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Scenario 5

Welcome to Integrated Bioinformatics. Friday, 18 November 2011. Scenario 5. Metabolic Modeling. The one and only concern I and most of my classmets have is the date of most modules needs to be updated in this website plus they need current informations.

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Scenario 5

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  1. Welcome toIntegrated Bioinformatics Friday, 18 November 2011 Scenario 5 Metabolic Modeling The one and only concern I and most of my classmets have is the date of most modules needs to be updated in this website plus they need current informations. 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. New! Friday, 16 November 2012 • What I learned from the questionnaires • The biological problem • Overview of glycolysis • Modeling a spontaneous reaction (ADP-As.pl) • Vmax and Km • Problem Set 5, #3 and maybe #11

  3. How things work At the beginning of each module the general principle is discussed… After this, time is spent more on programming and how to biologically use it. Takes up majority of the time writing/modifying perl programs. Not much time analyzing the output or finding answers to biological questions.

  4. How things work Lately we have been devoting the first hour to notes and defining a problem. The second hour is spent with Paul and Adam circulating to answer questions as the class works more or less independently. Usually, the first hour is devoted to lecture or going over the concepts of the module, and the next hour is spent working with Perl. About an hour of lecture, followed by an hour of coding.

  5. What things work Lectures so far have been a big part of it. The lectures help me greatly with understanding more of the complex concepts. Sitting and trying to figure out how to solve a problem helps me learn about it more. I learn best by doing, not seeing nor hearing.

  6. What things work I have no formal training in differential equations, but I've been able to work my through some biological scenarios that used them. I didn't understand the math,... I am very weak when it comes to math. I learn best by doing, not seeing nor hearing.

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

  8. 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

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

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

  11. 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

  12. 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.

  13. Modeling Glycolysis I have studied it in a number of classes I learned about the glycolytic pathway in the past Need a little review, but comfortable with the basics. I understand the concept but I am definitely not an expert at it. Glucose->->->Pyruvate ===free energy

  14. Modeling Glycolysis

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

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

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

  18. 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)

  19. 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)

  20. 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)

  21. 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)

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

  23. 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 +

  24. 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 +

  25. 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 +

  26. 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 +

  27. 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 +

  28. 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)

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

  30. 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 OH O O ADP ATP O O OH O O O What is glycolysis ATP ADP ATP ADP glucose-6P fructose-6P fructose-1,6 diP Ketone or aldehyde O Hexose-P isomerase Phosphofructokinase Hexokinase pyruvate O Aldolase O O O 2 Triose P isomerase OH OH 2 ATP + O Enol OH O O ATP Gla3P DHAP Pyr Kinase NAD+ ADP O O NADH O Enolase Gla 3-P dehydrogenase H2O O OH O H P-Glamutase O 3-P-glycerate (3PG) 2-P-glycerate (3PG)

  31. 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 OH O O ADP ATP O O OH O O O Whyis glycolysis ATP ADP ATP ADP glucose-6P fructose-6P fructose-1,6 diP Hexose-P isomerase Phosphofructokinase Hexokinase pyruvate Aldolase O O O 2 Triose P isomerase OH OH 2 ATP + O OH O O ATP Gla3P DHAP Pyr Kinase NAD+ ADP O O NADH O Enolase Gla 3-P dehydrogenase H2O O OH O H P-Glamutase O 3-P-glycerate (3PG) 2-P-glycerate (3PG)

  32. 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 OH O O ADP ATP O O OH O O O Whyis glycolysis ATP ADP ATP ADP glucose-6P fructose-6P fructose-1,6 diP Hexose-P isomerase Phosphofructokinase Hexokinase pyruvate Aldolase O O O 2 Triose P isomerase OH OH 2 ATP + O OH O O ATP Gla3P DHAP Pyr Kinase NAD+ ADP O O NADH O Enolase Gla 3-P dehydrogenase H2O O OH O H P-Glamutase O 3-P-glycerate (3PG) 2-P-glycerate (3PG)

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

  34. 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 TrypanosomabruceiHow arsenate poisons glycolysis? Normal glycolysis OH O O O-P-O-CH2—CH—C Glyceraldehyde-3-P H O NAD+ NADH OH OH

  35. 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 TrypanosomabruceiHow arsenate poisons glycolysis? Poisoned glycolysis OH O O O O-As-O O-P-O-CH2—CH—C Glyceraldehyde-3-P O H O NAD+ NADH H2O OH OH

  36. How to model this reaction?

  37. How to model this reaction?

  38. = 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 =

  39. = 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

  40. = 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

  41. = 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]

  42. [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]

  43. = 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]

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

  45. Characteristics of enzymesChemical reactions

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

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

  48. 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

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

  50. Characteristics of enzymesChemical reactions S0 Δt

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