652
Bioinorganic Chemistry
nitrogen. The oxygen of a peptide bond
is only a weak metal ion binder, and the
peptide nitrogen is not a proton or metal
ion binding site unless deprotonated.
For amide deprotonations, p
K
a
15. A
deprotonated peptide nitrogen serves as a
strong metal ion binder, but unless there
is an anchor for the metal ion, amide
deprotonation does not take place until the
solution is very basic. The Cu
2
+
–biuret
reaction is an amide deprotonation in very
basic solutions.
The tripeptide Gly-Gly-His serves as a
strong quadridentate ligand with an amino
nitrogen (an anchor), two deprotonated
peptide nitrogens, and an imidazole nitro-
gen (a second anchor) providing a planar
array of four donor atoms. Binding in this
mode occurs best in neutral and even
acidic solutions with Cu
2
+
,P
d
2
+
,a
n
d
Ni
2
+
, which undergoes a transition from
a blue, octahedral, high-spin complex to
a yellow, planar, low-spin complex upon
cooperative deprotonations of the peptide
nitrogens. In blood, Cu
2
+
interacts in this
binding mode with the amino terminus of
human serum albumin where histidine is
the third amino acid residue.
For neutral amides, the weakly basic
oxygen (p
K
a
≈−
1) is the proton and metal
ion binding site. The major determinant
of peptide oxygen basicity is the basicity
of the amino group making up the bond.
Among the 20 amino acids in proteins,
the amino group basicity of proline is
almost 1 log unit greater than that of
the other amino acids. As a result, the
peptide oxygen from the amino acid
linked to a proline nitrogen should be
relatively basic compared to other peptide
oxygens not linked likewise. Proline-linked
peptide oxygens appear disproportionately
as calcium ion binding sites in calcium
proteins. Proline itself never furnishes
the peptide oxygen that coordinates a
metal ion. How much a relatively greater
basicity, rather than appearance of proline
in loop regions, contributes to proline-
linked peptide oxygen occurrence as a
metal binder remains uncertain.
13.3
Proteins
Metal ions interact in numerous ways with
proteins, from the weak fairly nonspeci±c
interactions of many metal ions with
proteins such as serum albumin to the
highly speci±c protein sites made for
exclusive binding of a single kind of metal
ion. For example, the iron-transporting
protein of the plasma, transferrin, binds
two Fe
3
+
under blood plasma conditions
with conditional dissociation constants
of 10
22
M. Such a minuscule value
is necessary because the solubility of
goethite, FeO(OH), only allows 10
21
M
Fe
3
+
at pH 7.4. About 30% of all enzymes
contain metal ions, and in most of these,
only one kind of metal ion is bound almost
exclusively. Individual cases are the subject
of other articles in this volume.
13.4
Nucleosides
Let us designate the nucleic bases with
their usual alphabetical symbols, A, C, G,
T, and U. The order of decreasing basicity
is given by
H
+
:T3
>
U3
>
G1
À
C3
>
A1
>
G7
>
A7
In contrast, for a heavy-metal ion in neutral
solutions, the order of decreasing stability
is given by
Heavy-metal ion: G7
>
A7
>
C3
>
A1
>
G1
>
U3
>
T3
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