Chemistry Reference
In-Depth Information
Other factors that play an important role in determining the biological role of Mg
2
þ
are its coordination
number and coordination geometry, its solvent exchange rates, and its transport number.
1
Like Na
þ
,Mg
2
þ
is
invariably hexa-coordinate, whereas both K
þ
and Ca
2
þ
can adjust easily to 6, 7, or 8 coordination. Thus, Ca
2
þ
can
accommodate a more flexible geometry, compared to the octahedral geometry of the obligatory hexacoordinate
cations, resulting in deviations from the expected bond angle of 90
by up to 40
, compared with less than half that
for Mg
2
þ
. Likewise, bond lengths for oxy-ligands can vary by as much as 0.5
˚
for Ca
2
þ
, whereas the corre-
sponding values for Mg
2
þ
vary by only 0.2
˚
.
In contrast to the other three cations, Mg
2
þ
has a much slower exchange rate of water in its hydration sphere
(
Table 10.1
). Mg
2
þ
often participates in structures, for example, in ATP binding catalytic pockets of kinases and
other phosphoryl transferase enzymes, where the metal is bound to four or five ligands from the protein and the
ATP. This leaves one or two coordination positions vacant for occupation by water molecules, which can be
positioned in a particular geometry by the Mg
2
þ
to participate in the catalytic mechanism of the enzyme. This
capacity is an example of outer sphere activation of a substrate by a metal ion (
Figure 10.1
) as distinct from the
R
1
R
1
R
2
R
2
Mg
+2
Mg
+2
H
2
O
R
3
H
2
O
R
3
S
,
H
2
O
S
H
2
O
H
2
O
outer-sphere
inner-sphere
FIGURE 10.1
Comparison of inner- and outer-sphere modes of activation, where S is the substrate.
(Adapted from
Cowan, 2002
.
)
more usual inner-sphere activation. Unlike the other alkaline earth and transition metal ions, essentially on
account of its small ionic radius and consequent high electron density, Mg
2
þ
tends to bind the smaller water
molecules rather than bulkier ligands in the inner coordination sphere. Many Mg
2
þ
-binding sites in proteins have
only 3, 4, or even less direct binding contacts to the protein, leaving several sites in the inner coordination sphere
occupied by water, or in the phosphoryl transferases, by nucleoside di- or tri-phosphates.
In addition, the high charge density on Mg
2
þ
ensures that it is an excellent Lewis acid in reactions notably
involving phosphoryl transfers and hydrolysis of phosphoesters. Typically, Mg
2
þ
functions as a Lewis acid, either
by activating a bound nucleophile to a more reactive anionic form (e.g., water to hydroxide anion) or by stabilising
an intermediate.
MAGNESIUM-DEPENDENT ENZYMES
Many enzymes involved in the pathways of intermediary metabolism are Mg
2
þ
dependent, as are a great many of
the enzymes involved in nucleic acid metabolism. Of the ten enzymes involved in the glycolytic pathway
(Chapter 5), five are Mg
2
þ
dependent. This comes as no surprise since four of the five (hexokinase, phospho-
fructokinase, phosphoglycerate kinase, and pyruvate kinase) involve phosphoryl transfers. The fifth, enolase,
forms a complex with Mg
2
þ
before the 2-phosphoglycerate substrate is bound. The inhibition of glycolysis by
fluoride results from binding of F
e
, in the presence of phosphate, to the catalytic Mg
2
þ
, thus blocking substrate
binding and inactivating the enzyme. As we could anticipate from its being the most abundant cytosolic divalent
cation, Mg
2
þ
binds strongly to nucleoside di-and tri-phosphates such as ATP and ADP, and is therefore directly
involved in almost all reactions involving these molecules.
1. The transport number estimates the average number of solvent molecules associated with a cation sufficiently tightly to migrate with the
cation in solution.
