Biology Reference
In-Depth Information
for hydrolysis of cGMP, and others (PDEs 1, 2, 3, 10, and 11) hydrolyze both cNs.
Moreover, functional features of closely related PDEs can differ substantially,
a result that is encouraging for development of specific inhibitors for each family.
Some PDEs that exhibit the highest identity in amino acid sequence, for example,
PDEs 5 and 11 (catalytic domains have ~51% sequence identity) have very differ-
ent selectivities for cAMP and cGMP (Bender and Beavo
2006
; Omori and Kotera
2006
,
2007
). PDE5 exhibits ~100-fold greater affinity for cGMP than for cAMP,
although both are hydrolyzed at ~equal rates (Francis and Corbin
2009
). In contrast,
PDE11 hydrolyzes both cNs with similar affinities and efficiencies. In addition,
PDEs 5 and 11 exhibit very different affinities for potent PDE5 inhibitors currently
in clinical use, that is, vardenafil, sildenafil, and tadalafil; potencies of these
compounds for PDE5 compared to PDE11 differ by 7,000-, 950-, and 41-fold,
respectively (Weeks et al.
2007
).
In another example, the amino acid sequence identity of the catalytic domains of
PDEs 5 and 6, both of which are highly specific for cGMP, are very similar (~42%),
but the affinity of PDE6 catalytic site for cGMP (
K
m
~14
m
M), is seven times
weaker than that of PDE5 (~2
m
M), and the catalytic rate of PDE6 (~2,000
m
mol/
min/mg) exceeds that of PDE5 by ~1,000-fold (Cote
2006
; Francis et al.
2006
).
Moreover, PDE6, like PDE5, is potently inhibited by sildenafil, vardenafil, and
zaprinast, but tadalafil, a potent PDE5 inhibitor, is a weak inhibitor of PDE6 (Zhang
2006
). These data imply that subtle differences in the topography and chemical
characteristics of the active site can have profound effects on substrate preference,
catalytic efficiency, and inhibitor potencies.
In some instances, there are even significant distinctions among catalytic sites of
PDE isoforms within the same family. For example, PDE1A, PDE1B, and PDE1C
are products of three separate genes with catalytic domains that share ~75%
sequence homology but have quite different selectivity for cGMP (
K
m
¼
1
m
M for
PDE1C2, 3
m
M for PDE1B1, and 5
m
M for PDE1A2), compared to that for cAMP
(
K
m
¼
1
m
M, 24
m
M, and 113
m
M, respectively). Nevertheless, the maximum
catalytic activities of these PDEs for breakdown of cGMP and cAMP are similar
(Bender and Beavo
2006
).
1.4.2 Potencies of Inhibitors Within PDE Families
The potency of an inhibitor for PDEs within a family, among splice variants within
a subfamily, or between cytosolic and membrane-bound forms of the same PDE can
also differ significantly. For example, vinpocetine, a selective PDE1 inhibitor, more
potently blocks the catalytic activity of PDE1A and PDE1B than that of PDE1C
(Yan et al.
1996
). The inhibitory potency of IC86340, another selective PDE1
inhibitor, varies by ~7-fold among PDE1 isoforms; IC
50
values are: PDE1C
(0.06
m
M), PDE1B (0.21
m
M), PDE1A (0.44
m
M) (Miller et al.
2009
). Moreover,
potency of another PDE1-selective inhibitor, SCH51866, for several alternative
