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Scenario 5

Welcome to Integrated Bioinformatics. Friday, 18 November 2011. Scenario 5. Metabolic Modeling. This is best viewed as a slide show. To view it, click Slide Show on the top tool bar, then View show. Click to start. How things work.

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Scenario 5

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  1. Welcome toIntegrated Bioinformatics Friday, 18 November 2011 Scenario 5 Metabolic Modeling This is best viewed as a slide show.To view it, click Slide Show on the top tool bar, then View show. Click to start

  2. How things work 1) 1 hour of lecture / 1 hour of hands-on coding2) 1.25 hours of lecture / 45 minutes of hands-on coding3) 2 hours of lecture Brief (maybe 10-15 minute) recap...we'll spend some time on questions from notes or problem sets, then usually dive right in to coding. Usually we'll do one class of lecture on a new topic, then work for a few days on the programming aspects.

  3. What things work I learn best by doing, not seeing nor hearing. Looking at and modifying perl scripts has worked very good. I would have liked to spend more time doing the actual programming I like the recap we get in the beginning of most classes…

  4. Trypanosoma bruceiCausative agent of sleeping sickness Life Cycle Central Nervous SystemDeath

  5. Trypanosoma bruceiHow to stop it? Standard antibiotic targets Cell wall e.g. penicillins Bacterial ribosomes e.g. neomycin Bacterial RNA polymerase e.g. rifampicin Bacterial DNA gyrase e.g. nalidixic acid Trypanosomes have eukaryotic machinery, like us

  6. Glycolysis ATP Pyruvate Citric Acid Cycle ATP Trypanosoma bruceiHow to stop it? Them Us Glucose Glycolysis ATP Pyruvate

  7. Glycolysis Glycolysis ATP ATP Pyruvate Pyruvate Citric Acid Cycle ATP Trypanosoma bruceiHow to stop it? Them Us Glucose

  8. Symbolically Glucose Glucose-6-P + ATP + ADP Hexokinase Mathematically dG6P/dt = kf [Glc][ATP] Computationally $dG6P_dt = $kf*$glc*$atp Alternative to exhaustive lab testing inhibitor1 … exhaustive computational modeling

  9. dGlc/dt = +kf1 [Glcx] -kr2[Glc] -kf2[Glc][ATP] dG6P/dt = +kf2 [Glc][ATP] -kf3[G6P] dF6P/dt = +kf3 [G6P]-kr3[F6P] -kf4[F6P][AT] dFDP/dt = +kf4 [F6P][ATP]-kf5[FDP] dDHAP/dt = +kf5 [FDP]+kr6[G3P] -kf6[DHAP] dG3P/dt = +kf5 [FDP]+kf6[DHAP] -kr6[G3P] -kf7[G3P][NAD]+kry[13PGA][NADH] d13PGA/dt = kf7[G3P][NAD]-kry[13PGA][NADH] -kf8[13PGA][ADP]+kr8[3PGA][ATP] . . . Glycolysis This is a very detailed modeling of glycolysis. It seems not feasible to model the enzyme kinetics when dealing large system of metabolic model.

  10. Modeling Glycolysis Review… General understanding… I don’t know it verbatim…

  11. glucose O OH OH HO OH OH O O 2 OH pyruvate What is glycolysis blood cell Oxidation state electronegativityO > C > H 2 ATP +

  12. O OH OH HO OH OH O O 2 OH pyruvate What is glycolysis glucose permease blood cell

  13. O OH OH HO OH OH O O 2 OH pyruvate What is glycolysis glucose permease blood cell

  14. O O O O OH OH HO O-P-O O-P-O O-P-O OH OH O O O -Adenosine O O 2 OH pyruvate What is glycolysis glucose permease ATP blood cell Anhydride (acid + acid)

  15. O O O O OH OH HO O-P-O O-P-O O-P-O OH OH O O O -Adenosine O O 2 OH pyruvate What is glycolysis glucose permease ATP blood cell Anhydride (acid + acid)

  16. O O-P-O O O O O OH OH O-P-O O-P-O OH OH O O O O 2 OH pyruvate What is glycolysis glucose permease ADP blood cell -Adenosine Anhydride (acid + acid)

  17. O O O OH OH O O-P-O O-P-O OH OH O O O O 2 OH pyruvate What is glycolysis glucose permease ADP blood cell -Adenosine Anhydride (acid + acid)

  18. glucose O O OH OH OH OH O HO OH OH OH OH O O O O 2 OH pyruvate What is glycolysis ATP ADP glucose-6P Ketone or aldehyde Hexokinase ??? Enol 2 ATP +

  19. glucose O O O OH OH OH OH OH OH O O HO OH OH OH OH OH OH O O 2 OH pyruvate What is glycolysis ATP ADP glucose-6P Hexokinase ??? 2 ATP +

  20. glucose O O O O OH OH OH OH OH OH OH OH O O O HO OH OH OH OH OH OH OH OH O O 2 OH pyruvate What is glycolysis ATP ADP glucose-6P fructose-6P Hexose-P isomerase Hexokinase 2 ATP +

  21. glucose O O O O OH OH OH OH OH OH OH OH O O O HO OH O OH OH OH OH OH OH O O 2 OH pyruvate What is glycolysis ATP ADP ATP ADP glucose-6P fructose-6P fructose-1,6 diP Hexose-P isomerase Phosphofructokinase Hexokinase 2 ATP +

  22. glucose O O O O OH OH OH OH OH OH OH OH O O O HO OH OH O OH OH OH OH OH O O 2 OH pyruvate What is glycolysis ATP ADP ATP ADP glucose-6P fructose-6P fructose-1,6 diP Hexose-P isomerase Phosphofructokinase Hexokinase Aldolase O OH OH O O O Dihydroxyacetone P (DHAP) glyceraldehyde 3-P (Gla3P) 2 ATP +

  23. glucose O O O O OH OH OH OH OH OH OH OH O O O HO OH OH O OH OH OH OH OH O O 2 OH pyruvate What is glycolysis ATP ADP ATP ADP glucose-6P fructose-6P fructose-1,6 diP Hexose-P isomerase Phosphofructokinase Hexokinase Aldolase O Triose P isomerase OH OH O O O Gla3P DHAP 2 ATP +

  24. glucose O O O O OH OH OH OH OH OH OH OH O O O HO OH O OH OH OH OH OH OH OH O O ADP ATP O O O O 2 OH OH O pyruvate O O What is glycolysis ATP ADP ATP ADP glucose-6P fructose-6P fructose-1,6 diP Hexose-P isomerase Phosphofructokinase Hexokinase Aldolase O Triose P isomerase OH OH O O O Gla3P DHAP NAD+ NADH Gla 3-P dehydrogenase 2 ATP + 3-P-glycerate (3PG)

  25. Trypanosoma bruceiHow to exploit dependence on glycolysis? Treatment blood cell Arsenate(AsO4 = Asi) Competitivewith Pi

  26. O O-P-O O O O O O-P-O-CH2—CH—C- O-P-O O O ADP ATP O O O-P-O-CH2—CH—C-O 3-P-Glycerate O Trypanosoma bruceiHow to exploit dependence on glycolysis? O O O-P-O-CH2—CH—C Glyceraldehyde-3-P H O NAD+ NADH

  27. O O O O-P-O-CH2—CH—C- O-As-O O O ADP ATP O O O O-P-O-CH2—CH—C-O O-As-O + 3-P-Glycerate O O Trypanosoma bruceiHow to exploit dependence on glycolysis? O O O O-As-O O-P-O-CH2—CH—C Glyceraldehyde-3-P O H O NAD+ NADH H2O

  28. How to model this reaction?

  29. How to model this reaction?

  30. = d[Asi] / dt rate of change = d[AMP-P-Asi] / dt = – rate of change k rateconstant Characteristics of enzymesChemical reactions AMP-P-As AMP-P +Asi [AMP-P-As] = d[AMP-P ] / dt concentration rate of change =

  31. = d[AMP-P-Asi] / dt = – rate of change = d[S] / dt [S] = – A differential equation k k rateconstant Characteristics of enzymesChemical reactions AMP-P-As AMP-P +Asi [AMP-P-As] concentration

  32. = d[AMP-P-Asi] / dt = – rate of change [S] = Its solution? k rateconstant Characteristics of enzymesChemical reactions AMP-P-As AMP-P +Asi [AMP-P-As] concentration = d[S] / dt = –k[S] A differential equation

  33. = d[AMP-P-Asi] / dt = – rate of change [S] = S0 e -k(t-to) Its solution? = d[S] / dt Check: k rateconstant Characteristics of enzymesChemical reactions AMP-P-As AMP-P +Asi [AMP-P-As] concentration = d[S] / dt = –k[S] A differential equation = S0 (–k) e -k(t-to) = -k S0e -k(t-to) = -k [S]

  34. [S] = S0 e -k(t-to) Its solution? = d[S] / dt Check: Characteristics of enzymesChemical reactions Write an equation for the rate of increase of a rabbit population over time.(ignore all environmental effects) [R] = R0 2t/D = d[S] / dt = –k[S] A differential equation = S0 (–k) e -k(t-to) = -k S0e -k(t-to) = -k [S]

  35. = d[AMP-P-Asi] / dt = – rate of change [S] = S0 e -k(t-to) Its solution? = d[S] / dt Check: k rateconstant Characteristics of enzymesChemical reactions AMP-P-As AMP-P +Asi [AMP-P-As] concentration = d[S] / dt = –k[S] A differential equation = S0 (–k) e -k(t-to) = -k S0e -k(t-to) = -k [S]

  36. [S] = S0 e -k(t-to) = d[S] / dt = –k[S] Characteristics of enzymesChemical reactions

  37. Characteristics of enzymesChemical reactions

  38. [S] = S0 e -k(t-to) Δt Characteristics of enzymesChemical reactions [S] = S0

  39. [S] = S0 + Δt d[S] / dt = d[S] / dt = –k[S] Characteristics of enzymesChemical reactions S0 Δt

  40. Characteristics of enzymesChemical reactions SQ1. Let’s try it. Link to ADP-As.pl Upload and plot results in Excel. For comparison, calculate on the same graph the analytical solution, using constants provided in ADP-As.pl

  41. [S] = S0 e -k(t-to) = d[S] / dt = –k[S] Characteristics of enzymesChemical reactions SQ3. Why is it that the predicted levels are all lower than the calculated levels?

  42. Slope0 = -k[S0] [S1] = S0 + Δt d[S] / dt Slope1 = -k[S1] = d[S] / dt = –k[S] Characteristics of enzymesChemical reactions [S] = S0 + Δt d[S] / dt S0 Use average of Slope0 and Slope1 Δt

  43. = d[S] / dt = –k[S] Characteristics of enzymesChemical reactions [S] = S0 + Δt d[S] / dt Slope0 = -k[S0] [S1] = S0 + Δt d[S] / dt Slope1 = -k[S1] S0 Use average of Slope0 and Slope1 Runge-Kutta method Δt

  44. Characteristics of enzymesEnzymatic reactions inhibitor1

  45. = d[F6P] / dt = rate of change ??? k rateconstant Characteristics of enzymesEnzymatic reactions What is the rate equation? Glucose-6-phosphate Fructose-6-phosphate [G6P] concentration k ~ 0

  46. Characteristics of enzymesEnzymatic reactions

  47. E-complex Characteristics of enzymesEnzymatic reactions G6P +E G6P·E F6P·E F6P +E

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