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Manuscript information

Can yeast glycolysis be understood in terms of in vitro kinetics of the constituent enzymes? Testing biochemistry.

  • Bas Teusink
  • J Passarge
  • CA Reijenga
  • E Esgalhado
  • CC van der Weijden
  • M Schepper
  • MC Walsh
  • Barbara M Bakker
  • K van Dam
  • Hans V Westerhoff
  • Jacky L Snoep
Eur. J. Biochem. 2000; 267 (17): 5313-5329
Abstract
This paper examines whether the in vivo behavior of yeast glycolysis can be understood in terms of the in vitro kinetic properties of the constituent enzymes. In nongrowing, anaerobic, compressed Saccharomyces cerevisiae the values of the kinetic parameters of most glycolytic enzymes were determined. For the other enzymes appropriate literature values were collected. By inserting these values into a kinetic model for glycolysis, fluxes and metabolites were calculated. Under the same conditions fluxes and metabolite levels were measured. In our first model, branch reactions were ignored. This model failed to reach the stable steady state that was observed in the experimental flux measurements. Introduction of branches towards trehalose, glycogen, glycerol and succinate did allow such a steady state. The predictions of this branched model were compared with the empirical behavior. Half of the enzymes matched their predicted flux in vivo within a factor of 2. For the other enzymes it was calculated what deviation between in vivo and in vitro kinetic characteristics could explain the discrepancy between in vitro rate and in vivo flux.

Unit definitions 0

Unit definitions have no effect on the numerical analysis of the model. It remains the responsibility of the modeler to ensure the internal numerical consistency of the model. If units are provided, however, the consistency of the model units will be checked.

Name Definition

Compartments 1

Id Name Spatial dimensions Size
default_compartment — 3.0 1.0

Species 22

Id Name Initial quantity Compartment Fixed
ACE — 0.04 default_compartment ✘
BPG 1,3-bisphosphoglyceric acid 0.0 default_compartment ✘
CO2 — 1.0 default_compartment ✔
ETOH — 50.0 default_compartment ✔
F16P D-fructose 1,6-bisphosphate 0.1 default_compartment ✘
F6P D-fructose 6-phosphate 0.28 default_compartment ✘
G6P alpha-D-glucose 6-phosphate 1.39 default_compartment ✘
GLCi — 0.087 default_compartment ✘
GLCo — 50.0 default_compartment ✔
GLY — 0.15 default_compartment ✔
Glyc — 0.0 default_compartment ✔
NAD NAD(+) 1.2 default_compartment ✘
NADH NADH 0.39 default_compartment ✘
P2G 2-phospho-D-glyceric acid 0.1 default_compartment ✘
P3G 3-phospho-D-glyceric acid 0.1 default_compartment ✘
PEP phosphoenolpyruvate 0.1 default_compartment ✘
PYR pyruvate 3.36 default_compartment ✘
Prb — 5.0 default_compartment ✘
SUCC — 0.0 default_compartment ✔
TRIO — 5.17 default_compartment ✘
Trh — 0.0 default_compartment ✔
X — 0.0 default_compartment ✔

Initial assignments 0

Initial assignments are expressions that are evaluated at time=0. It is not recommended to create initial assignments for all model entities. Restrict the use of initial assignments to cases where a value is expressed in terms of values or sizes of other model entities. Note that it is not permitted to have both an initial assignment and an assignment rule for a single model entity.

Definition
Reactions 17
Id Name Objective coefficient Reaction Equation and Kinetic Law Flux bounds
v_1 hexokinase Prb + GLCi = G6P

VmGLK * (-(G6P * (SUMAXP - pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / ((1 - 4 * KeqAK) * KeqGLK)) + GLCi * (-SUMAXP + Prb - 4 * KeqAK * Prb + pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / (2 - 8 * KeqAK)) / (KmGLKATP * KmGLKGLCi * (1 + G6P / KmGLKG6P + GLCi / KmGLKGLCi) * (1 + (SUMAXP - pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / ((1 - 4 * KeqAK) * KmGLKADP) + (-SUMAXP + Prb - 4 * KeqAK * Prb + pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / ((2 - 8 * KeqAK) * KmGLKATP)))
v_10 2-Phospho-D-glycerate 2,3-phosphomutase P2G = PEP

VmENO / KmENOP2G * (P2G - PEP / KeqENO) / (1 + P2G / KmENOP2G + PEP / KmENOPEP)
v_11 2-phospho-D-glycerate hydro-lyase (phosphoenolpyruvate-forming) PEP = PYR + Prb

VmPYK / (KmPYKPEP * KmPYKADP) * (PEP * (SUMAXP - pow(pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2) - 2 * Prb * SUMAXP + 8 * KeqAK * Prb * SUMAXP + pow(SUMAXP, 2), 0.5)) / (1 - 4 * KeqAK) - PYR * ((Prb - 4 * KeqAK * Prb - SUMAXP + pow(pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2) - 2 * Prb * SUMAXP + 8 * KeqAK * Prb * SUMAXP + pow(SUMAXP, 2), 0.5)) / (2 - 8 * KeqAK)) / KeqPYK) / ((1 + PEP / KmPYKPEP + PYR / KmPYKPYR) * (1 + (Prb - 4 * KeqAK * Prb - SUMAXP + pow(pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2) - 2 * Prb * SUMAXP + 8 * KeqAK * Prb * SUMAXP + pow(SUMAXP, 2), 0.5)) / (2 - 8 * KeqAK) / KmPYKATP + (SUMAXP - pow(pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2) - 2 * Prb * SUMAXP + 8 * KeqAK * Prb * SUMAXP + pow(SUMAXP, 2), 0.5)) / (1 - 4 * KeqAK) / KmPYKADP))
v_12 ATP:pyruvate 2-O-phosphotransferase PYR = CO2 + ACE

VmPDC * (pow(PYR, nPDC) / pow(KmPDCPYR, nPDC)) / (1 + pow(PYR, nPDC) / pow(KmPDCPYR, nPDC))
v_13 pyruvate carboxy-lyase (acetaldehyde-forming) {2.0}ACE + {3.0}NAD = SUCC + {3.0}NADH

KSUCC * ACE
v_14 glucose transport GLCo = GLCi

VmGLT * (GLCo - GLCi / KeqGLT) / (KmGLTGLCo * (1 + GLCo / KmGLTGLCo + GLCi / KmGLTGLCi + 0.91 * GLCo * GLCi / (KmGLTGLCi * KmGLTGLCo)))
v_15 ethanol:NAD+ oxidoreductase ACE + NADH = NAD + ETOH

-(VmADH / (KiADHNAD * KmADHETOH) * (NAD * ETOH - NADH * ACE / KeqADH) / (1 + NAD / KiADHNAD + KmADHNAD * ETOH / (KiADHNAD * KmADHETOH) + KmADHNADH * ACE / (KiADHNADH * KmADHACE) + NADH / KiADHNADH + NAD * ETOH / (KiADHNAD * KmADHETOH) + KmADHNADH * NAD * ACE / (KiADHNAD * KiADHNADH * KmADHACE) + KmADHNAD * ETOH * NADH / (KiADHNAD * KmADHETOH * KiADHNADH) + NADH * ACE / (KiADHNADH * KmADHACE) + NAD * ETOH * ACE / (KiADHNAD * KmADHETOH * KiADHACE) + ETOH * NADH * ACE / (KiADHETOH * KiADHNADH * KmADHACE)))
v_16 gpdh NADH + TRIO = GLY + NAD

VmG3PDH * (-(GLY * NAD / KeqG3PDH) + NADH * TRIO / (1 + KeqTPI)) / (KmG3PDHDHAP * KmG3PDHNADH * (1 + NAD / KmG3PDHNAD + NADH / KmG3PDHNADH) * (1 + GLY / KmG3PDHGLY + TRIO / ((1 + KeqTPI) * KmG3PDHDHAP)))
v_17 ATP catabolic process Prb = X

KATPASE * ((Prb - 4 * KeqAK * Prb - SUMAXP + pow(pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2) - 2 * Prb * SUMAXP + 8 * KeqAK * Prb * SUMAXP + pow(SUMAXP, 2), 0.5)) / (2 - 8 * KeqAK))
v_2 ATP:D-glucose 6-phosphotransferase G6P = F6P

VmPGI / KmPGIG6P * (G6P - F6P / KeqPGI) / (1 + G6P / KmPGIG6P + F6P / KmPGIF6P)
v_3 — G6P + Prb = Glyc

KGLYCOGEN
v_4 — {2.0}G6P + Prb = Trh

KTREHALOSE
v_5 alpha-D-Glucose 6-phosphate ketol-isomerase F6P + Prb = F16P

gR * VmPFK * F6P * (-SUMAXP + Prb - 4 * KeqAK * Prb + pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) * (1 + F6P / KmPFKF6P + (-SUMAXP + Prb - 4 * KeqAK * Prb + pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / ((2 - 8 * KeqAK) * KmPFKATP) + gR * F6P * (-SUMAXP + Prb - 4 * KeqAK * Prb + pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / ((2 - 8 * KeqAK) * KmPFKATP * KmPFKF6P)) / ((2 - 8 * KeqAK) * KmPFKATP * KmPFKF6P * (L0 * pow(1 + CPFKF26BP * F26BP / KPFKF26BP + CPFKF16BP * F16P / KPFKF16BP, 2) * pow(1 + 2 * CPFKAMP * KeqAK * pow(SUMAXP - pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5), 2) / ((-1 + 4 * KeqAK) * KPFKAMP * (SUMAXP - Prb + 4 * KeqAK * Prb - pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5))), 2) * pow(1 + CiPFKATP * (-SUMAXP + Prb - 4 * KeqAK * Prb + pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / ((2 - 8 * KeqAK) * KiPFKATP), 2) * pow(1 + CPFKATP * (-SUMAXP + Prb - 4 * KeqAK * Prb + pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / ((2 - 8 * KeqAK) * KmPFKATP), 2) / (pow(1 + F26BP / KPFKF26BP + F16P / KPFKF16BP, 2) * pow(1 + 2 * KeqAK * pow(SUMAXP - pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5), 2) / ((-1 + 4 * KeqAK) * KPFKAMP * (SUMAXP - Prb + 4 * KeqAK * Prb - pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5))), 2) * pow(1 + (-SUMAXP + Prb - 4 * KeqAK * Prb + pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / ((2 - 8 * KeqAK) * KiPFKATP), 2)) + pow(1 + F6P / KmPFKF6P + (-SUMAXP + Prb - 4 * KeqAK * Prb + pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / ((2 - 8 * KeqAK) * KmPFKATP) + gR * F6P * (-SUMAXP + Prb - 4 * KeqAK * Prb + pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / ((2 - 8 * KeqAK) * KmPFKATP * KmPFKF6P), 2)))
v_6 ATP:D-fructose-6-phosphate 1-phosphotransferase F16P = {2.0}TRIO

VmALD * (F16P - KeqTPI * pow(TRIO, 2) / (KeqALD * pow(1 + KeqTPI, 2))) / (KmALDF16P * (1 + F16P / KmALDF16P + TRIO / ((1 + KeqTPI) * KmALDDHAP) + KeqTPI * TRIO / ((1 + KeqTPI) * KmALDGAP) + KeqTPI * F16P * TRIO / ((1 + KeqTPI) * KmALDF16P * KmALDGAPi) + KeqTPI * pow(TRIO, 2) / (pow(1 + KeqTPI, 2) * KmALDDHAP * KmALDGAP)))
v_7 D-fructose-1,6-bisphosphate D-glyceraldehyde-3-phosphate-lyase(glycerone-phosphate-forming) TRIO + NAD = BPG + NADH

(-(VmGAPDHr * BPG * NADH / (KmGAPDHBPG * KmGAPDHNADH)) + KeqTPI * VmGAPDHf * NAD * TRIO / ((1 + KeqTPI) * KmGAPDHGAP * KmGAPDHNAD)) / ((1 + NAD / KmGAPDHNAD + NADH / KmGAPDHNADH) * (1 + BPG / KmGAPDHBPG + KeqTPI * TRIO / ((1 + KeqTPI) * KmGAPDHGAP)))
v_8 D-glyceraldehyde-3-phosphate:NAD+ oxidoreductase (phosphorylating) BPG = P3G + Prb

VmPGK * (KeqPGK * BPG * (SUMAXP - pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / (1 - 4 * KeqAK) - (-SUMAXP + Prb - 4 * KeqAK * Prb + pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) * P3G / (2 - 8 * KeqAK)) / (KmPGKATP * KmPGKP3G * (1 + (SUMAXP - pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / ((1 - 4 * KeqAK) * KmPGKADP) + (-SUMAXP + Prb - 4 * KeqAK * Prb + pow(pow(SUMAXP, 2) - 2 * SUMAXP * Prb + 8 * KeqAK * SUMAXP * Prb + pow(Prb, 2) - 4 * KeqAK * pow(Prb, 2), 0.5)) / ((2 - 8 * KeqAK) * KmPGKATP)) * (1 + BPG / KmPGKBPG + P3G / KmPGKP3G))
v_9 ATP:3-phospho-D-glycerate 1-phosphotransferase P3G = P2G

VmPGM / KmPGMP3G * (P3G - P2G / KeqPGM) / (1 + P3G / KmPGMP3G + P2G / KmPGMP2G)

Parameters 0   88

Global parameters

Id Value
CPFKAMP 0.0845
CPFKATP 3.0
CPFKF16BP 0.397
CPFKF26BP 0.0174
CPFKF6P 0.0
CiPFKATP 100.0
F26BP 0.02
KATPASE 39.5
KGLYCOGEN 6.0
KPFKAMP 0.0995
KPFKF16BP 0.111
KPFKF26BP 0.000682
KSUCC 21.4
KTREHALOSE 2.4
KeqADH 0.000069
KeqAK 0.45
KeqALD 0.069
KeqENO 6.7
KeqG3PDH 4300.0
KeqGLK 3800.0
KeqGLT 1.0
KeqPGI 0.314
KeqPGK 3200.0
KeqPGM 0.19
KeqPYK 6500.0
KeqTPI 0.045
KiADHACE 1.1
KiADHETOH 90.0
KiADHNAD 0.92
KiADHNADH 0.031
KiPFKATP 0.65
KmADHACE 1.11
KmADHETOH 17.0
KmADHNAD 0.17
KmADHNADH 0.11
KmALDDHAP 2.4
KmALDF16P 0.3
KmALDGAP 2.0
KmALDGAPi 10.0
KmENOP2G 0.04
KmENOPEP 0.5
KmG3PDHDHAP 0.4
KmG3PDHGLY 1.0
KmG3PDHNAD 0.93
KmG3PDHNADH 0.023
KmGAPDHBPG 0.0098
KmGAPDHGAP 0.21
KmGAPDHNAD 0.09
KmGAPDHNADH 0.06
KmGLKADP 0.23
KmGLKATP 0.15
KmGLKG6P 30.0
KmGLKGLCi 0.08
KmGLTGLCi 1.1918
KmGLTGLCo 1.1918
KmPDCPYR 4.33
KmPFKATP 0.71
KmPFKF6P 0.1
KmPGIF6P 0.3
KmPGIG6P 1.4
KmPGKADP 0.2
KmPGKATP 0.3
KmPGKBPG 0.003
KmPGKP3G 0.53
KmPGMP2G 0.08
KmPGMP3G 1.2
KmPYKADP 0.53
KmPYKATP 1.5
KmPYKPEP 0.14
KmPYKPYR 21.0
L0 0.66
SUMAXP 4.1
VmADH 810.0
VmALD 322.258
VmENO 365.806
VmG3PDH 70.15
VmGAPDHf 1184.52
VmGAPDHr 6549.68
VmGLK 226.452
VmGLT 97.264
VmPDC 174.194
VmPFK 182.903
VmPGI 339.677
VmPGK 1306.45
VmPGM 2525.81
VmPYK 1088.71
gR 5.12
nPDC 1.9

Local parameters

Id Value Reaction

Rules 0   0   0

Assignment rules

Definition

Rate rules

Definition

Algebraic rules

Definition

Function definitions 0

Definition

Events 0

Trigger Assignments