, ATP, GLY, Pi, ADP, Keq, Kr, Vmaxf/Kf*a*G1P*a*ATP*a*GLY*(1-(a*Pi)^2*a*ADP/(a*G1P*a*ATP*Keq))/(1+a*G1P*a*ATP*a*GLY/Kf+a*GLY*(a*Pi)^2*a*ADP/Kr))
 
 ENO [1] lambda(Vmf, PG2, Kms, Vmr, PEP, Kmp, (Vmf*PG2/Kms-Vmr*PEP/Kmp)/(1+PG2/Kms+PEP/Kmp))
 
 PK [1] lambda(Vm, B, Kadp, A, Kpep, L, Q, Kiatp, F16P, Kfbp, P, Katp, Kpyr, Kapp, a, Vm*(a*B/Kadp/(1+a*B/Kadp)*a*A/Kpep*(1+a*A/Kpep)^3/(L*(1+a*Q/Kiatp)^4/(1+a*F16P/Kfbp)^4+(1+a*A/Kpep)^4)-a*Q*a*P/(Katp*Kpyr*Kapp)/(a*Q/Katp+a*P/Kpyr+a*Q*a*P/(Katp*Kpyr)+1)))
 
 LDH [1] lambda(Vmf, A, B, alfa, Ka, Kb, Vmr, P, Q, beta, Kp, Kq, (Vmf*A*B/(alfa*Ka*Kb)-Vmr*P*Q/(beta*Kp*Kq))/(1+A/Ka+B/Kb+A*B/(alfa*Ka*Kb)+P*Q/(beta*Kp*Kq)+P/Kp+Q/Kq))
 
 AK [1] lambda(Vf, ADP, ATP, AMP, Keq, Vf*ADP^2*(1-ATP*AMP/Keq)/((1+ADP)^2+(1+ATP)*(1+AMP)-1))
 
 DHase [1] lambda(Vf, NADH, NAD, Keq, Vf*NADH*(1-NAD/(NADH*Keq))/(1+NADH+1+NAD-1))
 
 DPHase [1] lambda(Vf, NADPH, NADP, Keq, Vf*NADPH*(1-NADP/(NADPH*Keq))/(1+NADPH+1+NADP-1))
 
 MPM [1] lambda(Vmf, PYR, y, Pi, ADP, O2, ATP, CO2, Keq, Vmf*PYR^(1/y)*Pi*ADP*O2^(5/(2*y))*(1-ATP*CO2^(3/y)/(PYR^(1/y)*O2^(5/(2*y))*Pi*ADP*Keq))/((1+PYR)^(1/y)*(1+O2)^(5/(2*y))*(1+Pi)*(1+ADP)+(1+ATP)*(1+CO2)^(3/y)-1))
 
 compartment Spatial dimensions: 3.0  Compartment size: 1.0
 
 GLC
Compartment: compartment
Initial concentration: 8.97E-4
 
 G6P
Compartment: compartment
Initial concentration: 0.00109
 
  ADP
Compartment: compartment
Initial concentration: 0.0027
 
 ATP
Compartment: compartment
Initial concentration: 0.0087
 
 F6P
Compartment: compartment
Initial concentration: 3.62E-5
 
 F16P
Compartment: compartment
Initial concentration: 3.67E-4
 
 E4P
Compartment: compartment
Initial concentration: 9.3E-4
 
 PGN
Compartment: compartment
Initial concentration: 1.0E-4
 
 GLC_e
Compartment: compartment
Initial concentration: 0.01
Constant
 
  NADP
Compartment: compartment
Initial concentration: 6.118E-7
 
 NADPH
Compartment: compartment
Initial concentration: 1.87082E-5
 
 BPG
Compartment: compartment
Initial concentration: 6.29E-5
 
 RU5P
Compartment: compartment
Initial concentration: 1.43E-4
 
 X5P
Compartment: compartment
Initial concentration: 2.42E-4
 
 R5P
Compartment: compartment
Initial concentration: 2.74E-5
 
 GAP
Compartment: compartment
Initial concentration: 1.53E-4
 
 S7P
Compartment: compartment
Initial concentration: 8.58E-5
 
  NADH
Compartment: compartment
Initial concentration: 5.00000000000001E-6
 
 NAD
Compartment: compartment
Initial concentration: 0.00134
 
 AMP
Compartment: compartment
Initial concentration: 0.00311
Constant
 
 PRPP
Compartment: compartment
Initial concentration: 0.0010
Constant
 
 G1P
Compartment: compartment
Initial concentration: 3.41E-5
 
 Pi
Compartment: compartment
Initial concentration: 0.02
Constant
 
 GLY
Compartment: compartment
Initial concentration: 0.208403745497308
Constant
 
 CIT
Compartment: compartment
Initial concentration: 0.00108
Constant
 
 F26P
Compartment: compartment
Initial concentration: 3.67E-6
Constant
 
 DHAP
Compartment: compartment
Initial concentration: 5.53E-4
 
 PG3
Compartment: compartment
Initial concentration: 3.07E-5
 
 PG2
Compartment: compartment
Initial concentration: 4.98E-6
 
 PEP
Compartment: compartment
Initial concentration: 5.79E-5
 
 PYR
Compartment: compartment
Initial concentration: 0.00183
 
 LAC
Compartment: compartment
Initial concentration: 0.0155
Constant
 
 CO2
Compartment: compartment
Initial concentration: 0.0214
Constant
 
 O2
Compartment: compartment
Initial concentration: 6.5E-5
Constant
 
Global Parameters (86)
 
 Atot
Value: 0.0114
Constant
 
 NPtot
Value: 1.932E-5
Constant
 
 Ntot
Value: 0.001345
Constant
 
  GPa_Vr
Value: 0.0177545693277311
 
 GPa_Keq
Value: 0.42
Constant
 
 GPb_Keq
Value: 16.62
Constant
 
  GPb_Vr
Value: 6.03725213205671E-5
 
  FBA_Vr
Value: 11.5595061728395
 
  TPI_Vr
Value: 49.2079666512274
 
  GAPDH_Vr
Value: 135.42497838741
 
  PGK_Vr
Value: 71.7220990679741
 
 FBA_Keq
Value: 0.0018
Constant
 
  PGI_Vmr
Value: 17486.5107913669
 
 PGI_Keq
Value: 0.0556
Constant
 
  PGLM_Vmr
Value: 0.203875968992248
 
 PGLM_Keq
Value: 17.2
Constant
 
 scale1e3
Value: 1000.0
Constant
 
 TPI_Keq
Value: 0.381
Constant
 
 GAPDH_Keq
Value: 0.3574
Constant
 
 PGK_Keq
Value: 11.369
Constant
 
 PGYM_Keq
Value: 1.6491
Constant
 
  PGYM_Vr
Value: 58.9795390787319
 
 ENO_Keq
Value: 1.4127
Constant
 
  ENO_Vr
Value: 179.83480680891
 
 LDH_Keq
Value: 3452.5
Constant
 
  LDH_Vr
Value: 54.0471638909003
 
  AMP
Value: 0.00311
 
 AKT
Value: 1.0
Constant
 
 AKT_MPM
Value: 1.0
Constant
 
  GLUT_Vf
Value: 23.03
 
  HK_Vf
Value: 86.85
 
  PGI_Vmf
Value: 7778.0
 
  G6PDH_Vf
Value: 1.008
 
  PGDH_Vf
Value: 31.02
 
  TKL_Vf
Value: 1056.0
 
  TKL2_Vf
Value: 0.1761
 
  FBA_Vf
Value: 14.63
 
  TPI_Vf
Value: 5.976
 
  GAPDH_Vf
Value: 109.1
 
  PGK_Vf
Value: 73.41
 
  GS_Vf
Value: 32040.0
 
  PFK_Vf
Value: 107.6
 
  ENO_Vf
Value: 160.9
 
  PK_Vf
Value: 27.81
 
  LDH_Vf
Value: 340.3
 
  DHase_Vf
Value: 4982000.0
 
  DPHase_Vf
Value: 127800.0
 
  MPM_Vf
Value: 9801000.0
 
   PGK_Kp
Value: 1.3E-4
Constant
 
   PGK_Kq
Value: 2.7E-4
Constant
 
   PGK_Ka
Value: 7.9E-5
Constant
 
   PGK_Kb
Value: 4.0E-5
Constant
 
   ENO_Kmp
Value: 6.0E-5
Constant
 
   ENO_Kms
Value: 3.8E-5
Constant
 
   PGLM_Vmaxf
Value: 7.364
Constant
 
   PGLM_KG6P
Value: 3.0E-5
Constant
 
   PGLM_KG1P
Value: 6.3E-5
Constant
 
   GPa_Vmaxf
Value: 0.03347
Constant
 
   GPa_KiGLYb
Value: 1.5E-4
Constant
 
   GPa_KiG1P
Value: 0.0101
Constant
 
   GPa_KiGLYf
Value: 0.0017
Constant
 
   GPa_KPi
Value: 0.0040
Constant
 
   GPb_Vmaxf
Value: 0.01049
Constant
 
   GPb_KiGLYb
Value: 0.0044
Constant
 
   GPb_KG1P
Value: 0.0015
Constant
 
   GPb_KiGLYf
Value: 0.015
Constant
 
   GPb_KiPi
Value: 0.0046
Constant
 
   FBA_Kdhap
Value: 8.0E-5
Constant
 
   FBA_Kg3p
Value: 1.6E-4
Constant
 
   FBA_Kfbp
Value: 9.0E-6
Constant
 
   TPI_Kmp
Value: 0.0016
Constant
 
   TPI_Kms
Value: 5.1E-4
Constant
 
   GAPDH_Kdpg
Value: 2.2E-5
Constant
 
   GAPDH_Knadh
Value: 1.0E-5
Constant
 
   GAPDH_Kg3p
Value: 1.9E-4
Constant
 
   GAPDH_Knad
Value: 9.0E-5
Constant
 
   GAPDH_Kp
Value: 0.029
Constant
 
   PGYM_Vmf
Value: 154.0
Constant
 
   PGYM_Kmp
Value: 1.2E-4
Constant
 
   PGYM_Kms
Value: 1.9E-4
Constant
 
   PGI_Kf6p
Value: 5.0E-5
Constant
 
   PGI_Kg6p
Value: 4.0E-4
Constant
 
   LDH_Kp
Value: 0.0047
Constant
 
   LDH_Kq
Value: 7.0E-5
Constant
 
   LDH_Ka
Value: 2.0E-6
Constant
 
   LDH_Kb
Value: 3.0E-4
Constant
 
GLUT (3)
 
   keq
Value: 1.0
Constant
 
   KGlc_e
Value: 0.01
Constant
 
   KGlc
Value: 0.0093
Constant
 
HK (5)
 
   Ka
Value: 1.0E-4
Constant
 
   Kb
Value: 0.0011
Constant
 
   Kapp
Value: 651.0
Constant
 
   Kp
Value: 2.0E-5
Constant
 
   Kq
Value: 0.0035
Constant
 
PGI (3)
 
   Kery4p
Value: 1.0E-6
Constant
 
   Kfbp
Value: 6.0E-5
Constant
 
   Kpg
Value: 1.5E-5
Constant
 
G6PDH (6)
 
   KG6P
Value: 6.67E-8
Constant
 
   KNADP
Value: 3.67E-9
Constant
 
   Kapp
Value: 2000.0
Constant
 
   KATP
Value: 7.49E-7
Constant
 
   KNADPH
Value: 3.12E-9
Constant
 
   KPGA23
Value: 2.289E-6
Constant
 
PGDH (7)
 
   K6PG1
Value: 1.0E-8
Constant
 
   KNADP
Value: 1.8E-8
Constant
 
   Kapp
Value: 141.7
Constant
 
   KPGA23
Value: 1.2E-7
Constant
 
   KATP
Value: 1.54E-7
Constant
 
   K6PG2
Value: 5.8E-8
Constant
 
   KNADPH
Value: 4.5E-9
Constant
 
RUPE (4)
 
   Vmax
Value: 1.471
Constant
 
   Keq_RUPE
Value: 2.7
Constant
 
   KRu5P
Value: 1.9E-7
Constant
 
   KX5P
Value: 5.0E-7
Constant
 
R5PI (4)
 
   Vmax
Value: 0.7646
Constant
 
   Keq_R5PI
Value: 3.0
Constant
 
   KRu5P
Value: 7.8E-7
Constant
 
   KR5P
Value: 2.2E-6
Constant
 
TKL (8)
 
   Keq_TKL
Value: 2.08
Constant
 
   K1
Value: 4.177E-7
Constant
 
   K2
Value: 3.055E-7
Constant
 
   K6
Value: 0.00774
Constant
 
   K3
Value: 1.2432E-5
Constant
 
   K5
Value: 0.41139
Constant
 
   K4
Value: 4.96E-9
Constant
 
   K7
Value: 48.8
Constant
 
TKL2 (8)
 
   Keq_TKL2
Value: 29.7
Constant
 
   K1
Value: 1.84E-9
Constant
 
   K2
Value: 3.055E-7
Constant
 
   K6
Value: 0.122
Constant
 
   K3
Value: 5.48E-8
Constant
 
   K5
Value: 0.0287
Constant
 
   K4
Value: 3.0E-10
Constant
 
   K7
Value: 0.215
Constant
 
TAL (9)
 
   Vmax
Value: 58.27
Constant
 
   Keq_TAL
Value: 2.703
Constant
 
   K1
Value: 8.23E-9
Constant
 
   K2
Value: 4.765E-8
Constant
 
   K6
Value: 0.4653
Constant
 
   K3
Value: 1.733E-7
Constant
 
   K5
Value: 0.8683
Constant
 
   K4
Value: 6.095E-9
Constant
 
   K7
Value: 2.524
Constant
 
PRPPS (4)
 
   Vmax
Value: 0.5104
Constant
 
   Kapp
Value: 100000.0
Constant
 
   KATP
Value: 3.0E-8
Constant
 
   KR5P
Value: 5.7E-7
Constant
 
GPa (2)
 
   KGLYb
Value: 1.5E-4
Constant
 
   KiPi
Value: 0.0047
Constant
 
PGK (2)
 
   alfa
Value: 1.0
Constant
 
   beta
Value: 1.0
Constant
 
GPb (4)
 
   KPi
Value: 2.0E-4
Constant
 
   KiG1P
Value: 0.0074
Constant
 
   nH
Value: 1.75
Constant
 
   Kamp
Value: 1.9E-12
Constant
 
GS (3)
 
   Kf
Value: 17400.0
Constant
 
   Keq
Value: 267100.0
Constant
 
   Kr
Value: 158.0
Constant
 
PFK (11)
 
   Katp
Value: 2.1E-5
Constant
 
   beta
Value: 0.98
Constant
 
   alfa
Value: 0.32
Constant
 
   Kf26bp
Value: 8.4E-7
Constant
 
   Kf6p
Value: 1.0
Constant
 
   L
Value: 4.1
Constant
 
   Kcit
Value: 6.8
Constant
 
   Kiatp
Value: 20.0
Constant
 
   Kadp
Value: 5.0
Constant
 
   Kfbp
Value: 5.0
Constant
 
   Kapp
Value: 247.0
Constant
 
PK (8)
 
   Kadp
Value: 0.4
Constant
 
   Kpep
Value: 0.014
Constant
 
   L
Value: 1.0
Constant
 
   Kiatp
Value: 2.5
Constant
 
   Kfbp
Value: 4.0E-4
Constant
 
   Katp
Value: 0.86
Constant
 
   Kpyr
Value: 10.0
Constant
 
   Kapp
Value: 195172.0
Constant
 
LDH (2)
 
   alfa
Value: 1.0
Constant
 
   beta
Value: 1.0
Constant
 
AK (2)
 
   Vf
Value: 141.2
Constant
 
   Keq
Value: 2.26
Constant
 
DHase (1)
 
   Keq
Value: 300.0
Constant
 
DPHase (1)
 
   Keq
Value: 0.2
Constant
 
MPM (2)
 
   y
Value: 12.5
Constant
 
   Keq
Value: 1000000.0
Constant
 
ATPase (1)
 
   k1
Value: 6210.0
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000426

Curator's comment: (updated: 14 Nov 2012 16:09:15 GMT)

The model compares two metabolic states generated by the specific variation of the fluxes regulated
by the activity of the PI3K/Akt/mTOR pathway. One state represents the metabolism of a
growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis (condition
H), while the other (condition L) represented the same metabolic network with a reduced
glycolytic rate, a reduced lactic acid production, but a higher mitochondrial pyruvate
metabolism, in relation to a lower activity of PI3K/Akt/mTOR.

Here, the model parameters corresponds to condition H (high PI3K/Akt/mTOR activity) and the table reproducing the corresponding metabolic fluxes (reported in the Appendix of the paper) has been obtained using Copasi v4.8 (Build 35).

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