Bioorganic Chemistry
5
carbonyl carbon to form the tetrahedral
intermediate, either the amine or the acetic
acid can be expelled to form the starting
materials. Most of the time, the acid will be
expelled because it is less able to contribute
its electrons to make an effective bond.
In the same way that carboxylic acids
can condense with alcohols to produce
esters, so can other acids such as phos-
phoric acid and sulfuric acid. In the
biological realm, condensation products
of phosphoric acid are of greatest inter-
est. It is useful to think of the chem-
istry
of
phosphoric
acid
condensation
products as analogous to carboxylic acid
condensation products (Fig. 3). A major
difference between the two is that phos-
phoric acid has three acidic OH groups
whereas carboxylic acids have only one.
The result of this is that phosphoric
acid can form multiple condensations.
The
most
important
of
these
in
the
molecular biology realm is the phospho-
diester linkage that forms part of the
backbone
of
DNA.
And
as
with
car-
boxylic acids, phosphoric acids can also
form anhydrides. In the same way that
carboxylic acid anhydrides are effective
acylating agents because of the quality
of the leaving group, phosphoric acid
anhydrides are effective phosphorylating
agents. The most well-known biologically
important phosphorylating agents are the
nucleotide triphosphates such as adeno-
sine 5
0
-triphosphate (ATP).
The formation of the phosphodiester
linkage between two nucleotides during
DNA biosynthesis demonstrates some of
the similarities and differences between
phosphorylation and acylation chemistry
(Fig. 4). The nucleophile in this case is the
3
0
-hydroxyl of the elongating nucleotide
strand. It attacks the alpha phosphate of the
next nucleotide triphosphate, forming a
pentacoordinate intermediate. (It is penta-
coordinate because the phosphate initially
has four groups attached.) The interme-
diate can then either revert to starting
materials or proceed to the diester product
by ejecting the pyrophosphate group (the
two attached phosphates). As with the acy-
lation of amines with acetic anhydride, the
reaction proceeds toward products because
of the superiority of the phosphate as a
leaving group compared to the attacking al-
cohol. In this reaction, the pyrophosphate
is the leaving group. Nucleotide triophos-
phates are frequently used in nature to
O
P
HO
OH
OH
RNH
2
(Amine)
R-OH
(Alcohol)
O
P
HO
OR
OH
(Phosphoric acid
and derivatives)
O
P
HO
N
OH
R
H
O
P
HO
OR
OR
O
P
HO
O
OH
P
O
OH
OR
(a) Phosphoramide
(b) Phosphodiester
(e.g. DNA)
(c) Phosphoric acid
anhydride
(e.g. adenoside
triphosphate)
Fig. 3
Phosphoric acid condensation products.
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