Lecture #12

Building Networks

Outline

• AMP biosynthesis and degradation– A dynamic balance (before the input is fixed)

• Genetic defects– Quite common in this pathway

• The AMP sub-network– Formulation, balancing, QC/QA, simulation

• Integration with coupled pathways– Integration issues are many, many points of contact

• Dynamic simulation for 50% in rate of ATP use• Path towards whole cell models

SOME BIOCHEMISTRYCofactors represent low flux but important pathways

Nucleotide metabolism:

associated with many diseased

states

Table of mutations & associated pathology

AMP metabolismForming a sub-network

AMP Salvage Network

AMP Salvage: S Matrixinternal exchange

AMP Salvage: pathway vectors

AMP Salvage Network:dynamic simulation to AMP increase

AMP Salvage: Dynamic Simulation

One of the degradation routes is activated

Adding AMP Salvage: Forming Integrated Networks

Glycolysis, PPP, & AMP: a metabolic network

Glycolysis, PPP, & AMP: S matrix

Glycolysis, PPP, & AMP: pathway vectors

Glycolysis

Integrated PPP AMP degradation

Pyr/Lac exchange

Futile cycleSalvage pathway

AMPdegradation

AMPdegradation

Integrated Model: Simulation

• Comparing responses from two models, glycolysis + PPP +/- AMP metabolism

• The AMP I/O behavior• More damped than

before

Toward a whole cell simulation: Metabolic demands and the ‘machine’ that meets them

Summary• Purine nucleotide metabolism is complicated and has many

pathological states associated with it• Nucleotides are synthesized and degraded to be in a steady

state that is dynamic and can respond to perturbations• A sub-network for AMP metabolism can be built and

synthesized, and its responses simulated• It can be integrated with the coupled glycolysis+PP

pathways to form a network model• Several integration issues show up• The number of pathways characterizing the null space

grows• The model can be simulated and the dampening effect of

the response to increased ATP rate of utilization demonstrated

• This network model can be expanded to a whole cell model

genotype

Variation (SNP) in

DNA sequence

Hexokinase: Chromosome

10 p11.2 (1667 T -> C)

model

Decrease in rate of glycolysis and ATP

production

Affects systemic functioning of

cell

Unable to maintain osmotic balance under stringent

ATP loads -> cells lyse

Phenotypic expression of

SNP

normal

pathological

GLU

ATP

G6PHK

ADP

0

V’max

0.5 V’max

S’=K’m SConcentration

0

V’max

0.5 V’max

S’=K’m SConcentration

Change in enzyme kinetic

properties

Vmax and Km values altered

by SNP

reconstruction