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Lecture #14 Regulatory Enzymes

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Outline Phosphofructokinase-1 Describing the bound states of activators and inhibitors Integration with glycolysis

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Phosphofructokinase-1

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Metabolic Role

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Background Tetramer 3 Isoforms: M,L,P (muscle, liver, platelet) 2 Natural Forms: R,T (relaxed, tight) Known inhibitors: ATP, citrate, PEP Known activators: AMP, cAMP, Pi, SO 4, FBP Catalytic Activity:

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PFK sub-network

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The Catalytic Mechanism: binding of the two substrates followed by the chemical reaction 1) 2) 3)

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AMP and ATP as regulatory ligands activation inhibition conformation

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Stoichiometric Matrix

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Pools and Ratios PFK – R state –All forms of R 0 + R 1 + R 2 + R 3 + R 4 PFK – T state –All forms of T 0 + T 1 + T 2 + T 3 + T 4 PFK – R catalytic state –All forms of R i,AF Ratios At steady state ~ r R = 90%, r cat = 12%

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DETERMINING THE STEADY STATE

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Let’s revisit the subnetwork Equilibrium v = 0 Steady State

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Constraints on the Network Total mass balance: Total flux: Known equilibrium constants

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Solving for the concentrations Note: When equilibrium constants are plugged in, all forward rate constants in equilibrium reactions fall out, leaving only the catalytic rate constants

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Estimating the catalytic rate constants Chosen Steady State k PFK k F6P k ATP

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INTEGRATION WITH GLYCOLYSIS

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Stoichiometric Matrix

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DYNAMIC SIMULATIONS

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Dynamic Simulation Two perturbations –Standard 50% increase in ATP utilization –Additional 15% decrease in ATP utilization

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Glycolysis Dynamics

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50% increase in ATP utilization15% decrease in ATP utilization

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Summary Enzymes can be explicitly represented in simulation modules as molecules Enzymes have many binding states Binding of regulators (inhibitors and activators) alters protein activity; leading to a ‘tug of war’ amongst the functional states (i.e. T and R) Ratios that represent what fraction of the enzyme is in an active or inhibited functional states can be formed Enzyme sub-networks can be seamlessly integrated with the scaffold metabolic network Regulator binding to PFK, a key glycolytic regulatory enzyme, was demonstrated

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