Using Pathway Tools & Matlab for Flux Balance Analysis Kent - - PowerPoint PPT Presentation

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Using Pathway Tools & Matlab for Flux Balance Analysis Kent - - PowerPoint PPT Presentation

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Using Pathway Tools & Matlab for Flux Balance Analysis Kent Peterson 25 Aug. 2009 Summary Flux Balance Analysis (FBA) Workflow: from Ptools to Matlab, and back again A simple example What next? 2 Lets start at the

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Using Pathway Tools & Matlab for Flux Balance Analysis

Kent Peterson 25 Aug. 2009

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Summary

  • Flux Balance Analysis (FBA)
  • Workflow: from Ptools to Matlab, and back again
  • A simple example
  • What next?

2

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Let’s start at the very beginning ...

Krebs cycle in A. thaliana (from Widipedia)

Bio Chemical Reaction Network

X1 X2 E12 k12

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Flux Balance Analysis (FBA)

  • Flux = “rate at which chemicals are transformed or transported”
  • Balanced = “input & output rates are equal” (a.k.a. steady-state)
  • Analysis = “optimize (balanced) flux with constraints”
  • Example: maximize product synthesis per unit feedstock,

while satisfying maintenance (biomass) requirements Cell Feedstock Product Biomass

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Software components

  • Pathway Tools1 (PGDB for organism)
  • SBML2 Toolbox (export metabolic description files)
  • COBRA3 (setup the LP)
  • GLPK4 (solve the LP)
  • Matlab5 (math’s programming & graphics)
  • 1. http://bioinformatics.ai.sri.com/ptools/
  • 2. http://sbml.org/Software/SBMLToolbox
  • 3. Palsson lab @ UCSD, http://gcrg.ucsd.edu/Downloads/Cobra_Toolbox
  • 4. GNU Linear Programming Kit, http://glpkmex.sourceforge.net/
  • 5. http://www.mathworks.com/
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Workflow

  • Load PGDB into PathwayTools
  • Export metabolic network into SBML file
  • Import SBML file into Matlab
  • Compute FBA solution in Matlab
  • Examine network & flux sol’n, using Matlab GUIs
  • Iterate
  • Write FBA sol’n to text file
  • Import sol’n to Pathway Tools Omics Viewer

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Pathway tools Matlab

Export Import Iterate

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Example

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Maximize anabolic “biomass” produced from a “feedstock”

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Getting the data from Ptools to Matlab

  • SBML export from Pathway Tools
  • SBML import into Matlab

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0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 (1) PROTONCCOTHYLUMCYA (2) CDP (3) PHOSPHOENOLPYRUVATE (4) 2PG (5) MET0009 (6) OXYGENMOLECULE (7) E (8) PYRUVATE (9) MET0001 (10) CMP (11) MET0004 (12) MET0002 (13) CTP (14) MET0003 (15) PPI (16) MET0007 (17) MET0008 (18) MET0006 (19) Oxidizedferredoxins (20) MET0005 (21) Reducedferredoxins (22) CARBONDIOXIDE (23) PROTON (24) G3P (25) NADP (26) NADPH (27) DPG (28) DIHYDROXYACETONEPHOSPHATE (29) FRUCTOSE16DIPHOSPHATE (30) ERYTHROSE4P (31) FRUCTOSE6P (32) GAP (33) WATER (34) DSEDOHEPTULOSE17P2 (35) Pi (36) DSEDOHEPTULOSE7P (37) XYLULOSE5PHOSPHATE (38) ATP (39) DRIBULOSE15P2 (40) ADP (41) RIBOSE5P (42) RIBULOSE5P (43) Biomass (1) RIB5PISOM (2) PHOSPHORIBULOKINASE (3) RIBULP3EPIM (4) SEDOHEPTULOSEBISPHOSPHATASE (5) 2TRANSKETO (6) 1TRANSKETO (7) F16BDEPHOS (8) SEDOBISALDOL (9) F16ALDOLASE (10) TRIOSEPISOMERIZATION (11) 1.2.1.13 (12) PHOSGLYPHOS (13) RUBISCO (14) RXN0001 (15) RXN0002 (16) RXN0003 (17) RXN0004 (18) RXN0005 (19) RXN0006 (20) RXN0007 (21) RXN0008 (22) RXN0009 (23) 1.18.1.2 (24) RXN4903650 (25) PSII (26) RXN0010 (27) 3PGAREARR (28) 2PGADEHYDRAT (29) PEPDEPHOS (30) CDPKIN (31) CMPKIN (32) INORGPYROPHOSPHAT (33) 3.6.3.14 (34) BiomassFormation

What a mess!

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Metabolite Reaction Product flux Substrate flux

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0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 (1) PROTONCCOTHYLUMCYA (2) CDP (3) PHOSPHOENOLPYRUVATE (4) 2PG (5) MET0009 (6) OXYGENMOLECULE (7) E (8) PYRUVATE (9) MET0001 (10) CMP (11) MET0004 (12) MET0002 (13) CTP (14) MET0003 (15) PPI (16) MET0007 (17) MET0008 (18) MET0006 (19) Oxidizedferredoxins (20) MET0005 (21) Reducedferredoxins (22) CARBONDIOXIDE (23) PROTON (24) G3P (25) NADP (26) NADPH (27) DPG (28) DIHYDROXYACETONEPHOSPHATE (29) FRUCTOSE16DIPHOSPHATE (30) ERYTHROSE4P (31) FRUCTOSE6P (32) GAP (33) WATER (34) DSEDOHEPTULOSE17P2 (35) Pi (36) DSEDOHEPTULOSE7P (37) XYLULOSE5PHOSPHATE (38) ATP (39) DRIBULOSE15P2 (40) ADP (41) RIBOSE5P (42) RIBULOSE5P (43) Biomass (1) RIB5PISOM (2) PHOSPHORIBULOKINASE (3) RIBULP3EPIM (4) SEDOHEPTULOSEBISPHOSPHATASE (5) 2TRANSKETO (6) 1TRANSKETO (7) F16BDEPHOS (8) SEDOBISALDOL (9) F16ALDOLASE (10) TRIOSEPISOMERIZATION (11) 1.2.1.13 (12) PHOSGLYPHOS (13) RUBISCO (14) RXN0001 (15) RXN0002 (16) RXN0003 (17) RXN0004 (18) RXN0005 (19) RXN0006 (20) RXN0007 (21) RXN0008 (22) RXN0009 (23) 1.18.1.2 (24) RXN4903650 (25) PSII (26) RXN0010 (27) 3PGAREARR (28) 2PGADEHYDRAT (29) PEPDEPHOS (30) CDPKIN (31) CMPKIN (32) INORGPYROPHOSPHAT (33) 3.6.3.14 (34) BiomassFormation

Matlab tools (1): Met/Rxn graph

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Calvin cycle

Metabolite Reaction Product flux Substrate flux

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Matlab tools (2): Met/Rxn browser

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Final product: an FBA solution

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0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 (1) PROTONCCOTHYLUMCYA (2) CDP (3) PHOSPHOENOLPYRUVATE (4) 2PG (5) MET0009 (6) OXYGENMOLECULE (7) E (8) PYRUVATE (9) MET0001 (10) CMP (11) MET0004 (12) MET0002 (13) CTP (14) MET0003 (15) PPI (16) MET0007 (17) MET0008 (18) MET0006 (19) Oxidizedferredoxins (20) MET0005 (21) Reducedferredoxins (22) CARBONDIOXIDE (23) PROTON (24) G3P (25) NADP (26) NADPH (27) DPG (28) DIHYDROXYACETONEPHOSPHATE (29) FRUCTOSE16DIPHOSPHATE (30) ERYTHROSE4P (31) FRUCTOSE6P (32) GAP (33) WATER (34) DSEDOHEPTULOSE17P2 (35) Pi (36) DSEDOHEPTULOSE7P (37) XYLULOSE5PHOSPHATE (38) ATP (39) DRIBULOSE15P2 (40) ADP (41) RIBOSE5P (42) RIBULOSE5P (43) Biomass (1) RIB5PISOM (2) PHOSPHORIBULOKINASE (3) RIBULP3EPIM (4) SEDOHEPTULOSEBISPHOSPHATASE (5) 2TRANSKETO (6) 1TRANSKETO (7) F16BDEPHOS (8) SEDOBISALDOL (9) F16ALDOLASE (10) TRIOSEPISOMERIZATION (11) 1.2.1.13 (12) PHOSGLYPHOS (13) RUBISCO (14) RXN0001 (15) RXN0002 (16) RXN0003 (17) RXN0004 (18) RXN0005 (19) RXN0006 (20) RXN0007 (21) RXN0008 (22) RXN0009 (23) 1.18.1.2 (24) RXN4903650 (25) PSII (26) RXN0010 (27) 3PGAREARR (28) 2PGADEHYDRAT (29) PEPDEPHOS (30) CDPKIN (31) CMPKIN (32) INORGPYROPHOSPHAT (33) 3.6.3.14 (34) BiomassFormation

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Import to Omics Viewer

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Recap

  • What have we accomplished?

– From stoichiometry (structure) of reaction network ...

  • Steady-state flux “subspace”,
  • Conserved “motifs”,

– From flux constraints ...

  • Unique steady-state operating point (solution of LP)
  • We used “biomass” optimization, but there are many

variations on the theme (e.g., MOMA, ROOM)

  • What is not represented?

– Quantity (Concentrations) – Thermodynamics (chemical potentials) – Dynamics (approach to steady-state, stability,...) – Spatial inhomogeneities – Regulation (neither metabolic nor transcriptional)

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v ∈ N(S) ˙ x ∈ N(ST )

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Network dynamics (1): Linearized

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Network dynamics (2): Nonlinear

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A network model can (should?) include:

  • Structure (connections, stoichiometric weights)
  • Flux (chemical flow)
  • Concentration (chemical potential)
  • Kinetics (flux/potential constitutive model)
  • Regulatory “feedback”

Ref: Krappmann, Lipscomb, Braus (2000) PNAS 97(25): 13585.

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Example of “Metabolic Control” from EcoCyc

T r a n s c r i p t i

  • n

a l c

  • n

t r

  • l

Modulatory control