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Welcome to Introduction to Bioinformatics Wednesday, 16 October Metabolic modeling

Welcome to Introduction to Bioinformatics Wednesday, 16 October Metabolic modeling. Table of Contents First exam: Rules of the game Sep 27, SQ4: Write subroutine to print score array PS1M.8: Probability of evolution. Trypanosoma brucei Causative agent of sleeping sickness. Life Cycle.

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Welcome to Introduction to Bioinformatics Wednesday, 16 October Metabolic modeling

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  1. Welcome toIntroduction to BioinformaticsWednesday, 16 OctoberMetabolic modeling • Table of Contents • First exam: Rules of the game • Sep 27, SQ4: Write subroutine to print score array • PS1M.8: Probability of evolution

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

  3. Entry of glucose Phosphorylation Breakdown to triose phosphates Asi AMP-P-As Conversion to pyruvate Release of pyruvate AMP-P +Asi Trypanosoma bruceiDependence on glycolysis Treatment Arsenate(AsO4 = Asi) Competitivewith Pi

  4. Trypanosoma bruceiDependence on glycolysis Treatment Something more specific? inhibitor1 Choice #1Starve the cell

  5. Trypanosoma bruceiDependence on glycolysis Treatment Something more specific? Choice #1Starve the cell Choice #2Stuff the cell pyruvate inhibitor2

  6. [I] 0 1 5 10 25 [ATP] [glucose]added Trypanosoma bruceiTest ideas for inhibitors inhibitor1 We knowcharacteristicsof enzymes

  7. One day (1/20) 32P 32S 1 atom of 32S20 atoms of 32P per day [32P] k = d[32S] / dt rateconstant concentration rate of change Characteristics of enzymesAnalogy of radioactivity How often does 32S appear? 1/20 of an atom per day? [X atoms of 32P] = __atoms of 32S per day

  8. One day (1/20) 32P 32S [32P] k = d[32S] / dt rateconstant concentration rate of change Characteristics of enzymesAnalogy of radioactivity Which quantity is an intrinsic characteristic?

  9. One day One day (1/3000000) (1/20) [32P] [14C] k k = d[14N] / dt = d[32S] / dt rateconstant rateconstant concentration concentration rate of change rate of change Characteristics of enzymesAnalogy of radioactivity

  10. [32P] k = d[32S] / dt rateconstant concentration rate of change Characteristics of enzymesChemical reactions AMP-P-As AMP-P +Asi

  11. = 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 =

  12. = 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

  13. = 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]

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

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

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

  17. Characteristics of enzymesChemical reactions (Program)

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

  19. 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

  20. = 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

  21. Characteristics of enzymesEnzymatic reactions inhibitor1

  22. = d[G6P] / dt = – rate of change k rateconstant Characteristics of enzymesEnzymatic reactions Glucose-6-phosphate Fructose-6-phosphate [G6P] concentration k  0

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

  24. Characteristics of enzymesEnzymatic reactions k1f k1cf G6P +E1 E1-complex F6P +E1 k1r k1cr d d[G6P] / dt = d[E1] / dt = d[E1-complex] / dt = d[F6P] / dt = -[G6P] [E1] k1f + [E1-complex] k1r -[G6P] [E1] k1f + [E1-complex] k1r+ [E1-complex] k1cf - [F6P][E1] k1cr +[G6P] [E1] k1f - [E1-complex] k1r- [E1-complex] k1cf + [F6P][E1] k1cr +[E1-complex] k1cf - [F6P][E1] k1cr

  25. Characteristics of enzymesEnzymatic reactions k1f k1cf G6P +E1 E1-complex F6P +E1 k1r k1cr k1if I+E1 E1-I-complex k1ir - [G6P] [E1] k1f + [E1-complex] k1r+[E1-complex] k1cf - [F6P][E1] k1cr - [I] [E1] k1if + [E1-I-complex] k1ir d[E1] / dt = d[I] / dt = d [E1-I-complex] / dt = d

  26. Characteristics of enzymesEnzymatic reactions k1f k1cf G6P +E1 E1-complex F6P +E1 k1r k1cr d d[G6P] / dt = d[E1] / dt = d[E1-complex] / dt = d[F6P] / dt = -[G6P] [E1] k1f + [E1-complex] k1r -[G6P] [E1] k1f + [E1-complex] k1r+ [E1-complex] k1cf - [F6P][E1] k1cr +[G6P] [E1] k1f - [E1-complex] k1r- [E1-complex] k1cf + [F6P][E1] k1cr +[E1-complex] k1cf - [F6P][E1] k1cr

  27. 0 (steady state assumption) Characteristics of enzymesEnzymatic reactions k1f k1c G6P +E1 E1-complex F6P +E1 k1r d[E1-complex] / dt = d[F6P] / dt = +[G6P] [E1] k1f - [E1-complex] k1r- [E1-complex] k1c + [F6P][E1] k1cr +[E1-complex] k1c - [F6P][E1] k1cr

  28. Characteristics of enzymesEnzymatic reactions k1f k1cf G6P +E1 E1-complex F6P +E1 k1r [G6P] [E1] k1f = [E1-complex] k1c - [E1-complex] k1r d[E1-complex] / dt = d[F6P] / dt = [G6P] ([Etotal]-[E1-complex]) k1f = [E1-complex] (k1c - k1r) +[G6P] [E1] k1f - [E1-complex] k1r- [E1-complex] k1c + [F6P][E1] k1cr +[E1-complex] k1c - [F6P][E1] k1cr

  29. Characteristics of enzymesEnzymatic reactions k1f k1cf G6P +E1 E1-complex F6P +E1 k1r [G6P] [E1] k1f = [E1-complex] k1c - [E1-complex] k1r d[F6P] / dt = [G6P] ([Etotal]-[E1-complex]) k1f = [E1-complex] (k1c - k1r) [G6P] [Etotal] k1f [G6P] [Etotal][G6P] + (k1c -k1r) [G6P] + (k1c -k1r)/k1f [E1-complex] = = +[E1-complex] k1c - [F6P][E1] k1cr

  30. Characteristics of enzymesEnzymatic reactions k1f k1cf G6P +E1 E1-complex F6P +E1 k1r d[F6P] / dt = +[E1-complex] k1c [G6P] [Etotal] k1c[G6P] + (k1c -k1r)/k1f = [G6P] [Etotal] k1c[G6P] + Km =

  31. Characteristics of enzymesEnzymatic reactions k1f k1cf G6P+E1 E1-complex F6P +E1 k1r d[F6P] / dt = +[E1-complex] k1c [G6P] [Etotal] k1c[G6P] + (k1c -k1r)/k1f = [G6P] [Etotal] k1c[G6P] + Km = [G6P][Etotal] k1c[G6P] + Km Max d[F6P] / dt = (Vmax) = [Etotal] k1c

  32. Characteristics of enzymesEnzymatic reactions k1f k1cf G6P+E1 E1-complex F6P +E1 k1r [G6P] VMax[G6P] + Km d[F6P] / dt = [S] VMax[S] + Km v (velocity) = d[product] / dt =

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