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Why do metabolic networks look like they do?

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Summarizing my research on metabolic networks.

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Why do metabolic networks look like they do?

  1. 1. Why do metabolic networks look like they do? Petter Holme
  2. 2. Whatis similar?
  3. 3. Whatis similar? Fundamental constraintsom physics,chemistry& biology.
  4. 4. Whatis similar? Whatis different? Fundamental constraintsom physics,chemistry& biology.
  5. 5. Whatis similar? Whatis different? Fundamental constraintsom physics,chemistry& biology. Mechanismsof evolution& adaptation.
  6. 6. What do metabolic networks look like?
  7. 7. What do metabolic networks look like?
  8. 8. What do metabolic networks look like? What is a metabolic network?
  9. 9. What do metabolic networks look like? What is a metabolic network? O+O₃→3O₂ 2O₂+CH₄→ CO₂+2H₂O OH⁻
  10. 10. What do metabolic networks look like? What is a metabolic network?
  11. 11. What do metabolic networks look like? What is a metabolic network?
  12. 12. What do metabolic networks look like? What is a metabolic network? Graphtypes
  13. 13. What do metabolic networks look like? What is a metabolic network? Representations/ projections Graphtypes
  14. 14. What do metabolic networks look like? What is a metabolic network? Currencymetabolites Representations/ projections Graphtypes
  15. 15. Complex Graph types Simple
  16. 16. Complex Graph types Simple littleinfo, manymethods
  17. 17. Complex Graph types Simple littleinfo, manymethods lots of info, fewmethods
  18. 18. Representations 2O₂+ CH₄→ CO₂+2H₂O CH₄ O₂ H₂O CO₂
  19. 19. Representations 2O₂+ CH₄→ CO₂+2H₂O CH₄ O₂ H₂O CO₂
  20. 20. Representations 2O₂+ CH₄→ CO₂+2H₂O CH₄ O₂ H₂O CO₂ SUBSTRATE–PRODUCTGRAPH
  21. 21. Representations 2O₂+ CH₄→ CO₂+2H₂O CH₄ O₂ H₂O CO₂ SUBSTRATE–SUBSTRATEGRAPH
  22. 22. Representations 2O₂+ CH₄→ CO₂+2H₂O CH₄ O₂ H₂O CO₂ SUBSTANCEGRAPH
  23. 23. Hypothesis:Networkclusters~functionalmodules Holme,Huss,Jeong,2003.Subnetworkhierarchiesof biochemicalpathways, Bioinformatics19:532–538.
  24. 24. Hypothesis:Networkclusters~functionalmodules Holme,Huss,Jeong,2003.Subnetworkhierarchiesof biochemicalpathways, Bioinformatics19:532–538.
  25. 25. Hypothesis:Networkclusters~functionalmodules Holme,Huss,Jeong,2003.Subnetworkhierarchiesof biochemicalpathways, Bioinformatics19:532–538.
  26. 26. matchingscore 0.25 0 0.75 0.5 substrate– product substrate– substrate substance Human(KEGG) S.cerevisiae(KEGG) S.cerevisiae(BiGG) C.elegans M.musculus R.norvegicus D.melanogaster M.genitalium E.coli Human(BiGG) Matchingnetworkclusters&annotatedfunctions
  27. 27. matchingscore 0.25 0 0.75 0.5 substrate– product substrate– substrate substance Human(KEGG) S.cerevisiae(KEGG) S.cerevisiae(BiGG) C.elegans M.musculus R.norvegicus D.melanogaster M.genitalium E.coli Human(BiGG) Holme,Huss,2010.Substancenetworksareoptimalsimple-graph representationsof metabolism,ChineseSci.Bull.55:3161-3168.
  28. 28. Currencymetabolites
  29. 29. Currencymetabolites
  30. 30. Currencymetabolites
  31. 31. Currencymetabolites
  32. 32. Currencymetabolites Existsthroughoutthecell (i.e.manymodules) Canreactwithagreatvariety of othersubstances
  33. 33. Currencymetabolites Existsthroughoutthecell (i.e.manymodules) Canreactwithagreatvariety of othersubstances Jing,Holme,2010.LectureNotesinOperationsResearch13:13–21.
  34. 34. Currencymetabolites Existsthroughoutthecell (i.e.manymodules) Canreactwithagreatvariety of othersubstances lowers the modularity
  35. 35. Currencymetabolites Existsthroughoutthecell (i.e.manymodules) Canreactwithagreatvariety of othersubstances lowers the modularity high degree
  36. 36. Currencymetabolites
  37. 37. Currencymetabolites
  38. 38. Currencymetabolites Existsthroughoutthecell(i.e. manymodules) Canreactwithagreatvariety of othersubstances lowers the modularity high degree
  39. 39. Currencymetabolites 1.calculatemodularity 2.removethevertexwithhighest degree 3.goto1 edeletedvertexsetwithhighest modularityarethecurrency metbolites
  40. 40. Currencymetabolites 0.15 0.14 ∆ 0.13 0.12 Orthophosphate Pyrophosphate CO2 CoA AMP NH3 UDP S–Adenosyl–L–methionine H2O H + O2 NADPH NADP NADH ATP NAD ADP L–Glutamate H2O2 deleted vertex number 1 5 10 15 + +
  41. 41. Currencymetabolites Wagner,Fell Schuster & al. Ma & Zeng ATP ATP ATP ADP ADP ADP NADP+ NADP+ NADP+ NADPH NADPH NAD+ NAD+ NADH Pi Pi H2O H2O H+ PPi CMP CO2 O2 NH3
  42. 42. Currencymetabolites Wagner,Fell Schuster & al. Ma & Zeng ATP ATP ATP ADP ADP ADP NADP+ NADP+ NADP+ NADPH NADPH NAD+ NAD+ NADH Pi Pi H2O H2O H+ PPi CMP CO2 O2 NH3 Huss,Holme,2007.Currencyandcommodity metabolites,IETSystemsBiology1:280–285.
  43. 43. So what do metabolic networks look like?
  44. 44. So what do metabolic networks look like? Broaddegreedistributions 0.1 10 –2 10 –3 10 –4 10 –5 10 –6 10 3 100101 p(k) degree,k
  45. 45. So what do metabolic networks look like? Broaddegreedistributions Core-peripherystructure+ aweak butsignificant modularstructure
  46. 46. So what do metabolic networks look like? Broaddegreedistributions Core-peripherystructure+ aweak butsignificant modularstructure
  47. 47. So what do metabolic networks look like? Broaddegreedistributions Core-peripherystructure+ aweak butsignificant modularstructure
  48. 48. So what do metabolic networks look like? Broaddegreedistributions Core-peripherystructure+ aweak butsignificant modularstructure Networkmodules~ subcellularlocalization N S H O2 pyruvate, CO2 H O2 CO2 ATP, ADP pyrophosphate NADPH, NADH substrate reaction node link in−flow out−flow −D−ribose 1−phosphate CoA orthophosphate adenine deoxyadenosine inosine adenosine hypoxanthine guanine guanosine deoxyguanosine D−glucosamine 1−phosphate 1−phosphate −acetyl−D−glucosamine acetyl−CoA dihydrolipoamide −D−ribose 1−pyrophosphate −acetyldihydrolipoamide pyrophosphate 2−deoxy−D−ribose 1−phosphate iiiiii
  49. 49. Compared to what?
  50. 50. Compared to what? eproblemof null-models
  51. 51. Compared to what? eproblemof null-models Rewired networksviolate massbalance
  52. 52. Compared to what? eproblemof null-models Rewired networksviolate massbalance Otherreactionsystems
  53. 53. Compared to what?
  54. 54. Compared to what? Holme,Huss,Lee,2011.Atmosphericreactionsystemsasnull-modelstoidentifystructuraltraces of evolutioninmetabolism,PLoSONE6:e19759. 0.1 0.2 0.3 0.4 0.5 0.6 10 3 100 10 3 100 10 40 2 3 4 5 6 1 7 numberof vertices,N numberof edges,M relativemodularity,∆ numberofcurrencyvertices,c 0 planets organisms
  55. 55. Finally:Why? Is theweakmodularity related torobustness?
  56. 56. Finally:Why? 3.3 3.4 3.5 3.6 3.7 3.8 0.70 0.75 0.80 0.85 modularity robustness 1.27 1.29 1.31 1.33 1.35 1.37 0.70 0.75 0.80 0.85 robustness modularity genetic perturbations chemical perturbations
  57. 57. x! MikaelHuss JingZhao SangHoonLee
  58. 58. x! MikaelHuss JingZhao SangHoonLee
  59. 59. Compared to what? Holme,2009.Modelvalidationof simple-graph representationsof metabolism.JRoySocInterface40:1027–1034.
  60. 60. Compared to what? Holme,2009.Modelvalidationof simple-graph representationsof metabolism.JRoySocInterface40:1027–1034.
  61. 61. Compared to what? Holme,2009.Modelvalidationof simple-graph representationsof metabolism.JRoySocInterface40:1027–1034.

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