Lecture #11

Coupling Pathways

Outline• Some biochemistry• The pentose pathway;

– a central metabolic pathway producing pentoses and NADPH

• Co-factor coupling – NADPH, CO2, GSH

• The stoichiometric matrix for PPP– Its null spaces

• Setting up a simulation model– Steady state

• Coupling to glycolysis• Interpreting the results from simulation

– Concentrations, fluxes, pools, ratios

BIOCHEMISTRY PRIMER

PPP: the oxidative and non-oxidative

branches

oxidative

non-oxidative

Coupling w/glycolysis

PPP: oxidative branch

Glutathione buffers NADPH: GSH + NADP GSSG + NADPH

23DPG

THE PENTOSE PHOSPHATE PATHWAY

Coupling Pathways

Reaction map

Pentose Phosphate PathwayCompounds

Elemental compositionReactions

PPP: S Matrix and Simulation

Stoichiometric matrix Reaction map

Pathways

PPP: Phase

Portraits

In to R5P node

Out off R5P node PPP exit into glycolysis

PPP exit into R5P synthesis

GLYCOLYSIS & the PENTOSE PHOSPHATE PATHWAY

Coupling Pathways

Coupled pathways: Glycolysis and the pentose pathway

The integrated S matrix

Coupling

Gly & PPP: Selected basis based on biochemical intuition

Kinetics Constants:

PERCs

SIMULATING FLUXES AND CONCENTRATIONS

Biochemistry

Glycolysis & PPP:Energy load

50% increase in this rate

Glycolysis & PPP: Phase Portraits

vPYR

vATP

vAMP

Glycolysis & PPP:Redox load

Double this rate

Dynamic Simulation

Increase in PPP fluxesDecrease in

glycolysis fluxes

Decrease in glycolytic concIncrease on PPP conc

SIMULATING POOLSSystems biology

Pools

Pooling matrixPx

Size and dynamics:PSv

SIMULATING RATIOSPhysiology

Dynamic Simulation

New slide

• Add more explanation of the ratios

Summary• The pentose pathway can be described in a similar way

as glycolysis• A simulation model can be formulated• The two stoichiometric matrices describing the two

pathways can be merged• The coupling metabolites are G6P, F6P, GAP• The structure of the null space for glycolysis alone and

the coupled pathways is similar• Pools and ratios can be formed as before• Simulation to 50% increase in rate of utilization of ATP is

similar to that of glycolysis alone • Systems biology shows up

– Definition of pathways, definition of pools