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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 23

Id Name Initial quantity Compartment Fixed
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 ✘
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 ✔
TRH — 0.00384697134241316 default_compartment ✔
glycogen — 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 19
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 = ATP + AMP

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

ATPasek*ATP
ENO — P2G = PEP

(ENOVmax*(P2G/ENOKp2g - PEP/(ENOKeq*ENOKp2g)))/(1 + P2G/ENOKp2g + PEP/ENOKpep)
FBA — F16bP = DHAP + GAP

(FBAVmax*(F16bP/FBAKf16bp - (DHAP*GAP)/(FBAKeq*FBAKf16bp)))/(1 + DHAP/FBAKdhap + F16bP/FBAKf16bp + GAP/FBAKgap + (DHAP*GAP)/(FBAKdhap*FBAKgap) + (F16bP*GAP)/(FBAKf16bp*FBAKigap))
GPM — P3G = P2G

(GPMVmax*(-(P2G/(GPMKeq*GPMKp3g)) + P3G/GPMKp3g))/(1 + P2G/GPMKp2g + P3G/GPMKp3g)
HXK — ATP + GLC = ADP + G6P

(HXKVmax*(-((ADP*G6P)/(HXKKatp*HXKKeq*HXKKglc)) + (ATP*GLC)/(HXKKatp*HXKKglc)))/((1 + ADP/HXKKadp + ATP/HXKKatp)*(1 + G6P/HXKKg6p + GLC/HXKKglc))
HXT — GLCx = GLC

(HXTVmax*(GLCx - GLC))/(HXTKglc*(1 + GLCx/HXTKglc + GLC/HXTKglc + (GLCx*HXTKi*GLC)/HXTKglc^2))
PDC — PYR = AcAld

(PDCVmax*(PYR/PDCKpyr)^PDCnH)/(1 + (PYR/PDCKpyr)^PDCnH)
PFK PFK ATP + F6P = ADP + F16bP

PFKgR * PFKVmax * 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)) / (PFKKatp * PFKKf6p * (PFKL0 * (1 + PFKCamp * AMP / PFKKamp)^2 * (1 + PFKCatp * ATP / PFKKatp)^2 * (1 + PFKCiatp * ATP / PFKKiatp)^2 * (1 + F26bP * PFKCf26 / PFKKf26 + PFKCf16 * F16bP / PFKKf16)^2 / ((1 + AMP / PFKKamp)^2 * (1 + ATP / PFKKiatp)^2 * (1 + F26bP / PFKKf26 + F16bP / PFKKf16)^2) + (1 + ADP / PFKKadp + ATP / PFKKatp + F16bP / PFKKf16 + PFKgR * ADP * F16bP / (PFKKadp * PFKKf16) + F6P / PFKKf6p + PFKgR * ATP * F6P / (PFKKatp * PFKKf6p))^2))
PGI — G6P = F6P

(PGIVmax*(-(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))
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))
TDH — GAP + NAD = BPG + NADH

(TDHVmax*((GAP*NAD)/(TDHKgap*TDHKnad) - (BPG*NADH)/(TDHKeq*TDHKgap*TDHKnad)))/((1 + BPG/TDHKbpg + GAP/TDHKgap)*(1 + NAD/TDHKnad + NADH/TDHKnadh))
TPI — DHAP = GAP

TPIk*(DHAP - GAP/TPIKeq)
glycerolbranch — DHAP + NADH = NAD + GLY

(glycerolbranchVmax*(-((GLY*NAD)/(glycerolbranchKdhap*glycerolbranchKeq*glycerolbranchKnadh)) + (DHAP*NADH)/(glycerolbranchKdhap*glycerolbranchKnadh)))/((1 + GLY/glycerolbranchKgly + DHAP/glycerolbranchKdhap)*(1 + NAD/glycerolbranchKnad + NADH/glycerolbranchKnadh))
glycogenbranch — ATP + G6P = ADP + glycogen

glycogenbranchk*ATP*G6P
succinatebranch — {2.0}AcAld + {3.0}NAD = SUC + {3.0}NADH

succinatebranchk*AcAld*NAD
trehalosebranch — ATP + {2.0}G6P = ADP + TRH

trehalosebranchk*ATP*G6P

Parameters 0   121

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
ATPasek 0.658333333333333
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 0.0367018202831552
FBAKdhap 2.0
FBAKeq 0.069
FBAKf16bp 0.3
FBAKgap 2.4
FBAKigap 10.0
FBAVmax 1.57816666666667
GLK1 0.0112717406104807
GPM1 0.182500074724267
GPMKeq 0.19
GPMKp2g 0.08
GPMKp3g 1.2
GPMVmax 43.0833333333333
HXK1 0.0041951864287446
HXK2 0.0153328384926289
HXKKadp 0.23
HXKKatp 0.15
HXKKeq 2000.0
HXKKg6p 30.0
HXKKglc 0.08
HXKVmax 3.945
HXTKglc 0.9
HXTKi 0.91
HXTVmax 3.35
NA 602214000000000000000
PDC1 0.266952694557084
PDC5 0.00308868608169189
PDC6 0.0016352160527653
PDCKpyr 4.33
PDCVmax 14.2966666666667
PDCnH 1.9
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
PFKVmax 1.83333333333333
PFKgR 5.12
PGI1 0.0345726768225249
PGIKeq 0.29
PGIKf6p 0.3
PGIKg6p 1.4
PGIVmax 17.6
PGK1 0.0644142281647388
PGKKadp 0.2
PGKKatp 0.3
PGKKbpg 0.003
PGKKeq 3200.0
PGKKp3g 0.53
PGKVmax 259.220125786164
PYK2 0.00151748381804475
PYKKadp 0.53
PYKKatp 1.5
PYKKeq 6500.0
PYKKpep 0.14
PYKKpyr 21.0
PYKVmax 16.6666666666667
TDH1 0.087716160700349
TDH2 0.0
TDH3 1.05110118662137
TDHKbpg 0.0098
TDHKeq 0.00533412710224736
TDHKgap 0.21
TDHKnad 0.09
TDHKnadh 0.06
TDHVmax 19.2
TPI1 0.073589454911377
TPIKeq 0.045
TPIk 7500.0
cell 1.0
energycharge 0.0
extracellular 1.0
fitconc 0.0
glycerolbranchKdhap 0.4
glycerolbranchKeq 4300.0
glycerolbranchKgly 1.0
glycerolbranchKnad 0.93
glycerolbranchKnadh 0.023
glycerolbranchVmax 0.785166666666667
glycogenbranchk 0.01480424934314
succinatebranchk 0.237257345562943
sumAXP 6.02
sumNAD 1.59
sumPXG 0.0
trehalosebranchk 0.00592169973725601
volume 0.00000000000002

Local parameters

Id Value Reaction

Rules 0   0   3

Assignment rules

Definition
fitconc = Sqrt((1 - (NA*sumPXG*volume)/1618640)^2 + (1 - (NA*volume*DHAP)/3496987)^2 + (1 - (NA*volume*F16bP)/13800392)^2 + (1 - (NA*volume*F6P)/708930)^2 + (1 - (NA*volume*G6P)/2326001)^2 + (1 - (NA*volume*GAP)/951170)^2 + (1 - (NA*volume*GLC)/18909525)^2 + (1 - (NA*volume*PEP)/1836769)^2 + (1 - (NA*volume*PYR)/6348755)^2)/3
sumPXG = P2G + P3G
energycharge = (ADP/2 + ATP)/sumAXP

Rate rules

Definition

Algebraic rules

Definition

Events 0

Trigger Assignments