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Scenario 5 Friday, 18 November 2011 Welcome to Integrated Bioinformatics Metabolic Modeling Click to start This is best viewed as a slide show. To view.

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Presentation on theme: "Scenario 5 Friday, 18 November 2011 Welcome to Integrated Bioinformatics Metabolic Modeling Click to start This is best viewed as a slide show. To view."— Presentation transcript:

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

2 Friday, 16 November 2012 What I learned from the questionnaires The biological problem Overview of glycolysis Modeling a spontaneous reaction (ADP-As.pl) V max and K m 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 I learn best by doing, not seeing nor hearing. 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.

6 What things work I learn best by doing, not seeing nor hearing. I am very weak when it comes to math. 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,...

7 Trypanosoma brucei Causative agent of sleeping sickness Life Cycle Central Nervous System Death

8 Trypanosoma brucei How 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 Trypanosoma brucei How to stop it? Glucose ATP Glycolysis Pyruvate ATP Glycolysis Pyruvate Citric Acid Cycle ATP ThemUs

10 Trypanosoma brucei How to stop it? Glucose ATP Glycolysis Pyruvate ATP Glycolysis Pyruvate Citric Acid Cycle ATP ThemUs

11 Alternative to exhaustive lab testing inhibitor 1 Glucose Glucose-6-P + ATP + ADP Hexokinase Symbolically dG6P/dt = k f [Glc][ATP] Mathematically $dG6P_dt = $kf*$glc*$atp Computationally … exhaustive computational modeling

12 Glycolysis dG6P/dt = +k f2 [Glc][ATP] -k f3 [G6P] dFDP/dt = +k f4 [F6P][ATP]-k f5 [FDP] dGlc/dt = +k f1 [Glc x ] -k r2 [Glc] -k f2 [Glc][ATP] dF6P/dt = +k f3 [G6P]-k r3 [F6P] -k f4 [F6P][AT] dDHAP/dt = +k f5 [FDP]+k r6 [G3P] -k f6 [DHAP] dG3P/dt = +k f5 [FDP]+k f6 [DHAP] -k r6 [G3P] -k f7 [G3P][NAD]+k ry [13PGA][NADH] d13PGA/dt = k f7 [G3P][NAD]-k ry [13PGA][NADH] -k f8 [13PGA][ADP]+k r8 [3PGA][ATP]... 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 What is glycolysis blood cell Oxidation state glucose O OHOH HOHO OHOH OHOH OHOH electronegativity O > C > H O OHOH 2 pyruvate O 2 ATP + OHOH O O OHOH <<<

16 What is glycolysis bloodcell glucose O OHOH 2 pyruvate O O OHOH HOHO OHOH OHOH OHOH permease

17 What is glycolysis bloodcell glucose O OHOH 2 pyruvate O O OHOH HOHO OHOH OHOH OHOH permease

18 What is glycolysis bloodcell glucose O OHOH 2 pyruvate O O OHOH HOHO OHOH OHOH OHOH permease O O O-P-OO-P-O -Adenosine O O O-P-OO-P-O O O O-P-OO-P-O ATP Anhydride (acid + acid)

19 What is glycolysis bloodcell glucose O OHOH 2 pyruvate O permease O O O-P-OO-P-O -Adenosine O O O-P-OO-P-O O O O-P-OO-P-O ATP Anhydride (acid + acid) O OHOH HOHO OHOH OHOH OHOH

20 What is glycolysis bloodcell glucose O OHOH 2 pyruvate O permease O O O-P-OO-P-O -Adenosine O O O-P-OO-P-O O O O-P-OO-P-O ADP Anhydride (acid + acid) O OHOH OHOH OHOH OHOH

21 What is glycolysis bloodcell glucose O OHOH 2 pyruvate O permease -Adenosine O O O-P-OO-P-O O O O-P-OO-P-O ADP Anhydride (acid + acid) O OHOH OHOH OHOH OHOH O

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

23 What is glycolysis O OHOH 2 pyruvate O glucose O OHOH HOHO OHOH OHOH OHOH 2 ATP + glucose-6P Hexokinase ??? O OHOH OHOH OHOH OHOH O O OHOH OHOH OHOH OHOH O ATP ADP ???

24 What is glycolysis O OHOH 2 pyruvate O glucose O OHOH HOHO OHOH OHOH OHOH 2 ATP + glucose-6P Hexokinase O OHOH OHOH OHOH OHOH O O OHOH OHOH OHOH OHOH O O OHOH OHOH OHOH OHOH O fructose-6P Hexose-P isomerase ATP ADP

25 What is glycolysis O OHOH 2 pyruvate O glucose O OHOH HOHO OHOH OHOH OHOH 2 ATP + glucose-6P Hexokinase O OHOH OHOH OHOH OHOH O O OHOH O OHOH OHOH O O OHOH OHOH OHOH OHOH O fructose-6P Hexose-P isomerase ATP ADP fructose-1,6 diP Phospho fructokinase

26 What is glycolysis O OHOH 2 pyruvate O glucose O OHOH HOHO OHOH OHOH OHOH 2 ATP + glucose-6P Hexokinase O OHOH OHOH OHOH OHOH O O OHOH O OHOH OHOH O O OHOH OHOH OHOH OHOH O fructose-6P Hexose-P isomerase ATP ADP fructose-1,6 diP Phospho fructokinase O O O OHOH OHOH O Dihydroxy acetone P (DHAP) glyceraldehyde 3-P (Gla3P) Aldolase

27 What is glycolysis O OHOH 2 pyruvate O glucose O OHOH HOHO OHOH OHOH OHOH 2 ATP + glucose-6P Hexokinase O OHOH OHOH OHOH OHOH O O OHOH O OHOH OHOH O O OHOH OHOH OHOH OHOH O fructose-6P Hexose-P isomerase ATP ADP fructose-1,6 diP Phospho fructokinase O O O OHOH OHOH O DHAP Gla3P Aldolase Triose P isomerase

28 What is glycolysis O OHOH 2 pyruvate O glucose O OHOH HOHO OHOH OHOH OHOH 2 ATP + glucose-6P Hexokinase O OHOH OHOH OHOH OHOH O O OHOH O OHOH OHOH O O OHOH OHOH OHOH OHOH O fructose-6P Hexose-P isomerase ATP ADP fructose-1,6 diP Phospho fructokinase O O O OHOH OHOH O DHAP Gla3P Aldolase Triose P isomerase O OHOH O O O NAD+ NADH O OHOH O O ADP ATP Gla 3-P dehydrogenase 3-P-glycerate (3PG)

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

30 What is glycolysis O OHOH 2 pyruvate O glucose O OHOH HOHO OHOH OHOH OHOH 2 ATP + glucose-6P Hexokinase O OHOH OHOH OHOH OHOH O O OHOH O OHOH OHOH O O OHOH OHOH OHOH OHOH O fructose-6P Hexose-P isomerase ATP ADP fructose-1,6 diP Phospho fructokinase O O O OHOH OHOH O DHAP Gla3P Aldolase Triose P isomerase O OHOH O O O NAD+ NADH O OHOH O O ADP ATP Gla 3-P dehydrogenase 3-P-glycerate (3PG) O O OHOH O H 2-P-glycerate (3PG) O O O Ketone or aldehyde O O Enol H2OH2O P-Gla mutase Enolase Pyr Kinase ATP ADP

31 Why is glycolysis O OHOH 2 pyruvate O glucose O OHOH HOHO OHOH OHOH OHOH 2 ATP + glucose-6P Hexokinase O OHOH OHOH OHOH OHOH O O OHOH O OHOH OHOH O O OHOH OHOH OHOH OHOH O fructose-6P Hexose-P isomerase ATP ADP fructose-1,6 diP Phospho fructokinase O O O OHOH OHOH O DHAP Gla3P Aldolase Triose P isomerase O OHOH O O O NAD+ NADH O OHOH O O ADP ATP Gla 3-P dehydrogenase 3-P-glycerate (3PG) O O OHOH O H 2-P-glycerate (3PG) O O O H2OH2O P-Gla mutase Enolase Pyr Kinase ATP ADP

32 Why is glycolysis O OHOH 2 pyruvate O glucose O OHOH HOHO OHOH OHOH OHOH 2 ATP + glucose-6P Hexokinase O OHOH OHOH OHOH OHOH O O OHOH O OHOH OHOH O O OHOH OHOH OHOH OHOH O fructose-6P Hexose-P isomerase ATP ADP fructose-1,6 diP Phospho fructokinase O O O OHOH OHOH O DHAP Gla3P Aldolase Triose P isomerase O OHOH O O O NAD+ NADH O OHOH O O ADP ATP Gla 3-P dehydrogenase 3-P-glycerate (3PG) O O OHOH O H 2-P-glycerate (3PG) O O O H2OH2O P-Gla mutase Enolase Pyr Kinase ATP ADP

33 Trypanosoma brucei How to exploit dependence on glycolysis? Arsenate (AsO 4 = As i ) Competitive with P i Treatment blood cell

34 Trypanosoma brucei How arsenate poisons glycolysis? O O O-P-OO-P-O O-P-O-CH2—CH—C O O O H NAD + NADH ADP ATP O-P-O-CH2—CH—C- O O O O O O-P-OO-P-O Glyceraldehyde-3-P O-P-O-CH2—CH—C-O O O O 3-P-Glycerate OHOH OHOH OHOH Normal glycolysis

35 O O O-As-O O-P-O-CH2—CH—C O O O H NAD + NADH ADP ATP Glyceraldehyde-3-P O-P-O-CH2—CH—C-O O O O 3-P-Glycerate O-P-O-CH2—CH—C- O O O O O O-As-O H2OH2O O O + OHOH OHOH OHOH Trypanosoma brucei How arsenate poisons glycolysis? Poisoned glycolysis

36 How to model this reaction?

37

38 Characteristics of enzymes Chemical reactions [AMP-P-As] concentration k rate constant = d[AMP-P ] / dt rate of change AMP-P-AsAMP-P +As i = = d[As i ] / dt rate of change = – = d[AMP-P-As i ] / dt rate of change

39 Characteristics of enzymes Chemical reactions [AMP-P-As] concentration k rate constant AMP-P-AsAMP-P +As i = – = d[AMP-P-As i ] / dt rate of change [S] k = – = d[S] / dt A differential equation

40 Characteristics of enzymes Chemical reactions [AMP-P-As] concentration k rate constant AMP-P-AsAMP-P +As i = – = d[AMP-P-As i ] / dt rate of change = d[S] / dt A differential equation = –k[S] = [S] Its solution?

41 Characteristics of enzymes Chemical reactions [AMP-P-As] concentration k rate constant AMP-P-AsAMP-P +As i = – = d[AMP-P-As i ] / dt rate of change = d[S] / dt A differential equation = –k[S] = S 0 e -k(t-to) [S] Its solution? = S 0 (–k) e -k(t-to) = -k S 0 e -k(t-to) = -k [S] = d[S] / dt Check:

42 Characteristics of enzymes Chemical reactions = d[S] / dt A differential equation = –k[S] = S 0 e -k(t-to) [S] Its solution? = S 0 (–k) e -k(t-to) = -k S 0 e -k(t-to) = -k [S] = d[S] / dt Check: Write an equation for the rate of increase of a rabbit population over time. (ignore all environmental effects) [R] = R 0 2 t/D

43 Characteristics of enzymes Chemical reactions [AMP-P-As] concentration k rate constant AMP-P-AsAMP-P +As i = – = d[AMP-P-As i ] / dt rate of change = d[S] / dt A differential equation = –k[S] = S 0 e -k(t-to) [S] Its solution? = S 0 (–k) e -k(t-to) = -k S 0 e -k(t-to) = -k [S] = d[S] / dt Check:

44 Characteristics of enzymes Chemical reactions = d[S] / dt = –k[S] [S] = S 0 e -k(t-to)

45 Characteristics of enzymes Chemical reactions

46 [S] = Δt [S] = S 0 e -k(t-to) S0S0

47 Characteristics of enzymes Chemical reactions Δt = d[S] / dt = –k[S] S0S0 + Δt d[S] / dt[S] =S0S0

48 Characteristics of enzymes Chemical 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 Characteristics of enzymes Chemical reactions = d[S] / dt = –k[S] [S] = S 0 e -k(t-to)

50 Characteristics of enzymes Chemical reactions Δt S0S0

51 Characteristics of enzymes Chemical reactions Δt = d[S] / dt = –k[S] S0S0 + Δt d[S] / dt[S] =S0S0 Slope 0 = -k[S 0 ] [S 1 ] =+ Δt d[S] / dtS0S0 Slope 1 = -k[S 1 ] Use average of Slope 0 and Slope 1

52 Characteristics of enzymes Chemical reactions Δt = d[S] / dt = –k[S] S0S0 + Δt d[S] / dt[S] =S0S0 Slope 0 = -k[S 0 ] [S 1 ] =+ Δt d[S] / dtS0S0 Slope 1 = -k[S 1 ] Use average of Slope 0 and Slope 1 Runge-Kutta method

53 inhibitor 1 Characteristics of enzymes Enzymatic reactions

54 [G6P] concentration k rate constant Glucose-6-phosphate Fructose-6-phosphate = = d[F6P] / dt rate of change k ~ 0 ??? What is the rate equation?

55 Characteristics of enzymes Enzymatic reactions

56 G6P + E G6P·EF6P·EF6P + E E-complex d[product] / dt = [S] V Max [S] + K m v (velocity) = [product] =+ Δt d[S] / dtS0S0

57 Characteristics of enzymes Enzymatic reactions d[product] / dt = [S] V Max [S] + K m v (velocity) = velocity [S]

58 Modeling systems of metabolic reactions Spontaneous vs Enzyme-catalyzed Spontaneous reaction [S] product v = k [AMP~P~As]

59

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