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Biomolecular Interaction: Enzyme + Substrate

LSM3241: Bioinformatics and Biocomputing Lecture 9: Biological Pathway Simulation Prof. Chen Yu Zong Tel: 6874-6877 Email: yzchen@cz3.nus.edu.sg http://xin.cz3.nus.edu.sg Room 07-24, level 7, SOC1, NUS. Biomolecular Interaction: Enzyme + Substrate.

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Biomolecular Interaction: Enzyme + Substrate

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  1. LSM3241: Bioinformatics and BiocomputingLecture 9: Biological Pathway Simulation Prof. Chen Yu ZongTel: 6874-6877Email: yzchen@cz3.nus.edu.sghttp://xin.cz3.nus.edu.sgRoom 07-24, level 7, SOC1, NUS

  2. Biomolecular Interaction: Enzyme + Substrate • This is a generalization of how a biochemist might represent the function of enzymes. E + S ==> E + P

  3. Biomolecular Interaction: Enzyme + Substrate • Here is an example of the generalization represented by two different ways. E + S ==> E + P kinase-ATP complex + inactive-enzyme ==> Kinase + ADP + active enzyme K P ATP ADP

  4. Biomolecular Interaction: Enzyme + Substrate • This is another representation. inactiveenzyme Kinase-ATPcomplex Activeenzyme ADP

  5. Spoke and Matrix Models of Protein-Protein Interactions Possible Actual Topology Matrix Vrp1 (bait), Las17, Rad51, Sla1, Tfp1, Ypt7 Spoke Theoretical max. no. of interactions, but many FPs Simple model Intuitive, more accurate, but canmisrepresent Bader&Hogue Nature Biotech. 2002 Oct 20(10):991-7

  6. Cell Polarity Cell Wall Maintenance Cell Structure Mitosis Chromosome Structure DNA Synthesis DNA Repair Unknown Others Synthetic Genetic Interactions in Yeast Tong, Boone

  7. Metabolic Pathway: ATP Production • Glycolysis • Phosphorylation • Pyruvate • Anaerobic respiration • Lactate production • 2 ATPs produced

  8. Cyclic Metabolic Pathway

  9. Methods of Metabolic Engineering

  10. Generic Signaling Pathway Signal Receptor (sensor) Transduction Cascade Targets Response Metabolic Enzyme Cytoskeletal Protein Gene Regulator Altered Metabolism Altered Gene Expression Altered Cell Shape or Motility

  11. Components of Signaling What can be the Signal? External message to the cell • Peptides / Proteins- Growth Factors • Amino acid derivatives - epinephrine, histamine • Other small biomolecules - ATP • Steroids, prostaglandins • Gases - Nitric Oxide (NO) • Photons • Damaged DNA • Odorants, tastants Signal = LIGAND Ligand- A molecule that binds to a specific site on another molecule, usually a protein, ie receptor

  12. Components of Signaling What are Receptors? Sensors, what the signal/ligand binds to initiate ST Hydrophillic Ligand Cell-Surface Receptor • Cell surface • Intracellular Plasma membrane Hydrophobic Ligand Carrier Protein Intracellular Receptor Nucleus

  13. Generic SignalTransduction

  14. RTK SignalTransduction

  15. Signal Transduction Downstream effectors Protein Signaling Modules (Domains) SH2 and PTB bind to tyrosine phosphorylated sites SH3 and WW bind to proline-rich sequences PDZ domains bind to hydrophobic residues at the C-termini of target proteins PH domains bind to different phosphoinositides FYVE domains specifically bind to Pdtlns(3)P (phosphatidylinositol 3-phosphate)

  16. Mechanisms for Activation of Signaling Proteins by RTKs Activation by membrane translocation Activation by a conformational change Activation by tyrosine phosphorylation

  17. Mechanisms for Attenuation & Termination of RTK Activation 1) Ligand antagonists 2) Receptor antagonists 3) Phosphorylation and dephosphorylation 4) Receptor endocytosis 5) Receptor degradation by the ubiquitin-proteosome pathway

  18. Activation of MAPK Pathways by Multiple Signals Growth, differentiation, inflammation, apoptosis -> tumorigenesis

  19. Overview of MAPK Signaling Pathways

  20. The MAPK Pathway Activated by RTK

  21. P RTK ST- PI3K pathway

  22. Apoptosis Pathways

  23. TGF Pathway

  24. Constructing a pathway model:things to consider 1.Dynamic nature of biological networks. Biological pathway is more than a topological linkageof molecular networks. Pathway models can be based on network characteristics including those of invariant features.

  25. Constructing a pathway model:things to consider 2.Abstraction Resolution: • How much do we get into details? • What building blocks do we use to describe the network? High resolution Low resolution (A) Substrates and proteins (B) Pathways (C) “special pathways”

  26. Constructing a pathway modelStep I - Definitions We begin with a very simple imaginary metabolic network represented as a directed graph: How do we define a biologically significant system boundary? Vertex – protein/substrate concentration. Edge - flux (conversion mediated by proteins of one substrate into the other) Internal flux edge External flux edge

  27. Constructing a pathway modelStep II: Interaction Kinetics E + S ==> E + P kinase-ATP complex + inactive-enzyme ==> Kinase + ADP + active enzyme K P ATP ADP

  28. Reversibility of Chemical Reactions: Equilibrium • Chemical reactions are reversible • Under certain conditions (concentration, temperature) both reactants and products exist together in equilibrium state H2 2H

  29. Reaction Rates Net reaction rate = forward rate – reverse rate • In equilibrium: Net reaction rate = 0 • When reactants “just” brought together: Far from equilibrium, focus only on forward rate • But, same arguments apply to the reverse rate

  30. The Differential Rate Law • How does the rate of the reaction depend on concentration? E.g. m+n: Overall order of the reaction 3A + 2B  C + D rate = k [A]m[B]n (Specific reaction) rate constant Order of reaction with respect to A Order of reaction with respect to B

  31. Rate Constants and Reaction Orders • Each reaction is characterized by its own rate constant, depending on the nature of the reactants and the temperature • In general, the order with respect to each reagent must be found experimentally (not necessarily equal to stoichiometric coefficient)

  32. Elementary Processes and Rate Laws • Reaction mechanism: The collection of elementary processes by which an overall reaction occurs • The order of an elementary process is predictable

  33. Elementary Processes and Rate Laws • Reaction mechanism: The collection of elementary processes by which an overall reaction occurs • The order of an elementary process is predictable

  34. Constructing a pathway modelStep III - Dynamic mass balance Concentration vector Stoichiometry Matrix Flux vector

  35. A ‘simple’ ODE model of yeast glycolysis

  36. A model pathway system and its time-dependent behavior Positive Feedback Loop

  37. A model pathway system and its time-dependent behavior

  38. A model pathway system and its time-dependent behavior

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