Prologue
1.3. Cyclic nucleotide phosphodiesterase enzyme - an overview
most diverse region of the phosphodiesterase enzyme structure, based on which the superfamily can also be classified in different groups, as shown in figure 1.4.
Figure 1.4 Structure based classification of PDEs based on regulatory domain
Phosphodiesterase members also differ in terms of substrate specificity and subcellular localization. These differences can be exploited for development of specific inhibitors (Russell et al., 1973). Table 1.1 provides complete details of various members of PDE superfamily. The table talks about various subtypes of PDE superfamily, their reported Km values for cGMP/cAMP, sites of expression, available inhibitors and the cellular activities influenced by inhibition of PDE.
Based on the substrate specificity, phosphodiesterases are divided into three groups (1) cAMP specific - PDE 4, 7 and 8 (2) cGMP specific - PDE 5, 6 and 9 and (3) dual specific (both cAMP and cGMP specific)- PDE 1, 2, 3, 10 and 11 (Conti and Beavo, 2007; Mehats et al., 2002). These specificity are determined by the catalytic domain but mechanism of specific recognition of substrate by phosphodiesterases is still a question [Ke et al., 2011;
Hou et al., 2011] (Hou et al., 2011; Ke et al., 2011). According to Zhang et al (2004),
“Glutamine switch mechanism” might be an important reason behind such selectivity. This is because γ-amino group of conserved invariant glutamine in the active site of PDEs can alternatively adopt two different orientations. In one orientation the hydrogen bond network supports guanine binding, resulting in cGMP selectivity, and in the second orientation the network supports adenine binding, leading to selectivity towards cAMP. Whereas in case of dual-specificity, the side chain of glutamine can switch over between the two orientations, resulting in specificity towards both the cyclic nucleotides (Jeon et al., 2005; Zhang et al., 2004). Binding patterns of invariant glutamine of different phosphodiesterases have been represented in figure 1.5.
Figure 1.5 Comparative binding patterns of invariant glutamine: (A) interaction of AMP with cAMP specific PDE4D by making two H-bonds between adenine moiety of AMP and invarient Q369; (B) interaction of GMP with cGMP specific PDE5A by two H-bonds between guanine base of GMP and invariant Q817, this interaction is in the opposite orientation of glutamine side chain as shown in AMP-PDE4D interaction; (C) Interaction pattern of dual specific PDE10A with AMP; (D) Interaction pattern of dual specific PDE10A with GMP
Phosphodiesterase 9A (PDE9A) is one of the most prominent phosphodiesterases among all PDEs due to its highest expression in brain and has highest affinity for cGMP. But complexity in structure and side effects associated with other PDEs makes the development of specific inhibitors targeting PDE9A a challenging task.
Table 1.1 Overview of cyclic nucleotide phosphodiesterase superfamily
PDE Sub- types
Properties Km Value Tissue expression
Therapeutic target Inhibitors Cellular function associated with PDE inhibition
References
PDE1 3 Ca++/ calmoduline- stimulated
PDE1A=112.7⁄
5.0µM [cAMP⁄cGMP]
PDE1B=
24.3⁄2.7µM [cAMP⁄cGMP]
PDE1C=1.7⁄1.3 µM
[cAMP⁄cGMP]
Brain, lung, Heart, smooth muscle
Neurodegenerative diseases such as Neuronal ischemia, epilepsy, Parkinson’s
& Alzheimer's disease (AD)
Calimidazolium, Dioclein, Phenethiazines,
SCH51866, Vinpocetine, Zaprinast
Apoptosis,
phosphorylation of AMPA receptors, enhancement of pulmonary
vasodilation
(Bender, 2006;
Dunkern and
Hatzelmann, 2007;
Evgenov et al., 2006; Gonçalves et al., 2009; Jiang et al., 1996; Medina, 2011)
PDE2 1 cGMP
stimulated
PDE2=10/30µ M
[cAMP⁄cGMP]
Adrenal gland, heart, lung, liver, platelets
Acute respiratory Distress Syndrome (ARDS), sepsis
EHNA, Bay 60-7550, MPB–forskolin, PDP
Endothelial cell permeability,
presynaptic inhibition
(Boess et al., 2004;
Hu et al., 2012;
Michie et al., 1996;
Surapisitchat et al., 2007; Witzenrath et al., 2009; Wunder et al., 2009)
PDE3 2 cGMP-
inhibited, cAMP- selective
PDE3=0.2/0.1µ M
[cAMP⁄cGMP]
Adipose tissue, heart, lung, liver, inflammatory cells, platelets
Asthma , chronic heart disease, cardiovascular disease, intermittent caudation, vascular smooth muscle relaxation
Amrinone, Bucladesine, Cilostazol, Cilostamide Enoximone, , Milrinone, Org 9935, Olprinone, SK&F 95654, Siguazodan, Saterinone
Induction of insulin secretion
(Ahmad et al., 2000;
Kieback and
Baumann, 2006;
Surapisitchat et al., 2007)
PDE4 4 cGMP-
insensitive, cAMP- specific
2–4 µM for cAMP
Sertoli cells, kidney, brain,liver, lung, inflammatory cells
Autoimmune disease, inflammatory disease,
neurodegenarative disease, cancer, allergic disorder.
Apremilast, NCS 613, Rolipram, Roflumilast
Long-term potentiation
(Mackenzie and Houslay, 2000;
Rabe, 2011; Schett et al., 2010;
Yougbare et al., 2011)
cGMP (catalytic domain PDE5A)
smooth muscle, hypertension, renal failure, sexual dysfunction, stroke
Wang et al., 2006;
Westermann et al., 2012; Zoraghi et al., 2007)
PDE6 3 Transducin- activated, cGMP specific
2.5 µM for cGMP
Photoreceptors, pineal gland
Sometime adverse effect on vision
Dipyridamole, Sildenafil, Vardenafil, Zaprinast
N/A (Cahill et al., 2012;
Lugnier, 2006)
PDE7 2 cAMP
specific, Rolipram- insensitive
0.03-0.2 µM for cAMP
Lung, hematopoietic cells, placenta, pancreas, brain, heart, thyroid, skeletal muscle, immune cells
Immune and inflammatory disorders,
neurological disease such as spinal cord injury
ASB16165, BAY 73-6691, PF-04447943, S14, VP1.15
Lessen inflammatory response, regulation of pro-inflammatory and immune T-cell functions, reduction in tissue injury, reduction in TNF-α, IL-6, COX-2 and iNOS expression
(Bender, 2006;
Castaño et al., 2009;
Paterniti et al., 2011)
PDE8 2 cAMP
specific, Rolipram- insensitive IBMX- insensitive
0.04–0.15 µM for cAMP
Testes, eye, liver, skeletal muscle, heart, kidney, ovary, brain, T lymphocytes
Polycystic ovary syndrome (PCOS)
Dipyridamole Suppression of Teff cell functions, lipid accumulation
(Lugnier, 2006;
Shimizu-Albergine et al., 2008; Vang et al., 2010)
PDE9 1 cGMP
specific, IBMX- insensitive
0.070-0.25 µM for cGMP 230 µM for cAMP
Brain, kidney, spleen, small intestine.
cardiovascular diseases, Insulin- resistance syndrome and diabetes, obesity,
neurodegenerative disorders
BAY73-6691, PF- 04447943
Synaptic plasticity, LTP(long term potentiation)
(Fisher et al., 1998;
Huai et al., 2004;
Soderling et al., 1998; Wang et al., 2010)
PDE10 1 Dual specific 0.05–0.26 µM for cAMP 3–7.2 µM for cGMP
Testes, striatum (brain)
Anxiety, cognition deficiency disorder, neurodegenerative disease
MP10 Long-term
potentiation
(Abdel-Magid, 2013)
PDE11 1 Dual specific 0.52 µM for cAMP
Skeletal muscle,
Asthma, adrenal, testicular, bipolar
Tadalafil Spermatogenesis (Makhlouf et al., 2006)