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The RNA World Hypothesis

The RNA World Hypothesis. -cofactors -ancient enzymes -ribozymes. Ribozymes. “Catalytic RNA”. Nobel prize - Chemistry 1989. T.R. Cech (Colorado, HHMI). S. Altman (Yale). RNase P. Tetrahymena group I. http://almaz.com/nobel/chemistry/1989b.html.

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The RNA World Hypothesis

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  1. The RNA World Hypothesis -cofactors -ancient enzymes -ribozymes

  2. Ribozymes “Catalytic RNA” Nobel prize - Chemistry 1989 T.R. Cech (Colorado, HHMI) S. Altman (Yale) RNase P Tetrahymena group I http://almaz.com/nobel/chemistry/1989b.html http://almaz.com/nobel/chemistry/1989a.html

  3. Ribozymes “Catalytic RNA” Catalysis Auto-catalysis -rate enhancement -turnover -rate enhancement on self reaction Small: hammerhead hepatitis d hairpin VS Medium: group I group II RNase P Large: ribosome spliceosome?

  4. Catalysis Acceleration

  5. Catalysis Turnover

  6. RNA Catalysis How fast?

  7. pre-rRNA processing -In eukaryotes, the gene is not continuous..."functional" sequences are interrupted "non-functional" sequences. -First discovered for adenovirus pre-mRNAs (PA Sharp 1977) -Intron/Exon structure (W. Gilbert) of eukaryotic genome Tetrahymena rRNA contains one intron (IVS). How is it removed? Exon Exon Intron

  8. Tetrahymena intron removal Two sequential transesterifications 5’ splice site 3’ 5’ 3’ 5’ 5’ 3’ 5’

  9. Stereochemical Course of Splicing -transesterification reactions of splicing are nucleophilic substitution reactions Recall: inversion

  10. mirror images R S Inversion Retention

  11. Prochiral Centre Made Chiral by S Substitution 5’ P P P 3’ Rp Sp

  12. Stereochemistry of Group I Splicing -Rp at 5’ splice site gives Sp in product -Sp at 3’ splice site gives Rp in product

  13. Stereochemistry of Group I Splicing Rp Rp Sp Sp

  14. Tetrahymena intron removal 3’ 5’ Nu LG 3’ 5’ 5’ 3’ 5’

  15. One Active Site in Group I Intron first step second step

  16. G Binding Site G Binding Site - Group I Intron C311 G G G264 G

  17. Specificity Swap at G Binding Site - Group I Intron - mutate G-C to A-U guanosine 2-aminopurine arginine citrulline

  18. Arg G C G G AP Cit U A A

  19. Creation of a Ribozyme

  20. Secondary Structure of Group I RNA

  21. P4-P6 X-ray Science (1996) 273: 1678-85

  22. Group I X-ray Science (1998) 282: 259-64

  23. Group I Intron X-ray Nature430, 45-50 (1 July 2004)

  24. Group I Intron X-ray Nature430, 45-50 (1 July 2004)

  25. Group I Intron X-ray Nature430, 45-50 (1 July 2004)

  26. Satellite Tobacco Ringspot Virus RNA

  27. Design of a Ribozyme substrate ribozyme

  28. Hammerhead Ribozyme

  29. Hammerhead X-ray Cell (1995) 81: 991-1002

  30. guanosine inosine

  31. Chemistry of Hammerhead Cleavage X Cell (1998) 92: 665-73

  32. Altered Hammerhead Conformation

  33. Altered Hammerhead Conformation Molecular Cell, Volume 23,4, 447-450,2006

  34. Altered Conformation: Active Site Cell, 126, 2, 309-320, 2006

  35. Hepatitis d Ribozyme

  36. Hepatitis d X-ray Nature (1998) 395:567-74

  37. Hepatitis d X-ray Nature (1998) 395:567-74

  38. General Base Catalysis in a Ribozyme Science (1999) 286: 123-6

  39. Imidazole Rescue of Ribozyme Activity Science (1999) 286: 123-6

  40. Imidazole Rescue of Ribozyme Activity Science (1999) 286: 123-6

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