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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 — 55.7500633495734 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 — 0.290344213186674 default_compartment ✘
EtOH — 55.472577854384 default_compartment ✔
F16bP — 1.14580464751733 default_compartment ✘
F6P — 0.0588603054728053 default_compartment ✘
G1P — 0.13481212658623 default_compartment ✘
G3P — 0.068500732297821 default_compartment ✘
G6P — 0.193120800911304 default_compartment ✘
GAP — 0.0789727571926259 default_compartment ✘
GLC — 1.5700004483456 default_compartment ✘
GLCx — 74.0 default_compartment ✔
GLY — 0.15 default_compartment ✔
NAD — 1.50329030201531 default_compartment ✘
NADH — 0.0867096979846952 default_compartment ✘
P2G — 0.0169344770274836 default_compartment ✘
P3G — 0.117456252783611 default_compartment ✘
PEP — 0.152501353339511 default_compartment ✘
PYR — 0.527117851793548 default_compartment ✘
SUC — 0.0 default_compartment ✔
T6P — 0.02 default_compartment ✘
TRH — 0.00384697134241316 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 30
Id Name Objective coefficient Reaction Equation and Kinetic Law Flux bounds
ADH — AcAld + NADH = NAD + EtOH

ADHVmax * (-(EtOH * NAD / (ADHKacald * ADHKeq * ADHKinadh)) + AcAld * NADH / (ADHKacald * ADHKinadh)) / (1 + ADHKnad * EtOH / (ADHKetoh * ADHKinad) + ADHKnadh * AcAld / (ADHKacald * ADHKinadh) + NAD / ADHKinad + EtOH * NAD / (ADHKetoh * ADHKinad) + ADHKnadh * AcAld * NAD / (ADHKacald * ADHKinad * ADHKinadh) + EtOH * AcAld * NAD / (ADHKetoh * ADHKiacald * ADHKinad) + NADH / ADHKinadh + ADHKnad * EtOH * NADH / (ADHKetoh * ADHKinad * ADHKinadh) + AcAld * NADH / (ADHKacald * ADHKinadh) + EtOH * AcAld * NADH / (ADHKacald * ADHKietoh * ADHKinadh))
AK — {2.0}ADP = AMP + ATP

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

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

ENOVmax * (P2G / ENOKp2g - PEP / (ENOKeq * ENOKp2g)) / (1 + P2G / ENOKp2g + PEP / ENOKpep)
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

GPMVmax * (-(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

PGKVmax * (ADP * BPG / (PGKKadp * PGKKbpg) - ATP * P3G / (PGKKadp * PGKKbpg * PGKKeq)) / ((1 + ADP / PGKKadp + ATP / PGKKatp) * (1 + BPG / PGKKbpg + P3G / PGKKp3g))
PGM — G6P = G1P

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

PYKVmax * (ADP * PEP / (PYKKadp * PYKKpep) - ATP * PYR / (PYKKadp * PYKKeq * PYKKpep)) / ((1 + ADP / PYKKadp + ATP / PYKKatp) * (1 + PEP / PYKKpep + PYR / PYKKpyr))
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

TPIk * (DHAP - GAP / TPIKeq)
TPP — T6P = TRH

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

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

rescaleTRH * 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

rescaleTRH * udptoutpk * ATP * UDP

Parameters 0   177

Global parameters

Id Value
ADH1 0.0409771277320022
ADH5 0.00106249605621922
ADHKacald 1.11
ADHKeq 14492.7536231884
ADHKetoh 17.0
ADHKiacald 1.1
ADHKietoh 90.0
ADHKinad 0.92
ADHKinadh 0.031
ADHKnad 0.17
ADHKnadh 0.11
ADHVmax 111.334973497906
AKKeq 0.45
AKk 0.75
ATPaseKatp 3.0
ATPaseVmax 1.13333333333333
CDC19 0.512097526792801
ENO1 0.171592988538958
ENO2 0.493611573294543
ENOKeq 6.7
ENOKp2g 0.04
ENOKpep 0.5
ENOVmax 3.36
EXTERNAL 0.0
F26bP 0.003
FBA1 0.334598664262206
FBAKdhap 2.0
FBAKeq 0.069
FBAKf16bp 0.4507
FBAKgap 2.4
FBAKigap 10.0
FBAkcat 4.139
GLK1 0.0112717406104807
GPD1 0.00170877794272468
GPD2 0.000198351416606057
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 0.182500074724267
GPMKeq 0.19
GPMKp2g 0.08
GPMKp3g 1.2
GPMVmax 43.0833333333333
GPPKg3p 3.5
GPPVmax 0.883333333333333
HOR2 0.0013683673909939
HXK1 0.0041951864287446
HXK2 0.0153328384926289
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
KeqHXK 2000.0
KeqTDH 0.00533412710224736
NA 602214000000000000000
PDC1 0.266952694557084
PDC5 0.00308868608169189
PDC6 0.0016352160527653
PDCPDC1Kpyr 8.5
PDCPDC1kcat 12.14
PDCPDC5Kpyr 7.08
PDCPDC5kcat 10.32
PDCPDC6Kpyr 2.92
PDCPDC6kcat 9.21
PFK1 0.0116962574765781
PFK2 0.00975915538330228
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 0.0345726768225249
PGIKeq 0.29
PGIKf6p 0.307
PGIKg6p 1.0257
PGIkcat 487.36
PGK1 0.0644142281647388
PGKKadp 0.2
PGKKatp 0.3
PGKKbpg 0.003
PGKKeq 3200.0
PGKKp3g 0.53
PGKVmax 259.220125786164
PGM1 0.000815573865768647
PGM2 0.00031467219294138
PGMKeq 0.1667
PGMKg1p 0.023
PGMKg6p 0.05
PGMVmax 0.00590833333333333
PYK2 0.00151748381804475
PYKKadp 0.53
PYKKatp 1.5
PYKKeq 6500.0
PYKKpep 0.14
PYKKpyr 21.0
PYKVmax 16.6666666666667
RHR2 0.0127951193429578
TDH1 0.087716160700349
TDH2 0.0
TDH3 1.05110118662137
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 0.073589454911377
TPIKeq 0.045
TPIk 7500.0
TPPKt6p 0.5
TPPVmax 0.108333333333333
TPS1 0.000848120435592663
TPS2 0.000664962953368736
TPSKg6p 3.8
TPSKudg 0.886
TPSVmax 0.02285
UGP1 0.00155052854965178
UGPKg1p 0.32
UGPKiudg 0.0035
UGPKiutp 0.11
UGPKutp 0.11
UGPVmax 0.613666666666667
acetatebranchk 0.00554339592436782
cell 1.0
energycharge 0.0
extracellular 1.0
fitconc 0.0
rescaleTRH 38.8857
succinatebranchk 0.00549663630823988
sumAXP 6.02
sumNAD 1.59
sumPXG 0.0
sumUXP 1.39784619487425
udptoutpk 0.00345026988011002
volume 0.00000000000002

Local parameters

Id Value Reaction

Rules 0   0   3

Assignment rules

Definition
energycharge = (ADP / 2.0 + ATP) / sumAXP
sumPXG = P2G + P3G
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

Rate rules

Definition

Algebraic rules

Definition

Function definitions 0

Definition

Events 0

Trigger Assignments