MIT6_047f08_lec21_slide21

MIT6_047f08_lec21_slide21 - MIT OpenCourseWare...

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MIT OpenCourseWare http://ocw.mit.edu 6.047 / 6.878 Computational Biology: Genomes, Networks, Evolution Fall 2008 For information about citing these materials or our Terms of Use, visit: http://ocw.mit.edu/terms .
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Introduction to Steady State Metabolic Modeling 6.047/6.878 Computational Biology: Genomes, Networks, Evolution
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Systems Biology and Metabolic Modeling Steady State Metabolic Modeling Expression, Regulation, and Steady State Metabolic Modeling Advanced Systems Modeling
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What is Metabolism? The totality of all chemical reactions that occur in living matter ” Matthews & van Holde, Biochemistry Most commonly, these refer to reactions involved in 1) The generation and storage of energy and oxidation- reduction products - ATP, NADH, NADPH 2) The creation or destruction of cell structural components - Proteins, Lipids, Carbohydrates, Nucleic Acids But we should also properly include: 3) The transduction and transmission of information - More commonly studies as signaling and genetics today
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Why Model Metabolism? • Predict the effects of drugs on metabolism – e.g. what genes should be disrupted to prevent mycolic acid synthesis • Interpret gene expression data in the context of metabolism – e.g. what metabolic state corresponds to a particular expression profile • Many infectious disease processes involve microbial metabolic changes – e.g. switch from sugar to fatty acid metabolism in TB in macrophages
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Enzymes Δ G o of reaction = --- 4 kcal/mol Reactants Products Course of reaction Final state Initial state Glucose 6-phosphate + ADP E A of uncatalyzed reaction in forward direction E A of enzyme-catalyzed reaction in forward direction Transition state (activated complex between glucose and ATP) Glucose + ATP Free energy Figure by MIT OpenCourseWare.
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Reaction Rates A +2B 3C Formation rates Reaction Rate = Reaction Velocity = Reaction Flux d[A] d[B] d[C] dt fA fB fC vv v == = d[A] 1 d[B] 1 d[C] = = dt 2 dt 3 dt v =
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Steady State Assumptions • Dynamics are transient • At appropriate time- scales and conditions, metabolism is in steady state A B D C vin v1 v3 v2 v5 vout v4 Two key implications 1. Fluxes are roughly constant 2. Internal metabolite concentrations are constant [ ] 13 0 dA vin v v dt =− =
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Metabolic Flux Input fluxes Volume of pool of water = metabolite concentration Output fluxes Figure by MIT OpenCourseWare.
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Reaction Stoichiometries Are Universal The conversion of glucose to glucose 6-phosphate always follows this stoichiometry : 1ATP + 1glucose = 1ADP + 1glucose 6-phosphate This is chemistry not biology . Biology => the enzymes catalyzing the reaction Enzymes influence rates and kinetics Activation energy Substrate affinity Rate constants Not required for steady state modeling!
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Metabolic Flux Analysis Use universal reaction stoichiometries to predict metabolic network capabilities at steady state * *Not precise, but more precision will come in later slides (Famili et al (2003) PNAS) Famili, Iman, et al. "Saccharomyces Cerevisiae Phenotypes can be Predicted by Using Constraint-based Analysis of a Genome-scale Reconstructed Metabolic Network.
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MIT6_047f08_lec21_slide21 - MIT OpenCourseWare...

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