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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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slide1

Quantitative Modeling of Metabolic Networks

Sai Jagan Mohan, Ph.D.

Sonali Das, Ph.D.

Anupama Bhat.

slide2
Problem definition and approach

Modules

The glutathione module

The bioenergetics module

Complementary modeling approaches

Constraint based modeling

Metabolic control analysis (MCA)

Summary

Overview

hepatotoxicity prediction is hard

Genetic

Drug / Dose

Physiology / Disease

Hepatotoxicity prediction is hard

Metabolism

Hepatotoxicity

intricate and dynamic 'system-level' interactions.

our approach
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
cytotoxicity modules
The glutathione metabolism module

The bioenergetics module

Cytotoxicity Modules
  • Characteristics
  • Non-linear ODE’s
  • Two compartments
  • Fluxes: Enzyme Kinetics/Mass Action
enzymes non linearity
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}
perturbations

Vmax* [S]

Venzyme=

KM + [S]

Perturbations

Vmax[Enzyme]T

the glutathione module
The Glutathione Module

d [-GC] /dt = VGCS – VGS

d [GSH] /dt = VGS + VGR – VGPx – Vgsh2ss –Vgsh2ca –VGST – VgshC2M –VgshM2C

validation

Simulation

1

2

3

Validation

Drug: Ethacrynic Acid (EA)

Experimental

2

3

1

asymptotic analysis
Asymptotic Analysis

Simulation: Vgcs= 0

Validation

Toxin: Buthionine Sulfoximine (BSO)

Target: -GlutamylCysteine Synthetase (GCS)

Depletes glutathione with a half –life of ~ 2 hours

slide13

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

slide14

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)

future work
MCA for insights into control and regulation

Parameter estimation

Experimental validation

Scaling laws for metabolic networks

Future Work
the linear approximation19

SS continuation analysis

Parameter : VmaxGS

Asymptotic Simulation VGCS = 0

Asymptotic Simulation VGS = 0

Homeostasis

The Linear Approximation