Why do metabolic networks look like they do?

1. Why do metabolic networks look like they do? Petter Holme

2. Whatis similar?

3. Whatis similar? Fundamental constraintsom physics,chemistry& biology.

4. Whatis similar? Whatis diﬀerent? Fundamental constraintsom physics,chemistry& biology.

5. Whatis similar? Whatis diﬀerent? Fundamental constraintsom physics,chemistry& biology. Mechanismsof evolution& adaptation.

6. What do metabolic networks look like?

7. What do metabolic networks look like?

8. What do metabolic networks look like? What is a metabolic network?

9. What do metabolic networks look like? What is a metabolic network? O+O₃→3O₂ 2O₂+CH₄→ CO₂+2H₂O OH⁻

12. What do metabolic networks look like? What is a metabolic network? Graphtypes

13. What do metabolic networks look like? What is a metabolic network? Representations/ projections Graphtypes

14. What do metabolic networks look like? What is a metabolic network? Currencymetabolites Representations/ projections Graphtypes

15. Complex Graph types Simple

16. Complex Graph types Simple littleinfo, manymethods

17. Complex Graph types Simple littleinfo, manymethods lots of info, fewmethods

18. Representations 2O₂+ CH₄→ CO₂+2H₂O CH₄ O₂ H₂O CO₂

19. Representations 2O₂+ CH₄→ CO₂+2H₂O CH₄ O₂ H₂O CO₂

20. Representations 2O₂+ CH₄→ CO₂+2H₂O CH₄ O₂ H₂O CO₂ SUBSTRATE–PRODUCTGRAPH

21. Representations 2O₂+ CH₄→ CO₂+2H₂O CH₄ O₂ H₂O CO₂ SUBSTRATE–SUBSTRATEGRAPH

22. Representations 2O₂+ CH₄→ CO₂+2H₂O CH₄ O₂ H₂O CO₂ SUBSTANCEGRAPH

23. Hypothesis:Networkclusters~functionalmodules Holme,Huss,Jeong,2003.Subnetworkhierarchiesof biochemicalpathways, Bioinformatics19:532–538.

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. 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. Currencymetabolites

32. Currencymetabolites Existsthroughoutthecell (i.e.manymodules) Canreactwithagreatvariety of othersubstances

33. Currencymetabolites Existsthroughoutthecell (i.e.manymodules) Canreactwithagreatvariety of othersubstances Jing,Holme,2010.LectureNotesinOperationsResearch13:13–21.

34. Currencymetabolites Existsthroughoutthecell (i.e.manymodules) Canreactwithagreatvariety of othersubstances lowers the modularity

35. Currencymetabolites Existsthroughoutthecell (i.e.manymodules) Canreactwithagreatvariety of othersubstances lowers the modularity high degree

38. Currencymetabolites Existsthroughoutthecell(i.e. manymodules) Canreactwithagreatvariety of othersubstances lowers the modularity high degree

39. Currencymetabolites 1.calculatemodularity 2.removethevertexwithhighest degree 3.goto1 edeletedvertexsetwithhighest modularityarethecurrency metbolites

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. 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. 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. So what do metabolic networks look like?

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. So what do metabolic networks look like? Broaddegreedistributions Core-peripherystructure+ aweak butsigniﬁcant modularstructure

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. Compared to what?

50. Compared to what? eproblemof null-models

51. Compared to what? eproblemof null-models Rewired networksviolate massbalance

52. Compared to what? eproblemof null-models Rewired networksviolate massbalance Otherreactionsystems

53. Compared to what?

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. Finally:Why? Is theweakmodularity related torobustness?

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. x! MikaelHuss JingZhao SangHoonLee

58. x! MikaelHuss JingZhao SangHoonLee

59. Compared to what? Holme,2009.Modelvalidationof simple-graph representationsof metabolism.JRoySocInterface40:1027–1034.