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

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Quantitative Modeling of Metabolic Networks

Sai Jagan Mohan, Ph.D.

Sonali Das, Ph.D.

Anupama Bhat.


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Problem definition and approach

Modules

The glutathione module

The bioenergetics module

Complementary modeling approaches

Constraint based modeling

Metabolic control analysis (MCA)

Summary

Overview


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Genetic

Drug / Dose

Physiology / Disease

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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The glutathione metabolism module

The bioenergetics module

Cytotoxicity Modules

  • Characteristics

  • Non-linear ODE’s

  • Two compartments

  • Fluxes: Enzyme Kinetics/Mass Action


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Enzymes => Non-linearity

  • VGCS =

  • Vmax{[ATP][Glu][Cys]/KmATPKmGlu(1+[GSH]/KiGSH)KmCys}

  • {1+[Glu]/KmGlu(1+[GSH]/KiGSH) + [Glu] [Cys]/KmGlu(1+[GSH]/KiGlu)KmCys+[Glu][ATP]/KmATPKmGlu(1+[GSH]/KiGSH) + [Glu][Cys][ATP]/KmATPKmGlu(1+[GSH]/KiGSH) KmCys}


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Vmax* [S]

Venzyme=

KM + [S]

Perturbations

Vmax[Enzyme]T



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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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Simulation

1

2

3

Validation

Drug: Ethacrynic Acid (EA)

Experimental

2

3

1


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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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Malate-Aspartate shuttle

NADH

NAD

Energy

Utilisation

PFK

ATP

ADP+Pi

ANT

NADH

NAD

Glycolysis

OXPHOS

TCA

cycle

ADP+Pi

ATP

ADP+Pi

ATP

NADH

NAD

Mitochondria

MAL

MAL-

mito

Cytosol

Metabolic Network for Cellular Energetics

21 state variables

17 differential equations

4 conservation laws


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ADK

2ADP

ATP + AMP

Keq

Conservation Laws

Adenylate kinase (ADK) reaction is rapid (operates near equilibrium)

ATP*AMP

constant

Keq

=

=

ADP*ADP

Total adenine pool in the cytosol = ATPe+ ADPe+AMPe= constant

(Ataullakhanov & Vitvitsky Bioscience Reports. 2002 22:501-511)




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MCA for insights into control and regulation

Parameter estimation

Experimental validation

Scaling laws for metabolic networks

Future Work



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SS continuation analysis

Parameter : VmaxGS

Asymptotic Simulation VGCS = 0

Asymptotic Simulation VGS = 0

Homeostasis

The Linear Approximation


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