Biology Reference
In-Depth Information
shapes and sizes of the active sites in different PDE families. Therefore, the
substrate specificity of PDEs is likely to be determined jointly by multiple elements
at the active site, yet the detailed mechanism needs further study.
Keywords cAMP
cGMP
Crystal structure
Substrate specificity
1
Introduction
The second messengers adenosine and guanosine 3
0
,5
0
-cyclic monophosphate
(cAMP and cGMP) mediate the response of cells to a wide variety of hormones
and neurotransmitters and modulate many physiological processes, including car-
diac and smooth muscle contraction, steroid hormone function, platelet aggrega-
tion, apoptosis, leukocyte migration, adrenal hyperplasia, inflammation, axon
guidance and regeneration, memory, and circadian regulation (Houslay
1998
;
Antoni
2000
; Zaccolo and Movsesian
2007
; Piper et al.
2007
; O'Neill et al.
2008
;
Horvath and Stratakis
2008
; Hannila and Filbin
2008
). The signaling of cAMP and
cGMP in vivo involves three types of enzymes: cyclases, cyclic nucleotide (cN)
phosphodiesterases (PDEs), and cN-dependent protein kinases. PDEs are the sole
enzymes that hydrolyze cN (Fig.
1
) and thus play pivotal roles in these cN signaling
pathways.
The human genome contains 21 PDE genes that are classified into 11 families
and encode more than 100 isoforms of PDE proteins via alternative mRNA splicing
(Bender and Beavo
2006
; Omori and Kotera
2007
; Conti and Beavo
2007
).
PDE molecules can typically be divided into a variable regulatory domain at the
N-terminus and a conserved catalytic domain at the C-terminus; in some instances,
additional regulatory elements are found near the C-terminus. The conserved
catalytic domains show different substrate preferences. PDEs 4, 7, and 8 preferen-
tially hydrolyze cAMP while PDEs 5, 6, and 9 are specific for cGMP. PDEs 1, 2, 3,
10, and 11 possess activities toward both nucleotides and are known as dual-specific
OH
OH
N
N
H
2
O
H
+
H
2
N
H
2
N
N
N
O
O
OH
P
O
O
Mg
2+
O
N
2-
N
N
N
OPO
3
O
OH
OH
N
N
H
2
O
H
+
O
O
N
N
O
OH
O
P
O
O
O
Mg
2+
HN
HN
N
2-
N
O
OPO
3
H
2
N
H
2
N
Fig. 1 Hydrolysis of cAMP and cGMP to 5
0
-AMP and 5
0
-GMP by PDEs
