Quantitative Modeling of Metabolic Networks

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Quantitative Modeling of Metabolic Networks
Sai Jagan Mohan, Ph.D. Sonali Das, Ph.D. Anupama
Bhat.
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Overview

• Problem definition and approach
• Modules
• The glutathione module
• The bioenergetics module
• Complementary modeling approaches
• Constraint based modeling
• Metabolic control analysis (MCA)
• Summary

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Hepatotoxicity prediction is hard
Metabolism
Hepatotoxicity intricate and dynamic
'system-level' interactions.
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Our Approach
A comprehensive model of homeostasis metabolism
in a liver cell Toxicity
Drug-induced perturbations

• Hepatotoxicity Mechanisms
• Cell Death of Functional Liver Cells
• Impaired Bile Flow
• Faulty Fat Processing

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Cytotoxicity Modules

• The glutathione metabolism module
• The bioenergetics module

• Characteristics
• Non-linear ODEs
• Two compartments
• Fluxes Enzyme Kinetics/Mass Action

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Enzymes gt Non-linearity
VGCS VmaxATPGluCys/?KmATPKmGlu(1GSH/
KiGSH)KmCys 1Glu/KmGlu(1GSH/KiGSH)
Glu Cys/ KmGlu (1GSH/KiGlu)KmCysGluATP
/KmATPKmGlu(1GSH/KiGSH) GluCysATP/?KmAT
PKmGlu(1GSH/KiGSH) KmCys
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Perturbations
Vmax ? EnzymeT
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The Oxidative Stress Module
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The Glutathione Module
d ?-GC /dt VGCS VGS d GSH /dt VGS
VGR VGPx Vgsh2ss Vgsh2ca VGST VgshC2M
VgshM2C
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Validation
Drug Ethacrynic Acid (EA)
Experimental
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3
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Asymptotic Analysis
Simulation Vgcs 0
Validation
Toxin Buthionine
Sulfoximine (BSO) Target
?-GlutamylCysteine Synthetase
(GCS) Depletes glutathione with a half life of
2 hours
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Thought simulation
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Metabolic Network for Cellular Energetics
21 state variables 17 differential equations 4
conservation laws
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Conservation Laws
Adenylate kinase (ADK) reaction is rapid
(operates near equilibrium)
ATPAMP
constant
Keq


ADPADP
Total adenine pool in the cytosol ATPe
ADPeAMPe constant
(Ataullakhanov Vitvitsky Bioscience Reports.
2002 22501-511)
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Constraint Based Modeling
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Metabolic Control Analysis (MCA)
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Future Work

• MCA for insights into control and regulation
• Parameter estimation
• Experimental validation
• Scaling laws for metabolic networks

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The Linear Approximation
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The Linear Approximation