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Lecture #12

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

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Lecture #12

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  1. Lecture #12 Building Networks

  2. 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

  3. Cofactors represent low flux but important pathways SOME BIOCHEMISTRY

  4. Nucleotide metabolism: associated with many diseased states

  5. Table of mutations & associated pathology

  6. Forming a sub-network AMP metabolism

  7. AMP Salvage Network

  8. AMP Salvage: S Matrix internal exchange

  9. AMP Salvage: pathway vectors

  10. AMP Salvage Network:dynamic simulation to AMP increase

  11. AMP Salvage: Dynamic Simulation One of the degradation routes is activated

  12. Adding AMP Salvage: Forming Integrated Networks

  13. Glycolysis, PPP, & AMP: a metabolic network

  14. Glycolysis, PPP, & AMP: S matrix

  15. Glycolysis, PPP, & AMP: pathway vectors Pyr/Lac exchange Glycolysis AMP degradation Integrated PPP AMP degradation AMP degradation Futile cycle Salvage pathway

  16. Integrated Model: Simulation • Comparing responses from two models, glycolysis + PPP +/- AMP metabolism • The AMP I/O behavior • More damped than before

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

  18. 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

  19. Variation (SNP) in DNA sequence Change in enzyme kinetic properties Phenotypic expression of SNP Affects systemic functioning of cell ATP ADP GLU G6P HK genotype normal model reconstruction pathological Hexokinase: Chromosome 10 p11.2 (1667 T -> C) Unable to maintain osmotic balance under stringent ATP loads -> cells lyse Decrease in rate of glycolysis and ATP production Vmax and Km values altered by SNP

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