Chemistry Reference
In-Depth Information
Figure 6.22 ATP hydrolysis with Co(
III
) and Mg(
II
).
phosphate bridging the two metal centers in
32
is hydrolyzed by a concerted mechan-
ism with both bond making (nucleophile) and breaking (leaving group) processes at
the transition state [96]. In contrast, the mechanism for hydrolysis of the free phos-
phate is largely dissociative in character, with very little bond formation to the nucleo-
phile at the transition state.
It is interesting to compare the reactivities of
32
and
28
. Phenyl phosphate in
28
[92]
is hydrolyzed about three orders of magnitude more rapidly than phenyl phosphate in
32
at pH 7. However, comparing the rate constants of the fully ionized species,
32
is
about two orders of magnitude more reactive than
28
. In the hydrolysis of ATP to ADP
and inorganic phosphate (
33
) [97], a third metal ion [Mg(
II
)] can be used to give leaving-
group activation in addition to the double Lewis acid and nucleophile activations pro-
vided by the other two metal ions [Co(
III
)] (Figure 6.22). Remarkably, Mg(
II
) provides a
ca. 3000-fold rate acceleration for the hydrolysis.
6.9
Phosphodiesterase Models
There has been much interest in developing artificial metalloenzymes that hydrolyze
the phosphate diester bonds of RNA and DNA. Chemical catalysts that hydrolyze nu-
cleic acids may provide valuable insights into how nucleases work. In addition, cat-
alysts that hydrolyze RNA sequence specifically [98-102] or DNA sequence specifically
[103] may be useful as therapeutic agents. Indeed, sequence-specific cleavage of RNA
is thought to be a natural defense mechanism against invading viruses [104]. Numer-
ous transition metal [105-113] and lanthanide complexes [114-119] that hydrolyze
phosphate diesters have been reported. Dinuclear Co(
III
) [120, 72, 75], Cu(
II
) [76,
77, 121-123] and Zn(
II
) [124-133] complexes are even more reactive than their mono-
nuclear analogs for hydrolyzing phosphate diesters. Not surprisingly, the active sites of
many phosphodiesterases contain two metal ions [1-3].
