Transcript Origins of Sugars in the Prebiotic World

Origins of Sugars in the Prebiotic World
• One theory: the formose reaction (discovered by
Butterow in 1861)
O
Mineral catalysis
H
H
mixture of sugars,
including a small
amount of ribose
eg Ca(OH)2
formaldehyde
H
Mechanism?
H
HOH
O
H
HO
H
O
O
O
O
H
O
O
OH
paraformaldehyde
H
H2O
slow, very
unfavorable
O
OH
O
O
*
O
O
H
OH
H
O
O
O
OH
n
*
OH
Con’t
O
O
O
OH
depolymerise
H
OH
O
glycolaldehyde:
simplest sugar &
a catalyst for
further rxns
H
Ca(OH)2
O
HO
HO
H
OH
O
-O
H
glyceraldehyde
H
H
ene-diloate
(enol)
pentoses, hexoses
via
ene-diolate
OH
O
H
OH
-OH
H
OH
OH
O
-O
O
OH
OH
OH
dihydroxyacetone
via
ene-diolate
H
O
OH
HO
OH
erythrose/threose
H
O
OH
-OH
2x
OH
HO
OH
erythrose/threose
retro-aldol
O
H
glycolaldehyde:
cycle back for
catalysis
• Today, similar reactions are catalyzed by thiazolium, e.g.,
Vitamin B1 (TPP), another cofactor:
• Cf Exp. 7: Benzoin
(PP) HO
S
condensation
H
• e.g.
N+
Py
H
OH
+
H
O
O
HO
OP
glycolaldehyde
OH
O
G3P
OH
HO
OP
D-xylulose-5-P
Mechanism? Uses thiazolium
O
HO
R
-OH
S
S
H
-
H
N+
N+
Py
Py
OH
R
OH
S
carbanion: zwitterionic;
stablized by +/- charge
interaction
N+
:B
H
OH
Py
N+ acidifies H
O
OP
OH
R
S
OH
N+
thiazolium anion
catalyst
regenerated
R
Py
HO
OH
OP
S
N+
Py
HO
+
O
HO
OH
OP
xylulose-5-P
HO
H
R
S
N
Py
OH
OH
enamine
• We have seen how the intermediacy of the resonancestablized oxonium ion accounts for facile substitution at
the anomeric centre of a sugar
• What about nitrogen nucleophiles?
CO2H
Many examples:
CO2H
RO
O
+
CO2H
N
quinolinate
N
NADH
CO2H
OH
RO
O
RO
O
OH
+
OPP
OH
OH
OH
OH
R = H or P
NH3
RO
O
+
NH2
nucleosides
OH
OH
Could this process have occurred in the prebiotic world?
•
Reaction of an oxonium ion with a nitrogenous base:
NUCLEOSIDES!
HO
OH
O
Mn+
Mineral days?
OH
O
Hydrothermal
vents?
OH
NH
N
H
&/or
apatite
HO
(mineral
phosphate)
O
O
NH
HO
+
O
O
N
O
O
OH
HO
O
P
OH
O
O
OH
OH
OH
OH
Thymidine (a nuclesoside)
OH
Activated leaving group:
CATALYSIS
•
Nucleosides are quite stable:
1)
2)
Weaker anomeric effect: N< O < Cl (low electronegativity of N)
N lone pair in aromatic ring  hard to protonate
O
1)
O
NH
NH
HO
O
HO
O
N
+
OH
O
N
O
-
Charge
separation:unfavorable,
since -ve charge is on
N, a less
electronegative group
OH
OH
OH
Anomeric effect: Cl > O > N (remember the glycosyl chloride
prefers Cl axial
O
2)
O
NH
NH
HO
O
N
O
H+
+
HO
O
X
OH
O
N
H
OH
OH
lone pair part of
aromatic sextet
OH
aromaticity destroyed
(i.e., pyridine & pyrrole)
• These effects stabilize the nucleoside making its
formation possible in the pre-biotic soup
• Thermodynamics are reasonably balanced
• However, the reaction is reversible
– e.g. deamination of DNA occurs ~ 10,000x/day/cell in vivo
– Deamination is due to spontaneous hydrolysis & by damage of
DNA by environmental factors
– Principle of microscopic reversibility: spontaneous reaction
occurs via the oxonium ion
Ribonucleosides & Deoxyribonucleosides
Ribonucleosides
• Contain ribose & found in RNA:
Cytosine
Uracil
Adenine
Guanine
+
+
+
+
Ribose
Ribose
Ribose
Ribose




Cytidine (C)
Uridine (U)
Adenosine (A)
Guanosine (G)
Deoxyribonucleosides
• Contain 2-deoxyribose, found in DNA
Cytosine
Thymine
Adenine
Guanine
+
+
+
+
2-dR
2-dR
2-dR
2-dR




2’-deoxycytidine (dC)
2’-deoxythymidine (dT)
2’-deoxyadenosine (dA)
2’-deoxyguanosine (dG)
Ribonucleosides
O
NH2
N
N
HO
O
OH
O
N
HO
O
OH
OH
NH2
H
N
O
N
HO
OH
OH
uridine (U)
cytidine (C)
O
O
N
N
N
N
HO
OH
O
OH
N
N
N
NH2
OH
guanosine (G)
adenosine (A)
Deoxyribonucleosides
O
NH2
N
N
HO
O
N
O
OH
2'-deoxycytidine (dC)
HO
O
N
NH2
H
N
O
OH
2'-deoxythymidine (dT)
HO
O
N
O
N
N
N
OH
2'-deoxyadenosine (dA)
HO
O
N
N
N
OH
2'-deoxyguanosine (dG)
NH2
Important things to Note:
• Numbering system:
– The base is numbered first (1,2, etc), then the sugar (1’, 2’, etc)
• Thymine (5-methyl uracil) replaces uracil in DNA
• Confusing letter codes:
– A represents adenine, the base
– A also represents adenosine, the nucleoside
– A also represents deoxyadenosine (i.e., in DNA sequencing,
where “d” is often omitted)
– A can also represent alanine, the amino acid
• Nucleoside + phoshphate  nucleotide
• In the modern world, enzymes (kinases) attach
phosphate groups
O
HO
O
A
-O
P
OH
OH
P
O
O
O
HO
A
OH
P
O
O
O
O
OH
OH
Adenosine-5'monophosphate (AMP)
OH
Adenosine-5'diphosphate (ADP)
O
HO
A
O
O
OH
P
P
O
O
O
P
O
O
O
Adenosine-5'triphosphate (ATP)
Energy source for cell
Central to metabolism
In the pre-RNA world, how might this happen?
P
O
O
A
O
OH
OH
Observation:
O
NH
HO
5'
clay
O
N
4'
5' phosphate + 3' phosphate + higher phosphates
(30 % + 50%)
O
(apatite)
1'
NUCLEOTIDES!
2'
3'
OH
OH
• Surprisingly easy to attach phosphate without needing
an enzyme
– One hypothesis: cyclo-triphosphate (explains preference for
triphosphate
O
O
O
P
P
O
O
O
O
O
P
ATP
O
HO
O
T
Primary OH?
sterics?
OH
OH
release of some
ring strain in
cylcotriphosphate
drives reaction?
• If correct, this indicates a central role for triphosphates of
nucleosides (NTPs) in early evolution of RNA (i.e.,
development of the RNA world)
• NTPs central to modern cellular biology