Cellular Metabolism Simulation in the Post Genomic Era by jvz18720

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									Cellular Metabolism Simulation in
      the Post Genomic Era

 Xin-Guang Zhu1, Eric deSturler2, Stephen P. Long1

1. Department of Plant Biology, UIUC
2. Department of Computer Science, UIUC
               Road-Map
• Why Metabolism Modeling
• Modeling Techniques
  – Constraint based modeling
  – Data based approach (top down approach)
  – Kinetic modeling
• Photosynthesis Modeling and Challenges
  ahead
    Why Metabolism Modeling
• Extract system properties or rules responsible for
  system regulation, robustness and efficiency
• Predict the alternation of metabolism under stress
  conditions or altered genetic conditions, provide
  ways for identify targets for genetic manipulation
• Discover new interactions between pathway in
  metabolism
• Extract new physiological parameters carrying
  information of system properties
  – Choice of steady state
  – Changes in metabolism path under different conditions
            More Reasons
• Metabolite levels are system properties,
  determined by activities of all enzymes
  and effectors
• Metabolism regulation of gene expression
• Silent Mutation.
  – Functional redundancy in metabolite system
  – Ability of system to stay in similar flux by
    varying substrate concentrations
            Techniques

• Constraint Based Modeling
• Data based Modeling
• Kinetic Modeling
  Constraint Based Modeling
• Assumption: system property can be
  effectively detected using the stochiometry &
  constraints.
• Data source
• Procedure for build a model
• Application
  –   Detection of elementary (or extreme) pathway
  –   Flux distribution under different conditions
  –   Phase plane analysis
  –   Relationship of extreme pathway & microarry data
• Weakness
Genome-scale Metabolic Network
       Reconstruction




                        Pallson et al Presentation
Edwards et al 2002 Environ. Microbio.
    Determining Regulation from
    Metabolic Network Structure
• Efficiency of an elementary mode – mode’s output
  (growth or ATP) relative to its “investment”




• Control effective fluxes for a reaction – average flux
  through this reaction for all elementary modes, weighed
  by each mode’s efficiency.




                                             Stelling et al 2002
     Determining Regulation from
     Metabolic Network Structure
As cellular control is achieved by
genetic regulation, control
effective flux (CEF) should
correlate with messenger RNA
levels.

Theoretical transcript ratios for
growth on two alternative
substrates:
Θ(S1,S2)=CEF(S1)/ CEF(S2)
in comparison with gene
expression data
(r2=0.6)



                                     Stelling et al 2002
              Weakness
• No dynamics
• No interface for combining the gene
  regulatory mechanism
• No interface for implementing discrete and
  stochastic events
• Can not include the inhibition effects of
  metabolites on enzymes



                                         Zhu, 2005
         Data Based Modeling
• The major assumption: “guilt by association”.
• Data: metabolomics, microarray
• Algorithm
   – Cluster Analysis – e.g. Fiehn et al, 2000; Roessner et al, 2001
   – Principal Component Analysis – e.g. Fiehn et al, 2000;
     Roessner et al, 2001
   – Simple Correlations – e.g. Roessner et al, 2001
   – Parallel Analysis of Transcript and Metabolic Profiles. E.g.
     Urbanczyk-Wochniak et al., 2003
   – Methods to infer reaction mechanisms – e.g. Crampin et al,
     2004
    Principle Component Analysis
• Application:
   – Capture the major variance of the
     dataset
   – potentially identify pioneer signaling
     molecules
   – PCA should be done before cluster
     analysis to improve the accuracy of
     CA.

• Algorithm:
   – Singular Value Decomposition (SVD)
     on the covariance matrix of the data.
   – The first PC is the eigenvector with
     the greatest eigenvalue for the
     covariance matrix of the dateset.


                    http://www.ucl.ac.uk/oncology/MicroCore/HTML_resource/PCA_1.htm
Methods to Deduce Biochemical
   Network Mechanisms (1)
• Perturbation Methods
  – Assumption: linear behavior near steady state
  – Data : periodic random perturbation, or using different
    initial conditions.
  – Application: study the interaction between different
    substrates (entries of J) and the stability of the system
    (eigenvalue of J)




                                      Crampin et al (2004) Prog. Biophy & Mol. Biol.
Methods to Deduce Biochemical
   Network Mechanisms (2)
• Network Connectivity
  – Assumption: guilt by
    association
  – Data: time series data
    after perturbation
  – Application: study
    connectivity between
    different metabolites.




                             Crampin et al (2004) Prog. Biophy & Mol. Biol.
Methods to Deduce Biochemical
   Network Mechanisms (3)
• Nonlinear Reaction Model
  – Assumption: explicitly representation of mass action in
     model increase ability to identify reaction mechanism
  – Data source: biochemical time series data
  – -Application: study reaction mechanisms
  – Algorithm: See equation. Genetic Programming needed
     for parameterization




                                      Crampin et al (2004) Prog. Biophy & Mol. Biol.
            Weakness
• Difficult to infer reaction mechanism
• Generally good in fitting the training data,
  not well for new data set
• Large number of degree of freedom for
  parameters, make it intractable.
• Difficult to define the complexity of the
  model, e.g. number of the basis functions
         Kinetic Modeling
• Philosophy: The more complete, the
  better.
• Parameter data
• Data for validating model
• Algorithm for Model development
• Applications
• Weakness
      Algorithm for Building Kinetic Models
Establish the reaction diagram

  Build the rate equations


      Construct the ODE


   Solve the system of ODE
                                       Yes
                                 No                     No
      Stable Solution ?               Algorithm ?

             Yes
                                                              No
    Numerical experiments              Realistic ?
                                                         Finish
                                                Yes

                                                Zhu, 2004 , PHD Thesis
        Photosynthesis
• Set the maximum potential crop yield
• Sink for atmospheric CO2, help
  alleviate the greenhouse gases
• Easy to probe with biophysical
  methods, e.g. CO2 uptake, O2 release,
  fluorescence, spectroscopy.
• Easily to separate into independent
  units
                             Zhu, 2004 , PHD Thesis
Photosynthesis is a series of molecular steps that
  depends on proteins located in chloroplasts;
photosynthesis uses light energy, utilizes CO2 and
         H2O to generate carbohydrate.
                                                                                                                                                                                                         V                                     Vi               V
                                                                                                                                                                               Q            V                           H+ + ISP (ox)
                                                                                                                                                                               -                       Q bf Q                                  n                i
                                                                                                                                                                                            bf
                                                                                                                                                        S                                              i 7                                     p                n
                                                                                                                       S                                                                    5
                                                                                                                                                                 O2                V                                                                            c
                                                                                                                                                        0                                    E.bL.bH                                        V                             V
                                                                                                                       1                                                                                                                         Vi
                                                                                                                                                                 +4H+              bf        -
                                                                                                                                                                                                                                            f A                 U         f
         Light                                                                                                                                                                     6                                                             pc
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                                                                                                        -                                                        2H2                                                                        V    Vi                       V
                                                                                                                                                                              Q
                                                                                    z                                                                   S        O            2-                  V                                         d    cp                       d
                                                                            e                                          S                                                                                                                                                                 Fd     NAD
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                                                                                                                                                        4                                                                                 -
                                U                                                                                      2                                     e                     V              4                   ISPH+(ox)      Cytf     P
                                                                                                                                                             -
         Periphe                o
                                           P6                                               Ph              P6                                                                              -.b + H+ + Q
                                                                                                                                                                                        E.bL H                                                C+
                                                          P680        P680+                                                                                                        qi
           ral                                                                              e-              80
                                                                                                                                e           S
                                           80             *                                                                     -                                                                   V                   V                            V           V                V    V
         Antenn                                                       Phe-                                                                  3
                                U          Ph                                               P680+           Ph                                                                                      bf                  bf                           bf          bf               bf   bf
            a                   c                         Ph                                                                                                                  QH2
                                           e                                                Phe             e              Oxygen Evolution Complex
                                                                                                                                                                                                    3
                                                                                                                                                                                                 E.bL.bH.QH· + ISPH(red)8                            9           10               15   16
                                                          e                                                                                                                                                                          Cytf        P              P700            A    F    NADPH
                                                                                                                                                                                                                                                                +               -
                                                                                                                                                                                                                                                 C                                   d
                                                                                        e
                                                                                        -
                                                                                                                                                                                                                 V
          Fluoresce                                                                                                                                                                                              bf
           nce and                                                                                                                                                                                               2
                                                                                                                                                                                                       E.bL.bH.ISP(ox).QH2
             Heat QAQ                           QA-                 QAQB-                          QA-QB-                  QAQB2-                       QA-QB2-
                          B                     QB                                                                                                                                                                                                                                                Sink
                                                                                                                                                                                                                                                                                                  s of
                                                                                                                                                                                                                                                                                                  NAD
                                                PQred                                              PQox                                                                                                   QH2 V ISP (ox)
                                                                                                                                                                                                                                                                                                  PH
                                                              Through cytbf                                                                                                                                    bf
                                                                                                                                                                                                           E.bL.bH
                                                              complex                                                                                                                                          1


                                                                                                                                        1
                               Ru5           Ru5                                Ru5                                                     3
                                                                                                    ATP                ADP
                              1P            1P                                  P




                                                                                                                                                                                                                                                                                                Stroma
                              1 Ri5P        2 Xu5
                                              P                                                                                                                                                                                    111
                                                                                                                                                                 RUBP                                                                                           PGCA
                                                                                1                                                                                                                               O2
                                       1                                                                         Starch
                                            S7P                                 2                                                                                                                                            PGA
                                       0              Pi                                                                                                                                               ADP                                                          112
                                           9
                                                                                                                                                                                                                                                                                    Pi
                                                                                                                            ADP                                                                                                    113
                                           SBP                                                                               PPi                2           CO2                                                                                                       GCA
                                                      8                                                                     G                       P                                                   ATP
                                                                                                                                                5
               Stroma




                                                                                                                                                                                                                        GCEA
                                                              E4P               Xu5P                             2                                  i
                                                                                                                 3                                           1
                                                                      7                                           G1                ATP                                                                                                         101
                                                                                                                  P        22
                                                                                                   21                                                                                                                  GCEA
                                                                          F6P                                                                                                                                                                                       GCA
                                                                                                                 G6P                                              PGA +                                                                                                             O2
                                                                                                                                                                                                        NADH
                                                                                             Pi




                                                                                                                                                                                                                                                                                              e
                                                                                                                                                                                                                                                                                              Peroxysom
                                                                           6                                                                                                                                                                                    121
                                                                                                                                                                   PGA ATP                                                         123
                                                                                                                                                                                                                                                                                    H2O2
                                                                          FBP
                                                                                                                                                              2
                                                                            5                                                                                                                                                                                         GOA
                                                                                                             NADP+OP                                                                                      NAD+
                                                                                                                                        NADPH+H                         ADP                                                  HPR
                                                                                                                                                                                                                                                                                     GLU
    Pi                          GAP        DHAP           GAP       DHAP        GAP
                        DHA                                                                        GAP                                                      DPGA                                                                                          122                 124
                        P    P                            4                                  P                                      3                                                                                                                                               KG
3                            i                                                               i
                          3                                                                    3                                                                                                 SER                           131                                  GLY




                                                                                                                                                                                                                                                                                               Mitochon
2
                          1 P                                                                  3
                         DHA i                                                                P                                                                                                                                             Gly + NAD+
Pi                                                                                                  GAP                                                                                                    CO2 + NADH
                         P                                                                    i
         PGA
   CRITERIA          Divide and Conquer Strategy
• Relatively
  independent                            Light ! Electron ! PQH2
                      Primary Events
  from other
  metabolism,
  i.e. the input   ∆pH, ∆ψ     e-
  and output
  molecules are                          PQH2 ! Electron transfer
  minimized.         Electron Transfer    ! NADPH + ATP
• Having
  measurable
  signal to        ATP         Stromal pH,
                   NADPH
  detect the                   [Thioredoxin]
  performance
  of modules.                            The Calvin cycle,
                                         PCOP, Starch synthesis,
                     Carbon Metabolism
                                         TP export
                                                     Zhu, 2004 , PHD Thesis
Carbon Metabolism




               Zhu, 2004 , PHD Thesis
         Maximum Enzyme Rates
Max.                                         Vm
Vel.       Enzyme             Reaction      mmol l-1    Reference
                                              s-1
 V1        Rubisco        RuBP+CO2→2PGA                 (Harris &
                                             3.738      Koniger 1997)
 V2      PGA Kinase       PGA+ATP → ADP +               (Harris &
                               DPGA          11.76      Koniger 1997)
 V3         GAP            DPGA+NADPH                   (Harris &
        dehydragenase     →GAP + OP+NADP     5.04       Koniger 1997)
 V4    Triose phosphate     DHAP ↔GAP                   (Harris &
          isomerase                          40.53      Koniger 1997)
 V5        Aldolase       GAP+DHAP →FBP                 (Harris &
                                             5.52       Koniger 1997)



                                                    Zhu, 2004 , PHD Thesis
      Michaelis Menton Constant
RN1    Reaction    Paramet Value     2Description     Reference
                       er    (m
                             M)
111   RuBP + CO2     KO      330         O2          (Long 1991)
       ! 2 PGA
111   RuBP + CO2     KC      0.46       CO2          (Long 1991)
       ! 2 PGA
112    2-PGCA       KM112    0.026     PGCA         (Christeller &
        +H2O !                                          Tolbert
        GCA + Pi                                         1978)
112    2-PGCA       KI1121    94        GCA         (Christeller &
        +H2O !                                          Tolbert
        GCA + Pi                                         1978)



                                                    Zhu, 2004 , PHD Thesis
Initial Metabolite Concentrations
  Metabolite   Concentration         Reference
                 (mmol l-1)
   DHAP           0.480        (Harris & Koniger 1997)

    FBP           0.670        (Harris & Koniger 1997)

    E4P           0.050        (Harris & Koniger 1997)

    S7P           2.000        (Harris & Koniger 1997)

    SBP           0.300        (Harris & Koniger 1997)

    ATP           0.680        (Igamberdiev et al. 2001)

  NADPH           0.210          (Giersch et al. 1980)




                                         Zhu, 2004 , PHD Thesis
                      Rate Equation

                        A+B ↔ C+D
                                            [C ][ D]
                                 [ A][ B] −
                                              ke
v1 = Vm
                       [ A] [ B]     [C ] [ D] [ A] [ B]   [C ] [ D]
        K mA K mB (1 +     +      +        +       +     +           )
                       K mA K mB K mC K mD K mA K mB K mC K mD


If inhibitor (E) exist,                 A+B → C+D
                                     [ A][ B]
             v 2 = Vm
                                        [E]
                      ([ A] + K mA (1 +     ))([ B ] + K mB )
                                        KI
                                            (Cleland, 1963, Segal, 1975)
 Reactions not Following
Michaelis-Menten Equation
 ADP-glucose pyrophosphorylase,
 Phosphate translocator
 ATP synthase
 Rubisco
   vC = WC × min{1, [ Rt ] /[ Et ]}
                VC max [CO2 ]
  WC =
                              [O2 ]
         [CO2 ] + K M 11 (1 +        )
                              K M 12
                                    Pettersson and Ryde-pettersson 1988;
                                    Von Caemmerer, 2000
                                                                                                                                                                                     111
                                                                                                                                                                        O2

                                                                vc                                            PGA                                                RuBP                                 PGCA


                                        v13




                                                                                                                                                                                                                               Stroma
         Ru5P                                               RuBP                                                                                                  ADP
                                                                                                                                                                               PGA
                                                                                                                                                                                                          11
                                                                                                                                                                                                          2
                                                                                                                                                                                                                      Pi
                                                                                         vo                                                                                          113

                                                                                                              PGA + PGCA                                              ATP
                                                                                                                                                                              GCEA
                                                                                                                                                                                                          GCA



                      d [ RuBP ]
                                 = v 13 − v c − v o
                           dt                                                                                                                                                                 101



                                                                                                                                                                             GCEA
                                                                                                                                                                                                          GCA
                                                                                                              13
                Ru5P               Ru5P                       Ru5P                                                                                                                                                    O2
                                                                                   ATP            ADP                                                                 NADH
               11                 12
                  Ri5P               Xu5P




                                                                                                                                                                                                                             Peroxysome
                                                                                                                                                                                                      121

                         10       S7P
                                            Pi
                                                              12                           Starch                            RuBP
                                                                                                                               RUBP
                                                                                                                                               O2
                                                                                                                                                                                     123
                                                                                                                                                                                                                      H2O2

                              9
                                                                                                         ADPG                                                                                             GOA
                              SBP                                                                         PPi      25        CO2                                      NAD+
                                        8                                                                               Pi               PGA+ PGCA                             HPR
                                                 E4P          Xu5P                         23
Stroma




                                                                                                                                                                                                                       GLU
                                                                                                                               1
                                                        7                                   G1P           ATP
                                                                              21                    22
                                                                                                                                                                                                    122         124
                                                            F6P                             G6P                                    PGA    +
                                                                        Pi                                                         PGA
                                                             6                                                                                ATP                                                                     KG
                                                            FBP                                                                2
                                                             5                           NADP+OP               NADPH+H                        ADP
                  GAP         DHAP           GAP       DHAP       GAP                                                                                           SER                 131
                                                                                                                                                                                                          GLY




                                                                                                                                                                                                                             Mitochon
         DHAP                                                                 GAP                                            DPGA                         Pi
                 Pi                          4                          Pi                                3
          31                                                             33                                                                         32
                                                                                                                                                                                           Gly + NAD+
             Pi                                                                                                                                                        CO2 + NADH
         DHAP                                                            Pi        GAP                                                                   Pi

                                                                                                                                                          PGA
    The System of ODE
dx/dt = f(x, y, t)
x is metabolites used in the model
y is some constants
f is a nonlinear systems
• No analytical solution
• Stiff system.
• ode15s of MATLAB

                            Zhu, 2004 , PHD Thesis
                           4
Concentration (mmol l-1)




                           3

                                         S7P
                                                                                                                 The system reach a
                           2       Gly
                                                                                                                 steady state solution.
                           1
                                                            RuBP
                                                                                            PGA
                           0
                               0         50          100           150                               200
                                                                                            45
                                               Time (t, second)

                                                                                            40

                                                                         A (µmol m-2 s-1)                         1%   [O2] 21%
                                                                                            35
                               The system keep its
                                                                                            30
                               right kinetics under
                               perturbation.                                                25


                                                                                            20


                                                                                            15
                                                                                                 0         200        400         600    800
                                                                                                                   Time (t, second)
                                                                                                                               Zhu, 2004 , PHD Thesis
           3 .2                                                                             3 .2
                                         RuBP                                     PGA
           2 .8                                                                             2 .8
                                                                    [O2]
           2 .4                                                                             2 .4
                            [O2]
           2 .0                                                                             2 .0
                      1%           21%
           1 .6                                                                             1 .6

           1 .2                                                                             1 .2




                                                                                                   mmol l-1
mmol l-1




           0 .8                                                                             0 .8
                                            S7P                      [O2]     G ly c in e


             2                                                                              2

                            [O2]
             1                                                                              1




             0                                                                             0
                  0   300          600            0            300          600         900

                                         T im e (t, s e c o n d )            Zhu, 2004 , PHD Thesis
                                                        20                                                                                                  6




                     CO2 assimilation rate (µmol m-2 s-1)




                                                                                                                                                                   s )
                                                                                                                                                                 -2 -1
                                                                                                                                                            5




                                                                                                                                                                  CO2 assimilation rate (µmol m
                                                        15
                                                                                                                                                            4


                                                        10                                                                                                  3


                                                                                                                                                            2
                                                            5
                                                                                                                                                            1
                                                                                          Ambient [O2]                                  Elevated [O2]

                                            200
                                              0                                                                                                             0
Electron transfer rate (µmol m-2 s-1)




                                                                                                                                                            200




                                                                                                                                                                                Electron transfer rate (µmol m s )
                                                                                                                                                                                                              -2 -1
                                            150
                                                                                                                                                            150


                                            100
                                                                                                                                                            100



                                                        50                                                                                                  50

                                                                                         Ambient [O2]                                    Elevated [O2]
                                                            0                                                                                                0
                                                                0.6   0.8   1.0   1.2   1.4    1.6   1.8   2.0 0.6   0.8   1.0   1.2    1.4   1.6   1.8   2.0

                                                                                              Relative enzyme activity                 Zhu, 2004 , PHD Thesis
Carbon Metabolism




               Zhu, 2004 , PHD Thesis
       PCOP Metabolism
• Simulations revealed that :
  – enzymes in PCOP are in excess of what is
    needed to maintain the flux of PCOP under
    current atmospheric conditions.
  – This excess of enzyme activities may be an
    insurance against environmental conditions
    that promote photorespiration that could
    otherwise result in carbon accumulating within
    PCOP and slowing regeneration of RuBP.


                                      Zhu, 2004 , PHD Thesis
                                                                                                                                                                                                         V                                     Vi               V
                                                                                                                                                                               Q            V                           H+ + ISP (ox)
                                                                                                                                                                               -                       Q bf Q                                  n                i
                                                                                                                                                                                            bf
                                                                                                                                                        S                                              i 7                                     p                n
                                                                                                                       S                                                                    5
                                                                                                                                                                 O2                V                                                                            c
                                                                                                                                                        0                                    E.bL.bH                                        V                             V
                                                                                                                       1                                                                                                                         Vi
                                                                                                                                                                 +4H+              bf        -
                                                                                                                                                                                                                                            f A                 U         f
         Light                                                                                                                                                                     6                                                             pc
                                                                                    Y                   e                                                                                                                                   p                             c
                                                                                                        -                                                        2H2                                                                        V    Vi                       V
                                                                                                                                                                              Q
                                                                                    z                                                                   S        O            2-                  V                                         d    cp                       d
                                                                            e                                          S                                                                                                                                                                 Fd     NAD
                                                                            -               P680                                                                                                  bf                                        p               P700          c A            r      P
                                                                                                                                                        4                                                                                 -
                                U                                                                                      2                                     e                     V              4                   ISPH+(ox)      Cytf     P
                                                                                                                                                             -
         Periphe                o
                                           P6                                               Ph              P6                                                                              -.b + H+ + Q
                                                                                                                                                                                        E.bL H                                                C+
                                                          P680        P680+                                                                                                        qi
           ral                                                                              e-              80
                                                                                                                                e           S
                                           80             *                                                                     -                                                                   V                   V                            V           V                V    V
         Antenn                                                       Phe-                                                                  3
                                U          Ph                                               P680+           Ph                                                                                      bf                  bf                           bf          bf               bf   bf
            a                   c                         Ph                                                                                                                  QH2
                                           e                                                Phe             e              Oxygen Evolution Complex
                                                                                                                                                                                                    3
                                                                                                                                                                                                 E.bL.bH.QH· + ISPH(red)8                            9           10               15   16
                                                          e                                                                                                                                                                          Cytf        P              P700            A    F    NADPH
                                                                                                                                                                                                                                                                +               -
                                                                                                                                                                                                                                                 C                                   d
                                                                                        e
                                                                                        -
                                                                                                                                                                                                                 V
          Fluoresce                                                                                                                                                                                              bf
           nce and                                                                                                                                                                                               2
                                                                                                                                                                                                       E.bL.bH.ISP(ox).QH2
             Heat QAQ                           QA-                 QAQB-                          QA-QB-                  QAQB2-                       QA-QB2-
                          B                     QB                                                                                                                                                                                                                                                Sink
                                                                                                                                                                                                                                                                                                  s of
                                                                                                                                                                                                                                                                                                  NAD
                                                PQred                                              PQox                                                                                                   QH2 V ISP (ox)
                                                                                                                                                                                                                                                                                                  PH
                                                              Through cytbf                                                                                                                                    bf
                                                                                                                                                                                                           E.bL.bH
                                                              complex                                                                                                                                          1


                                                                                                                                        1
                               Ru5           Ru5                                Ru5                                                     3
                                                                                                    ATP                ADP
                              1P            1P                                  P




                                                                                                                                                                                                                                                                                                Stroma
                              1 Ri5P        2 Xu5
                                              P                                                                                                                                                                                    111
                                                                                                                                                                 RUBP                                                                                           PGCA
                                                                                1                                                                                                                               O2
                                       1                                                                         Starch
                                            S7P                                 2                                                                                                                                            PGA
                                       0              Pi                                                                                                                                               ADP                                                          112
                                           9
                                                                                                                                                                                                                                                                                    Pi
                                                                                                                            ADP                                                                                                    113
                                           SBP                                                                               PPi                2           CO2                                                                                                       GCA
                                                      8                                                                     G                       P                                                   ATP
                                                                                                                                                5
               Stroma




                                                                                                                                                                                                                        GCEA
                                                              E4P               Xu5P                             2                                  i
                                                                                                                 3                                           1
                                                                      7                                           G1                ATP                                                                                                         101
                                                                                                                  P        22
                                                                                                   21                                                                                                                  GCEA
                                                                          F6P                                                                                                                                                                                       GCA
                                                                                                                 G6P                                              PGA +                                                                                                             O2
                                                                                                                                                                                                        NADH
                                                                                             Pi




                                                                                                                                                                                                                                                                                              e
                                                                                                                                                                                                                                                                                              Peroxysom
                                                                           6                                                                                                                                                                                    121
                                                                                                                                                                   PGA ATP                                                         123
                                                                                                                                                                                                                                                                                    H2O2
                                                                          FBP
                                                                                                                                                              2
                                                                            5                                                                                                                                                                                         GOA
                                                                                                             NADP+OP                                                                                      NAD+
                                                                                                                                        NADPH+H                         ADP                                                  HPR
                                                                                                                                                                                                                                                                                     GLU
    Pi                          GAP        DHAP           GAP       DHAP        GAP
                        DHA                                                                        GAP                                                      DPGA                                                                                          122                 124
                        P    P                            4                                  P                                      3                                                                                                                                               KG
3                            i                                                               i
                          3                                                                    3                                                                                                 SER                           131                                  GLY




                                                                                                                                                                                                                                                                                               Mitochon
2
                          1 P                                                                  3
                         DHA i                                                                P                                                                                                                                             Gly + NAD+
Pi                                                                                                  GAP                                                                                                    CO2 + NADH
                         P                                                                    i
         PGA
                   70                          1000
                            A             B




                                                      Fluorescence Level
                   60
A (µmol m-2 s-1)                               800
                   50




                                                      (µmol m-2 s-1)
                   40                          600
                   30                          400
                   20
                                               200
                   10
                    0                          0
                             C             D
                                               7.0
                   8.5




                                                      Lumenal pH
Stromal pH




                                               6.5
                   8.0
                                               6.0
                   7.5
                                               5.5

                   7.0                         5.0
                         Time (Second)
                                         Zhu, 2004 , PHD Thesis
  Applications of Kinetic Models
• Control Analysis
• System function dynamics
• System Property analysis
   – Stability of the steady states
   – Phase plane and vector field
   – Elementary bifurcations:
      • One central question: what determines what states system
        need to be in; or which metabolism status?
• Reverse engineering to infer post-translational
  regulatory properties
• Gene function identification
• Identification of targets for genetic engineering
  “better” metabolism for desired property.
            Acknowledgement
Prof. Stephen P. Long (Plant Biology/UIUC)
Prof. Eric deSturler (Computer Science/UIUC)
Prof. Keith Mott (Biology/USU)
Dr. Xin-Guang Zhu (Plant Biology/UIUC)
Dr. Nahil Sobh (NCSA/UIUC)
Dr. Lei Liu

Contact: Xinguang Zhu (zhu3@uiuc.edu)

NSF, NCSA

								
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