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Biochemistry 430/530 Andrew MacMillan [email protected] MedSci 4-39 (by appointment) 492-3813 http://www2.biochem.ualberta.ca/ MacMillanLab/ “Course Notes”
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Biochemistry 430/530Andrew [email protected] 4-39 (by appointment)492-3813
http://www2.biochem.ualberta.ca/MacMillanLab/
“Course Notes”
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Medicine/Physiology Chemistry
Szostak, Greider, Blackburn Steitz, Ramakrishnan, Yonath
1989 Sidney Altman, Thomas R. Cech2006 Andrew Z. Fire, Craig C. Mello1993 Richard J. Roberts, Phillip A. Sharp
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Classical Gene Regulation
1) RNA Structure/Reactivity (1)2) Ribozymes/Riboswitches(2)3) pre-mRNA Splicing (3)4) RNA Degradation/RNAi(2)
RNA
information
function
structure
Central Dogma
DNA RNA Protein
Central Dogma
DNA RNA Protein
DNA RNA Protein
Central Dogma
ProcessingprecursorRNAspre-mRNApre-tRNApre-rRNApre-snoRNAcap formationend formationsplicingeditingchemical modification(rare bases)RNAi (siRNA, miRNA)
Hammerhead Ribozyme
UG
CU
C
CC
GC
GC
GG
UC
UGA
GUCCG
GAC
ACA
GG
AA
5'3'
XA
5' 3'
3'5'
Ribosome - Large SubunitH. marismortui
Science (2000) 289:920-30
-2833 nt-27 proteins
Chemistry Review!
El LG Nu ElNu
LG+
H A H BB
A+
M2+
+ R-O-H R-O-HM2+
Acid/Base - Bronsted Base
Acid/Base - Lewis Acid
Nucleophilic Substitution
RNA Structure and Reactivity
N
NN
N N
NN
N
N
N
N
N
N
NH
O
H
OH
N
OO O
H
O
NH
HN
H
H
H
G A
U 5-Me-U C
OO
O O
Base
PO
P
O
HO
O O
O
1
23
4
567
8
9
3
216
54
1’2’3’
4’
5’
Nucleic AcidsChemical
Functionalities-Hydrogen Bonding-Metal Coordination-Acid/Base-Nucleophilic Reactions
Hydrogen Bonding
N
NN
N
NN
HN
O
H
O
NH
H
H
G
C
N
NN
N
NN
HN
O
H
O
NH
H
H
G
C
D
A
~3-5 kcal/mol
Hydrogen Bonding
N
NN
N
NN
HN
O
H
O
NH
H
H
G
C
N
NN
N
NN
HN
O
H
O
NH
H
H
G
C
D
A
~3-5 kcal/mol(excluding entropy - how much is this worth?)
Metal Coordination
Na+, K+, Mg2+, Mn2+
O
POO
O
M2+
-
G5
G16.2
Acid/Base
N
N
HN
O
H
H+
N
N
HN
O
H
pKa ~ 4
O
OH OH
NO
O OH
N
P
O
O
O-
Acid/Base
N
N
HN
O
H
H+
N
N
HN
O
H
pKa ~ 4
O
OH OH
N
pKa ~ 12
O
O OH
N
P
O
O
O-
pKa ~ 14
Nucleophilic Reactions I
N
NN
N
H
O
NH
H
S
O
OCH3CH3O
O
N
NN
N
O
NH
H
N
NN
N
H
O
NH
H
CH3+
CH3
Nucleophilic Reactions I
N
NN
N
H
O
NH
H
S
O
OCH3CH3O
O
N
NN
N
O
NH
H
N
NN
N
H
O
NH
H
CH3+
CH3
Nucleophilic Reactions II
O
OHO
P
O
O
O-
NO
OO
N
P
O O-
Minor
Major
B-Form DNA
Dickerson and coworkers
A-Form RNA
Minor
Major
N
NN
N
N
NN
N
NN
NN
H
O
H N
O
O
H
O
NH
HN
H
H
H
G
A
U
C
N
NN
N
N
N
H
O
O
HN
H
A
U
Base-Pairing in RNA
Watson-Crick Hoogsteen
N
NN
N
N
NN
N
NN
NN
H
O
H N
O
O
H
O
NH
HN
H
H
H
G
A
U
C
N
NN
N
N
N
H
O
O
HN
H
A
U
Base-Pairing in RNA
Watson-Crick Hoogsteen
Major
Minor
A+-C in Double-Stranded RNA
J. Mol. Biol. 283, 977 (1998)
Higher Order Structure in Nucleic AcidsFrom Non-WC Base-Pairs
N
NN
N
H
O
NH
H
G
N
N
NN
H
O
N
H
H
N
N N
N
H
O
NH
H
N
N
N N
H
O
N
H
H
G
G
G
M+
