Loading in 5 sec....

Quantitative Modeling of Metabolic NetworksPowerPoint Presentation

Quantitative Modeling of Metabolic Networks

- 227 Views
- Updated On :

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)

Related searches for Quantitative Modeling of Metabolic Networks

Download Presentation
## PowerPoint Slideshow about 'Quantitative Modeling of Metabolic Networks' - Antony

**An Image/Link below is provided (as is) to download presentation**

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript

Problem definition and approach

Modules

The glutathione module

The bioenergetics module

Complementary modeling approaches

Constraint based modeling

Metabolic control analysis (MCA)

Summary

Overview

Drug / Dose

Physiology / Disease

Hepatotoxicity prediction is hardMetabolism

Hepatotoxicity

intricate and dynamic 'system-level' interactions.

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

The glutathione metabolism module

The bioenergetics module

Cytotoxicity Modules- Characteristics
- Non-linear ODE’s
- Two compartments
- Fluxes: Enzyme Kinetics/Mass Action

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}

The Glutathione Module

d [-GC] /dt = VGCS – VGS

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

Asymptotic Analysis

Simulation: Vgcs= 0

Validation

Toxin: Buthionine Sulfoximine (BSO)

Target: -GlutamylCysteine Synthetase (GCS)

Depletes glutathione with a half –life of ~ 2 hours

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

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)

MCA for insights into control and regulation

Parameter estimation

Experimental validation

Scaling laws for metabolic networks

Future WorkParameter : VmaxGS

Asymptotic Simulation VGCS = 0

Asymptotic Simulation VGS = 0

Homeostasis

The Linear Approximation
Download Presentation

Connecting to Server..