Intro_metmodeling_2010

Intro_metmodeling_2010 - Introduction to Steady State...

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1 Introduction to Steady State Metabolic Modeling Concepts • What is a metabolic network? • Modeling chemical reactions as flows • Enzyme Kinetics, Michaelis-Menten equation • Transcription (Repression and Induction) • Mathematical notation and solving systems of ODEs computationally using numerical integration Applications Predicting knockout phenotypes Quantitative Flux Prediction Introduction to Steady State Metabolic Modeling Reading (today) Section 2.2.1-2.2.2 in Systems Biology by Klipp et al. For next week: Section 2.1 Sources Shanks lecture notes, 2008 Notes: David Fell talk: The Metabolic Network
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2 Why Model Metabolism? • Predict the effects of drugs on metabolism – e.g. what genes should be disrupted to prevent mycolic acid synthesis • Many infectious disease processes involve microbial metabolic changes – e.g. switch from sugar to fatty acid metabolism in TB in macrophages Genome Wide View of Metabolism Streptococcus pneumoniae • Explore capabilities of global network How do we go from a pretty picture to a model we can manipulate?
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3 Online Metabolic Databases Pathlogic/BioCyc Kegg Metabolic Pathways Metabolites glucose Enzymes phosphofructokinase 1 F6P => 1 FBP Kinetics Regulation gene regulation metabolite regulation hexokinase phosphoglucoisomerase phosphofructokinase aldolase triosephosphate isomerase G3P dehydrogenase phosphoglycerate kinase phosphoglycerate mutase enolase pyruvate kinase
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4 Metabolic Modeling: The Dream uptake Steady State Assumptions • Dynamics are transient • At appropriate time- scales and conditions, metabolism is in steady state A B uptake conversion secretion Two key implications 1. Fluxes are roughly constant 2. Internal metabolite concentrations are constant [ ] constant 0 uptake d A dt t Conversion t Steady state
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5 Metabolic Flux Output fluxes Input fluxes Volume of pool of water = metabolite concentration Slide Credit: Jeremy Zucker 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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6 Metabolic Flux Analysis Use universal reaction stoichiometries to predict network metabolic capabilities at steady state Stoichiometry As Vectors • We can denote the stoichiometry of a reaction by a vector of coefficients • One coefficient per metabolite – Positive if metabolite is produced – Negative if metabolite is consumed Example: Metabolites: [ A B C D ] T Reactions: 2A + B -> C C -> D Stoichiometry Vectors: [ -2 -1 1 0 ] T [ 0 0 -1 1 ] T
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Intro_metmodeling_2010 - Introduction to Steady State...

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