Phosphodiesterase 11A (PDE11A) is a recently identified family of cAMP and
cGMP hydrolyzing enzymes. Thus far. a single splice variant designated as P
DE11A1 has been reported. In this study, we identify and characterize two a
dditional splice variants of PDE11A. PDE11A2 and PDE11A3. The full-length c
DNAs are 2,141 bp for PDE11A2 and 2205 bp for PDE11A3. The ORF of PDE11A2 p
redicts a protein of 576 aa with a molecular mass of 65.8 kDa. The ORF of P
DE11A3 predicts a protein of 684 aa with a molecular mass of 78.1 kDa. Comp
arison of the PDE11A2 sequence with that of PDE11A1 indicates an additional
86 aa at the N terminus of PDE11A2. Part of this sequence extends the pote
ntial cGMP binding region (GAF domain) present in PDE11A1. Compared with PD
E11A2, PDE11A3 has an additional 108 N-terminal amino acids. Sequence analy
sis of PDE11A3 indicates the presence of another GAF domain in this region.
This diversification of regulatory sequences in the N-terminal region of P
DE11A splice variants suggests the interesting possibility of differential
regulation of these enzymes. Recombinant PDE11A2 and -A3 proteins expressed
in the Baculovirus expression system have the ability to hydrolyze both cA
MP and cGMP. The K-m values for cAMP hydrolysis are 3.3 muM and 5.7 muM for
PDE11A2 and PDE11A3. respectively. The K-m values for cGMP hydrolysis are
3.7 muM and 4.2 muM for PDE11A2 and PDE11A3. respectively. Both PDEs showed
a V-max ratio for cAMP/cGMP of approximately 1.0. PDE11A2 is sensitive to
dipyridamole, with an IC50 of 1.8 muM. and to zaprinast, with an IC50 of 28
muM. PDE11A3 demonstrated similar pattern of inhibitor sensitivity with IC
50 values of 0.82 and 5 muM for dipyridamole and zaprinast, respectively.