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Manuscript information

A model of yeast glycolysis based on a consistent kinetic characterisation of all its enzymes.

  • Kieran Smallbone
  • Hanan L Messiha
  • Kathleen M Carroll
  • Catherine L Winder
  • Naglis Malys
  • Warwick B Dunn
  • Ettore Murabito
  • Neil Swainston
  • Joseph O Dada
  • Farid Khan
  • Pınar Pir
  • Evangelos Simeonidis
  • Irena Spasić
  • Jill Wishart
  • Dieter Weichart
  • Neil W Hayes
  • Daniel Jameson
  • David S Broomhead
  • Stephen G Oliver
  • Simon J Gaskell
  • John E G McCarthy
  • Norman W Paton
  • Hans V Westerhoff
  • Douglas B Kell
  • Pedro Mendes
FEBS Lett. 2013; 587 (17): 2832-2841
Abstract
We present an experimental and computational pipeline for the generation of kinetic models of metabolism, and demonstrate its application to glycolysis in Saccharomyces cerevisiae. Starting from an approximate mathematical model, we employ a "cycle of knowledge" strategy, identifying the steps with most control over flux. Kinetic parameters of the individual isoenzymes within these steps are measured experimentally under a standardised set of conditions. Experimental strategies are applied to establish a set of in vivo concentrations for isoenzymes and metabolites. The data are integrated into a mathematical model that is used to predict a new set of metabolite concentrations and reevaluate the control properties of the system. This bottom-up modelling study reveals that control over the metabolic network most directly involved in yeast glycolysis is more widely distributed than previously thought.

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 29

Id Name Initial quantity Compartment Fixed
ACE — 223.000253398294 default_compartment ✔
ADP — 1.29 default_compartment ✘
AMP — 0.44 default_compartment ✘
ATP — 4.29 default_compartment ✘
AcAld — 0.178140579850657 default_compartment ✘
BPG — 0.000736873499865602 default_compartment ✘
DHAP — 1.1613768527467 default_compartment ✘
EtOH — 221.890311417536 default_compartment ✔
F16bP — 4.58321859006931 default_compartment ✘
F6P — 0.235441221891221 default_compartment ✘
G1P — 0.539248506344921 default_compartment ✘
G3P — 0.274002929191284 default_compartment ✘
G6P — 0.772483203645216 default_compartment ✘
GAP — 0.315891028770503 default_compartment ✘
GLC — 6.28000179338242 default_compartment ✘
GLCx — 74.0 default_compartment ✔
GLY — 0.15 default_compartment ✔
NAD — 1.50329030201531 default_compartment ✘
NADH — 0.0867096979846952 default_compartment ✘
P2G — 0.0677379081099344 default_compartment ✘
P3G — 0.469825011134444 default_compartment ✘
PEP — 0.610005413358042 default_compartment ✘
PYR — 2.10847140717419 default_compartment ✘
SUC — 0.0 default_compartment ✔
T6P — 0.02 default_compartment ✘
TRH — 0.0153878853696526 default_compartment ✔
UDG — 0.467246194874247 default_compartment ✘
UDP — 0.2815 default_compartment ✘
UTP — 0.6491 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 33
Id Name Objective coefficient Reaction Equation and Kinetic Law Flux bounds
ADHADH1 — AcAld + NADH = NAD + EtOH

ADH1 * ADHADH1kcat * (-(EtOH * NAD / (ADHADH1Kacald * ADHADH1Kinadh * KeqADH)) + AcAld * NADH / (ADHADH1Kacald * ADHADH1Kinadh)) / (1 + ADHADH1Knad * EtOH / (ADHADH1Ketoh * ADHADH1Kinad) + ADHADH1Knadh * AcAld / (ADHADH1Kacald * ADHADH1Kinadh) + NAD / ADHADH1Kinad + EtOH * NAD / (ADHADH1Ketoh * ADHADH1Kinad) + ADHADH1Knadh * AcAld * NAD / (ADHADH1Kacald * ADHADH1Kinad * ADHADH1Kinadh) + EtOH * AcAld * NAD / (ADHADH1Ketoh * ADHADH1Kiacald * ADHADH1Kinad) + NADH / ADHADH1Kinadh + ADHADH1Knad * EtOH * NADH / (ADHADH1Ketoh * ADHADH1Kinad * ADHADH1Kinadh) + AcAld * NADH / (ADHADH1Kacald * ADHADH1Kinadh) + EtOH * AcAld * NADH / (ADHADH1Kacald * ADHADH1Kietoh * ADHADH1Kinadh))
ADHADH5 — AcAld + NADH = NAD + EtOH

ADH5 * ADHADH5kcat * (-(EtOH * NAD / (ADHADH5Kacald * ADHADH5Kinadh * KeqADH)) + AcAld * NADH / (ADHADH5Kacald * ADHADH5Kinadh)) / (1 + ADHADH5Knad * EtOH / (ADHADH5Ketoh * ADHADH5Kinad) + ADHADH5Knadh * AcAld / (ADHADH5Kacald * ADHADH5Kinadh) + NAD / ADHADH5Kinad + EtOH * NAD / (ADHADH5Ketoh * ADHADH5Kinad) + ADHADH5Knadh * AcAld * NAD / (ADHADH5Kacald * ADHADH5Kinad * ADHADH5Kinadh) + EtOH * AcAld * NAD / (ADHADH5Ketoh * ADHADH5Kiacald * ADHADH5Kinad) + NADH / ADHADH5Kinadh + ADHADH5Knad * EtOH * NADH / (ADHADH5Ketoh * ADHADH5Kinad * ADHADH5Kinadh) + AcAld * NADH / (ADHADH5Kacald * ADHADH5Kinadh) + EtOH * AcAld * NADH / (ADHADH5Kacald * ADHADH5Kietoh * ADHADH5Kinadh))
AK — {2.0}ADP = AMP + ATP

AKk * (pow(ADP, 2) - AMP * ATP / AKKeq)
ATPase — ATP = ADP

ATPaseVmax * ATP / (ATPaseKatp * (1 + ATP / ATPaseKatp))
ENOENO1 — P2G = PEP

ENO1 * ENOENO1kcat * (P2G / ENOENO1Kp2g - PEP / (ENOENO1Kp2g * KeqENO)) / (1 + P2G / ENOENO1Kp2g + PEP / ENOENO1Kpep)
ENOENO2 — P2G = PEP

ENO2 * ENOENO2kcat * (P2G / ENOENO2Kp2g - PEP / (ENOENO2Kp2g * KeqENO)) / (1 + P2G / ENOENO2Kp2g + PEP / ENOENO2Kpep)
FBA — F16bP = DHAP + GAP

FBA1 * FBAkcat * (F16bP / FBAKf16bp - DHAP * GAP / (FBAKeq * FBAKf16bp)) / (1 + DHAP / FBAKdhap + F16bP / FBAKf16bp + GAP / FBAKgap + DHAP * GAP / (FBAKdhap * FBAKgap) + F16bP * GAP / (FBAKf16bp * FBAKigap))
GPD GPD DHAP + NADH = G3P + NAD

GPDVmax * (-(G3P * NAD / GPDKeq) + DHAP * NADH) / (GPDKdhap * GPDKnadh * (1 + ADP / GPDKadp + ATP / GPDKatp + F16bP / GPDKfbp) * (1 + DHAP / GPDKdhap + G3P / GPDKg3p) * (1 + NAD / GPDKnad + NADH / GPDKnadh))
GPM — P3G = P2G

GPM1 * GPMkcat * (-(P2G / (GPMKeq * GPMKp3g)) + P3G / GPMKp3g) / (1 + P2G / GPMKp2g + P3G / GPMKp3g)
GPP — G3P = GLY

GPPVmax * G3P / (GPPKg3p * (1 + G3P / GPPKg3p))
HXKGLK1 — ATP + GLC = ADP + G6P

GLK1 * HXKGLK1kcat * (-(ADP * G6P / (HXKGLK1Katp * HXKGLK1Kglc * KeqHXK)) + ATP * GLC / (HXKGLK1Katp * HXKGLK1Kglc)) / ((1 + ADP / HXKGLK1Kadp + ATP / HXKGLK1Katp) * (1 + G6P / HXKGLK1Kg6p + GLC / HXKGLK1Kglc))
HXKHXK1 HXKHXK1 ATP + GLC = ADP + G6P

HXK1 * HXKHXK1kcat * (-(ADP * G6P / (HXKHXK1Katp * HXKHXK1Kglc * KeqHXK)) + ATP * GLC / (HXKHXK1Katp * HXKHXK1Kglc)) / ((1 + ADP / HXKHXK1Kadp + ATP / HXKHXK1Katp) * (1 + G6P / HXKHXK1Kg6p + GLC / HXKHXK1Kglc + T6P / HXKHXK1Kit6p))
HXKHXK2 HXKHXK2 ATP + GLC = ADP + G6P

HXK2 * HXKHXK2kcat * (-(ADP * G6P / (HXKHXK2Katp * HXKHXK2Kglc * KeqHXK)) + ATP * GLC / (HXKHXK2Katp * HXKHXK2Kglc)) / ((1 + ADP / HXKHXK2Kadp + ATP / HXKHXK2Katp) * (1 + G6P / HXKHXK2Kg6p + GLC / HXKHXK2Kglc + T6P / HXKHXK2Kit6p))
HXT — GLCx = GLC

HXTVmax * (GLCx - GLC) / (HXTKglc * (1 + GLCx / HXTKglc + GLC / HXTKglc + GLCx * HXTKi * GLC / pow(HXTKglc, 2)))
PDCPDC1 — PYR = AcAld

PDC1 * PDCPDC1kcat * PYR / (PDCPDC1Kpyr * (1 + PYR / PDCPDC1Kpyr))
PDCPDC5 — PYR = AcAld

PDC5 * PDCPDC5kcat * PYR / (PDCPDC5Kpyr * (1 + PYR / PDCPDC5Kpyr))
PDCPDC6 — PYR = AcAld

PDC6 * PDCPDC6kcat * PYR / (PDCPDC6Kpyr * (1 + PYR / PDCPDC6Kpyr))
PFK PFK ATP + F6P = ADP + F16bP

PFKgR * PFKkcat * (PFK1 + PFK2 - abs(PFK1 - PFK2)) * ATP * (1 - ADP * F16bP / (PFKKeq * ATP * F6P)) * F6P * (1 + ADP / PFKKadp + ATP / PFKKatp + F16bP / PFKKf16 + PFKgR * ADP * F16bP / (PFKKadp * PFKKf16) + F6P / PFKKf6p + PFKgR * ATP * F6P / (PFKKatp * PFKKf6p)) / (2 * PFKKatp * PFKKf6p * (PFKL0 * pow(1 + PFKCamp * AMP / PFKKamp, 2) * pow(1 + PFKCatp * ATP / PFKKatp, 2) * pow(1 + PFKCiatp * ATP / PFKKiatp, 2) * pow(1 + F26bP * PFKCf26 / PFKKf26 + PFKCf16 * F16bP / PFKKf16, 2) / (pow(1 + AMP / PFKKamp, 2) * pow(1 + ATP / PFKKiatp, 2) * pow(1 + F26bP / PFKKf26 + F16bP / PFKKf16, 2)) + pow(1 + ADP / PFKKadp + ATP / PFKKatp + F16bP / PFKKf16 + PFKgR * ADP * F16bP / (PFKKadp * PFKKf16) + F6P / PFKKf6p + PFKgR * ATP * F6P / (PFKKatp * PFKKf6p), 2)))
PGI — G6P = F6P

PGI1 * PGIkcat * (-(F6P / (PGIKeq * PGIKg6p)) + G6P / PGIKg6p) / (1 + F6P / PGIKf6p + G6P / PGIKg6p)
PGK — ADP + BPG = ATP + P3G

PGK1 * PGKkcat * pow(ADP / PGKKadp, -1 + PGKnHadp) * (ADP * BPG / (PGKKadp * PGKKbpg) - ATP * P3G / (PGKKadp * PGKKbpg * PGKKeq)) / ((1 + pow(ADP / PGKKadp, PGKnHadp) + ATP / PGKKatp) * (1 + BPG / PGKKbpg + P3G / PGKKp3g))
PGM — G6P = G1P

PGMVmax * (-(G1P / (PGMKeq * PGMKg6p)) + G6P / PGMKg6p) / (1 + G1P / PGMKg1p + G6P / PGMKg6p)
PYKCDC19 PYKCDC19 ADP + PEP = ATP + PYR

CDC19 * PYKCDC19kcat * (ADP * PEP - ATP * PYR / KeqPYK) / (PYKCDC19Kadp * PYKCDC19Kpep * (1 + ADP / PYKCDC19Kadp + ATP / PYKCDC19Katp) * (1 + PYKCDC19L0 * (1 + ATP / PYKCDC19Kiatp) / (1 + F16bP / PYKCDC19Kf16p) + PEP / PYKCDC19Kpep + PYR / PYKCDC19Kpyr))
PYKPYK2 PYKPYK2 ADP + PEP = ATP + PYR

PYK2 * PYKPYK2kcat * (ADP * PEP - ATP * PYR / KeqPYK) / (PYKPYK2Kadp * PYKPYK2Kpep * (1 + ADP / PYKPYK2Kadp + ATP / PYKPYK2Katp) * (1 + PYKPYK2L0 * (1 + ATP / PYKPYK2Kiatp) / (1 + F16bP / PYKPYK2Kf16p) + PEP / PYKPYK2Kpep + PYR / PYKPYK2Kpyr))
TDHTDH1 — GAP + NAD = BPG + NADH

TDH1 * TDHTDH1kcat * (GAP * NAD / (TDHTDH1Kgap * TDHTDH1Knad) - BPG * NADH / (KeqTDH * TDHTDH1Kgap * TDHTDH1Knad)) / ((1 + BPG / TDHTDH1Kbpg + GAP / TDHTDH1Kgap) * (1 + NAD / TDHTDH1Knad + NADH / TDHTDH1Knadh))
TDHTDH2 — GAP + NAD = BPG + NADH

TDH2 * TDHTDH2kcat * (GAP * NAD / (TDHTDH2Kgap * TDHTDH2Knad) - BPG * NADH / (KeqTDH * TDHTDH2Kgap * TDHTDH2Knad)) / ((1 + BPG / TDHTDH2Kbpg + GAP / TDHTDH2Kgap) * (1 + NAD / TDHTDH2Knad + NADH / TDHTDH2Knadh))
TDHTDH3 — GAP + NAD = BPG + NADH

TDH3 * TDHTDH3kcat * (GAP * NAD / (TDHTDH3Kgap * TDHTDH3Knad) - BPG * NADH / (KeqTDH * TDHTDH3Kgap * TDHTDH3Knad)) / ((1 + BPG / TDHTDH3Kbpg + GAP / TDHTDH3Kgap) * (1 + NAD / TDHTDH3Knad + NADH / TDHTDH3Knadh))
TPI — DHAP = GAP

TPI1 * TPIkcat * (DHAP - GAP / TPIKeq) / (TPIKdhap * (1 + DHAP / TPIKdhap + GAP * (1 + pow(GAP, 4) / pow(TPIKigap, 4)) / TPIKgap))
TPP — T6P = TRH

TPPVmax * T6P / (TPPKt6p * (1 + T6P / TPPKt6p))
TPS — G6P + UDG = T6P + UDP

TPSVmax * G6P * UDG / (TPSKg6p * TPSKudg * (1 + G6P / TPSKg6p) * (1 + UDG / TPSKudg))
UGP — G1P + UTP = UDG

UGPVmax * G1P * UTP / (UGPKg1p * UGPKutp * (UGPKiutp / UGPKutp + G1P / UGPKg1p + UGPKiutp * UDG / (UGPKiudg * UGPKutp) + G1P * UDG / (UGPKg1p * UGPKiudg) + UTP / UGPKutp + G1P * UTP / (UGPKg1p * UGPKutp)))
acetatebranch — AcAld + NAD = NADH + ACE

acetatebranchk * AcAld * NAD
succinatebranch — PYR + {3.0}NAD = {0.75}SUC + {3.0}NADH

succinatebranchk * NAD * PYR
udptoutp — ATP + UDP = ADP + UTP

udptoutpk * ATP * UDP

Parameters 0   203

Global parameters

Id Value
ADH1 0.163908510928009
ADH5 0.00424998422487687
ADHADH1Kacald 0.4622
ADHADH1Ketoh 17.0
ADHADH1Kiacald 1.1
ADHADH1Kietoh 90.0
ADHADH1Kinad 0.92
ADHADH1Kinadh 0.031
ADHADH1Knad 0.17
ADHADH1Knadh 0.11
ADHADH1kcat 176.0
ADHADH5Kacald 1.11
ADHADH5Ketoh 17.0
ADHADH5Kiacald 1.1
ADHADH5Kietoh 90.0
ADHADH5Kinad 0.92
ADHADH5Kinadh 0.031
ADHADH5Knad 0.17
ADHADH5Knadh 0.11
ADHADH5kcat 0.0
AKKeq 0.45
AKk 0.75
ATPaseKatp 3.0
ATPaseVmax 6.16
CDC19 2.0483901071712
ENO1 0.686371954155832
ENO2 1.97444629317817
ENOENO1Kp2g 0.043
ENOENO1Kpep 0.5
ENOENO1kcat 7.6
ENOENO2Kp2g 0.104
ENOENO2Kpep 0.5
ENOENO2kcat 19.87
EXTERNAL 0.0
F26bP 0.003
FBA1 1.33839465704882
FBAKdhap 2.0
FBAKeq 0.069
FBAKf16bp 0.4507
FBAKgap 2.4
FBAKigap 10.0
FBAkcat 4.139
GLK1 0.0450869624419226
GPD1 0.00683511177089872
GPD2 0.000793405666424228
GPDKadp 2.0
GPDKatp 0.73
GPDKdhap 0.54
GPDKeq 10000.0
GPDKfbp 4.8
GPDKg3p 1.2
GPDKnad 0.93
GPDKnadh 0.023
GPDVmax 0.783333333333333
GPM1 0.73000029889707
GPMKeq 0.19
GPMKp2g 1.41
GPMKp3g 1.2
GPMkcat 400.0
GPPKg3p 3.5
GPPVmax 0.883333333333333
HOR2 0.0054734695639756
HXK1 0.0167807457149784
HXK2 0.0613313539705155
HXKGLK1Kadp 0.23
HXKGLK1Katp 0.865
HXKGLK1Kg6p 30.0
HXKGLK1Kglc 0.0106
HXKGLK1kcat 0.0721
HXKHXK1Kadp 0.23
HXKHXK1Katp 0.293
HXKHXK1Kg6p 30.0
HXKHXK1Kglc 0.15
HXKHXK1Kit6p 0.2
HXKHXK1kcat 10.2
HXKHXK2Kadp 0.23
HXKHXK2Katp 0.195
HXKHXK2Kg6p 30.0
HXKHXK2Kglc 0.2
HXKHXK2Kit6p 0.04
HXKHXK2kcat 63.1
HXTKglc 0.9
HXTKi 0.91
HXTVmax 3.35
KeqADH 14492.7536231884
KeqENO 6.7
KeqHXK 2000.0
KeqPYK 6500.0
KeqTDH 0.00533412710224736
NA 602214000000000000000
PDC1 1.06781077822834
PDC5 0.0123547443267676
PDC6 0.00654086421106118
PDCPDC1Kpyr 8.5
PDCPDC1kcat 12.14
PDCPDC5Kpyr 7.08
PDCPDC5kcat 10.32
PDCPDC6Kpyr 2.92
PDCPDC6kcat 9.21
PFK1 0.0467850299063124
PFK2 0.0390366215332091
PFKCamp 0.0845
PFKCatp 3.0
PFKCf16 0.397
PFKCf26 0.0174
PFKCiatp 100.0
PFKKadp 1.0
PFKKamp 0.0995
PFKKatp 0.71
PFKKeq 800.0
PFKKf16 0.111
PFKKf26 0.000682
PFKKf6p 0.1
PFKKiatp 0.65
PFKL0 0.66
PFKgR 5.12
PFKkcat 209.6
PGI1 0.1382907072901
PGIKeq 0.29
PGIKf6p 0.307
PGIKg6p 1.0257
PGIkcat 487.36
PGK1 0.257656912658955
PGKKadp 0.2
PGKKatp 1.99
PGKKbpg 0.003
PGKKeq 3200.0
PGKKp3g 4.58
PGKkcat 58.6
PGKnHadp 2.0
PGM1 0.00326229546307459
PGM2 0.00125868877176552
PGMKeq 0.1667
PGMKg1p 0.023
PGMKg6p 0.05
PGMVmax 0.12762
PYK2 0.00606993527217899
PYKCDC19Kadp 0.243
PYKCDC19Katp 1.5
PYKCDC19Kf16p 0.2
PYKCDC19Kiatp 9.3
PYKCDC19Kpep 0.281
PYKCDC19Kpyr 21.0
PYKCDC19L0 100.0
PYKCDC19kcat 20.146
PYKPYK2Kadp 0.3
PYKPYK2Katp 1.5
PYKPYK2Kf16p 0.2
PYKPYK2Kiatp 9.3
PYKPYK2Kpep 0.19
PYKPYK2Kpyr 21.0
PYKPYK2L0 100.0
PYKPYK2kcat 0.0
RHR2 0.0511804773718313
TDH1 0.350864642801396
TDH2 0.0
TDH3 4.20440474648547
TDHTDH1Kbpg 0.0098
TDHTDH1Kgap 0.495
TDHTDH1Knad 0.09
TDHTDH1Knadh 0.06
TDHTDH1kcat 19.12
TDHTDH2Kbpg 0.0098
TDHTDH2Kgap 0.77
TDHTDH2Knad 0.09
TDHTDH2Knadh 0.06
TDHTDH2kcat 8.633
TDHTDH3Kbpg 0.909
TDHTDH3Kgap 0.423
TDHTDH3Knad 0.09
TDHTDH3Knadh 0.06
TDHTDH3kcat 18.162
TPI1 0.294357819645508
TPIKdhap 6.454
TPIKeq 0.045
TPIKgap 5.25
TPIKigap 35.1
TPIkcat 564.38
TPPKt6p 0.5
TPPVmax 2.33999999999999
TPS1 0.00339248174237065
TPS2 0.00265985181347494
TPSKg6p 3.8
TPSKudg 0.886
TPSVmax 0.49356
UGP1 0.00620211419860714
UGPKg1p 0.32
UGPKiudg 0.0035
UGPKiutp 0.11
UGPKutp 0.11
UGPVmax 13.2552
acetatebranchk 0.00554339592436782
cell 1.0
energycharge 0.0
extracellular 1.0
fitconc 0.0
succinatebranchk 0.0
sumAXP 6.02
sumNAD 1.59
sumPXG 0.0
sumUXP 1.39784619487425
udptoutpk 0.0745258294103764
volume 0.000000000000005

Local parameters

Id Value Reaction

Rules 0   0   3

Assignment rules

Definition
fitconc = sqrt(pow(1.0 - NA * sumPXG * volume / 1618640.0, 2.0) + pow(1.0 - NA * volume * DHAP / 3496987.0, 2.0) + pow(1.0 - NA * volume * F16bP / 13800392.0, 2.0) + pow(1.0 - NA * volume * F6P / 708930.0, 2.0) + pow(1.0 - NA * volume * G6P / 2326001.0, 2.0) + pow(1.0 - NA * volume * GAP / 951170.0, 2.0) + pow(1.0 - NA * volume * GLC / 18909525.0, 2.0) + pow(1.0 - NA * volume * PEP / 1836769.0, 2.0) + pow(1.0 - NA * volume * PYR / 6348755.0, 2.0)) / 3.0
sumPXG = P2G + P3G
energycharge = (ADP / 2.0 + ATP) / sumAXP

Rate rules

Definition

Algebraic rules

Definition

Function definitions 0

Definition

Events 0

Trigger Assignments