Cyclic nucleotide phosphodiesterase (PDE) hydrolyzes adenosine or guanosine
3',5'-cyclic phophate (cAMP or cGMP) to 5'-AMP and 5’-GMP. Cyclic AMP and
cyclic GMP are intercellular second messengers, mediating the response
of cells to a wide variety of hormones and neurotransmitters and signal
transduction processes. Regulation of cAMP and cGMP concentration in vivo
is an essential step for many metabolic processes, such as cardiac and
smooth muscle contraction, glycogenolysis, platelet aggregation, secretion,
lipolysis, learning, ion channel conductance, apoptosis, and growth control.
Selective PDE inhibitors towards a certain family of PDEs have been widely
studied as therapeutic agents. For example, the PDE3 inhibitor cilostamide
is used for treatment of heart diseases and the PDE5 inhibitor VIAGRA is
for erectile dysfunction of male patients.
Ribbon diagram of the catalytic domain of PDE4D2. R-rolipram is shown
as the pink balls while two divalent metals are drawn as green balls.
cAMP binding at the catalytic pocket of PDE4D2. Zn1 coordinates with
His164, His200, Asp201, and Asp318 (golden). Zn2 represents the second
metal and binds to Asp318 and a water molecule.