View source for PDE1

{{Short description|Enzyme}}
{{Infobox enzyme
| Name       = Phosphodiesterase I
| EC_number  = 3.1.4.1
| CAS_number = 9025-82-5
| GO_code    =
| image      =
| width      =
| caption    =
}}
'''Phosphodiesterase 1''', '''PDE1''', EC 3.1.4.1, systematic name '''oligonucleotide 5{{prime}}-nucleotidohydrolase''') is a [[phosphodiesterase]] [[enzyme]] also known as [[calcium]]- and [[calmodulin]]-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase (PDE1-PDE11). Phosphodiesterase 1 has three [[subtypes]], PDE1A, PDE1B and PDE1C which divide further into various [[isoforms]]. The various isoforms exhibit different affinities for [[Cyclic adenosine monophosphate|cAMP]] and [[cyclic guanosine monophosphate|cGMP]].<ref name=Lugnier/><ref name=Bender/>
==Discovery ==
The existence of the Ca<sup>2+</sup>-stimulated Phosphodiesterase 1 was first demonstrated by Cheung (1970), Kakiuchi and Yamazaki (1970) as a result of their research on [[bovine]] [[brain]] and [[rat]] brain respectively.<ref name= Lugnier>{{cite journal |author=Lugnier C |title=Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents |journal=Pharmacol. Ther. |volume=109 |issue=3 |pages=366–98 |date=March 2006 |pmid=16102838 |doi=10.1016/j.pharmthera.2005.07.003 }}</ref><ref name=Kakkar>{{cite journal |doi=10.1007/s000180050364 |vauthors=Kakkar R, Raju RV, Sharma RK |title=Calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) |journal=Cell. Mol. Life Sci. |volume=55 |issue=8–9 |pages=1164–86 |date=July 1999 |pmid=10442095 |s2cid=23724340 |url=http://link.springer.de/link/service/journals/00018/bibs/90558-9/90551164.htm |pmc=11146777 }}{{Dead link|date=April 2020 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> It has since been found to be widely distributed in various [[mammalian]] [[Biological tissue|tissues]] as well as in other [[eukaryotes]]. It is now one of the most intensively studied member of the [[Phosphodiesterase|PDE]] superfamily of enzymes,<ref name=Kakkar/> which today represents 11 [[gene]] families,<ref name=Lugnier/><ref name=Jeon>{{cite journal  |vauthors=Jeon YH, Heo YS, Kim CM, etal |title=Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development |journal=Cell. Mol. Life Sci. |volume=62 |issue=11 |pages=1198–220 |date=June 2005 |pmid=15798894 |doi=10.1007/s00018-005-4533-5|s2cid=9806864 |pmc=11139162 }}</ref> and the best characterized one as well.<ref name=Kakkar/>
Further research in the field along with increased availability of [[monoclonal antibodies]] has shown that various phosphodiesterase 1 [[isoenzymes]] exist and have been identified and purified. It is now known that phosphodiesterase 1 exists as tissue specific isozymes.<ref name=Kakkar/>
==Structure ==
The phosphodiesterase 1 isozyme family belongs to a Class I enzymes,<ref name=Bender>{{cite journal |vauthors=Bender AT, Beavo JA |title=Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use |journal=Pharmacol. Rev. |volume=58 |issue=3 |pages=488–520 |date=September 2006 |pmid=16968949 |doi=10.1124/pr.58.3.5 |s2cid=7397281 }}</ref><ref name=Dousa>{{cite journal |author=Dousa TP |title=Cyclic-3{{prime}},5{{prime}}-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney |journal=Kidney Int. |volume=55 |issue=1 |pages=29–62 |date=January 1999 |pmid=9893113 |doi=10.1046/j.1523-1755.1999.00233.x|doi-access=free }}</ref> which includes all [[vertebrate]] phosphodiesterases and some [[yeast]] enzymes.<ref name=Dousa/> Class I enzymes all have a catalytic core of at least 250 [[amino acids]] whereas Class II enzymes lack such a common feature.<ref name=Dousa/>
Usually vertebrate PDEs are [[protein dimer|dimers]] of linear 50–150&nbsp;kDa [[proteins]].<ref name=Dousa/> They consist of three functional [[protein domain|domains]]; a conserved catalytic core, a regulatory [[N-terminus]] and a [[C-terminus]] [3-5]. The proteins are [[Fusion protein|chimeric]] and each domain is associated with their particular function.<ref name=Bender/>
The regulatory ''N''-terminus is substantially different in various phosphodiesterase types.<ref name=Jeon/><ref name=Dousa/> They are flanked by the catalytic core and include regions that auto-inhibit the catalytic domains. They also target sequences that control [[subcellular]] localization. In phosphodiesterase 1 this region contains a calmodulin binding domain.<ref name=Jeon/>
The catalytic domains of phosphodiesterase 1 (and other types of phosphodiesterases) have three [[Helix|helical]] subdomains: an N-terminal cyclin-fold region, a linker region and a C-terminal helical bundle. A deep [[hydrophobic]] pocket is formed at the interface of  these subdomains. It is composed of four [[subsites]]. They are: a [[metal]] binding site (M site), core pocket (Q pocket), hydrophobic pocket (H pocket) and lid region (L region). The M site is placed at the bottom of the hydrophobic pocket with several metal [[atoms]]. The metal atoms bind to residues that are completely conserved in all phosphodiesterase family members. The identity of the metal atoms is not known with absolute certainty. However, some evidence indicate that at least one of the metals is [[zinc]] and the other is likely to be [[magnesium]]. The zinc [[coordination sphere]] is composed of three [[histidines]], one [[aspartate]] and two water [[molecules]]. The magnesium coordination sphere involves the same aspartate along with five water molecules, one of which is shared with the zinc molecule. The reputed role of the metal ions include structure stabilization as well as activation of [[hydroxide]] to mediate [[catalysis]].<ref name=Jeon/>
The domains are separated by "hinge" regions where they can be experimentally separated by limited proteolysis.<ref name=Bender/>
The phosphodiesterase 1 isoenzyme family (along with the phosphodiesterase 4 family) is the most diverse one and includes numerous splice variant PDE1 isoforms. It has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms.<ref name=Lugnier/><ref name=Bender/>
==Localization==
The localization of PDE1 isoforms in different tissues/cells and their location within the cells is as follows:
{| class="wikitable"
! Isoform
! Tissue/cellular localization
! Intracellular localization
|-
| PDE1A ({{Gene|PDE1A}})
| Smooth muscle, heart, lung, brain, sperm <ref name=Bender/>
| Predominantly cytosolic <ref name=Bender/>
|-
| PDE1A1
| Heart, lung <ref name=Bender/>
| Predominantly cytosolic <ref name=Bender/>
|-
| PDE1A2
| Brain <ref name=Bender/>
| Predominantly cytosolic <ref name=Bender/>
|-
| PDE1B1 ({{Gene|PDE1B}})
| Neurons, lymphocytes, smooth muscle <ref name=Bender/> brain, heart, skeletal muscle <ref name=Lugnier/>
| Cytosolic <ref name=Bender/>
|-
| PDE1B2
| Macrophages, lymphocytes <ref name=Bender/>
| Cytosolic <ref name=Bender/>
|-
| PDE1C ({{Gene|PDE1C}})
| Brain, proliferating human smooth muscle, spermatids <ref name=Bender/>
| Cytosolic <ref name=Bender/>
|-
| PDE1C1
| Brain, heart, testis <ref name=Menniti>{{cite journal |vauthors=Menniti FS, Faraci WS, Schmidt CJ |title=Phosphodiesterases in the CNS: targets for drug development |journal=Nat Rev Drug Discov |volume=5 |issue=8 |pages=660–70 |date=August 2006 |pmid=16883304 |doi=10.1038/nrd2058|s2cid=419810 }}</ref>
| -
|-
| PDE1C2
| Olfactory epithelium <ref name=Bender/>
| Cytosolic <ref name=Bender/>
|-
| PDE1C4/5
| mRNA is present in the testis <ref name=Menniti/>
| -
|}
''Table 1. Various PDE1s location in tissues and  within cells.''
Most PDE1 isoforms are reported to be [[cytosolic]]. However, there are instances of PDE1s being localized to subcellular regions but little is known about the molecular [[wikt:mechanism|mechanisms]] responsible for such localization. It is thought to be likely that the unique N-terminal or C-terminal regions of the various isoforms allow the different proteins to be targeted to specific subcellular domains.<ref name=Bender/>
==Functional role==
Phosphodiesterase1 [[catalysis|catalyses]] the following [[chemical reaction]]:<ref>{{cite book | chapter = Phosphodiesterases | title = The Enzymes | vauthors = Khorana GH |year = 1961 |volume = 5 |pages = 79–94 |veditors = Boyer PD, Lardy H, Myrbäck K |edition  = 2nd |publisher = Academic Press |location = New York }}</ref>
: Hydrolytically removes 5{{prime}}-[[nucleotide]]s successively from the 3{{prime}}-[[hydroxyl|hydroxy]] termini of 3{{prime}}-hydroxy-terminated [[oligonucleotide]]s
It [[hydrolyse]]s both [[ribonucleotide]]s and [[deoxyribonucleotide]]s, but it has low activity towards [[polynucleotide]]s.
Intracellular second messengers such as cGMP and cAMP undergo rapid changes in concentration in a response to a wide variety of cell specific stimuli. The concentration of these second messengers is determined to a large extent by the relative synthetic activity of [[adenylate cyclase|cyclase]] and degrative activity of cyclic nucleotide PDE.<ref name=Kakkar/> PDE1 degrades both cGMP and cAMP.<ref name=Bischoff>{{cite journal |author=Bischoff E |title=Potency, selectivity, and consequences of nonselectivity of PDE inhibition |journal=Int. J. Impot. Res. |volume=16 |issue=Suppl 1|pages=S11–4 |date=June 2004 |pmid=15224129 |doi=10.1038/sj.ijir.3901208|doi-access=free }}</ref>
[[Image:Mynd 1a.GIF|thumb|250px|right|Binding of PDE to cGMP and cAMP, respectively]]
<!-- comment because images are not found
[[Image:Mynd2a.GIF|thumb|250px|Right|''Figure 2. PDE1B apo-structure. The  metal ions are shown as
white spheres.<ref name=Jeon/>
'']]
[[Image:Mynd3.GIF|thumb|250px|Right|''Figure 3. GMP bound to PDE1B.<ref name=Jeon/>
'']]
[[Image:Mynd4.GIF|thumb|250px|Right|''Figure 4. AMP bound to PDE1B.<ref name=Jeon/> '']]
-->
The various isoforms exhibit different affinities for cAMP and cGMP. PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C degrades both cAMP and cGMP with high affinity. For example, in airway [[smooth muscles]] of humans and other species, generic PDE1 accounts for more than 50% of the hydrolytic activity of cyclic nucleotides.<ref name=Giembycz>{{cite journal |author=Giembycz MA |title=Life after PDE4: overcoming adverse events with dual-specificity phosphodiesterase inhibitors |journal=Curr Opin Pharmacol |volume=5 |issue=3 |pages=238–44 |date=June 2005 |pmid=15907909 |doi=10.1016/j.coph.2005.04.001 }}</ref> It has been demonstrated that deletion and [[overexpression]] of PDE1 produces strong effects on [[agonist]]-induced cAMP signalling but has little effect on the basal cAMP level.<ref name=Thevelein>{{cite journal |doi=10.1046/j.1365-2958.1999.01538.x |vauthors=Thevelein JM, de Winde JH |title=Novel sensing mechanisms and targets for the cAMP-protein kinase A pathway in the yeast ''Saccharomyces cerevisiae'' |journal=Mol. Microbiol. |volume=33 |issue=5 |pages=904–18 |date=September 1999 |pmid=10476026 |doi-access=free }}</ref> At cortical and [[Thalamus|thalamic]] inputs to the [[striatum]], PDE1 activity regulates [[neurotransmitter]] release via cGMP.<ref>{{Cite journal |last1=Fieblinger |first1=Tim |last2=Perez-Alvarez |first2=Alberto |last3=Lamothe-Molina |first3=Paul J |last4=Gee |first4=Christine E |last5=Oertner |first5=Thomas G |date=2022-08-03 |title=Presynaptic cGMP sets synaptic strength in the striatum and is important for motor learning |journal=EMBO Reports |language=en |volume=23 |issue=8 |pages=e54361 |doi=10.15252/embr.202154361 |pmid=35735260 |pmc=9346481 |issn=1469-221X}}</ref>
===Pharmacology===
Because of [[in vitro]] regulation by Ca<sup>2+</sup>/calmodulin, PDE1s are believed to function as a mechanism for integrating cell signalling pathways mediated by cGMP and cAMP with pathways that regulate intracellular calcium levels.<ref name=Bender/> The precise function of PDE1 isozymes in various [[pathophysiological]] processes is not clear because most of the studies have been carried out in vitro. Therefore, it is essential to direct further research to in vivo studies.<ref name=Kakkar/>
PDE1 has been implicated to play a role in a number of [[physiological]] and [[pathological]] processes:
* PDE1A most likely serves to regulate [[Blood vessel|vascular]] smooth muscle concentration and has been found to be up-regulated in rat aorta in response to chronic [[nitroglycerin]] treatment. It is also possible that it plays a role in [[spermatozoon|sperm]] function.<ref name=Bischoff/>
* [[PDE1B]] [[knockout]] mice have increased [[Animal locomotion|locomotor]] activity and in some [[paradigms]] decreased memory and learning abilities. [[PDE1B]] is also involved in [[dopaminergic]] signalling and is induced in several types of activated [[immune]] cells.<ref name=Bischoff/> [[PDE1B]] [[mRNA]] is induced in PHA or anti-CD3/CD28-activated human [[T-lymphocytes]] and participates in IL-13 regulation implicated in [[allergic]] diseases.<ref name=Lugnier/>
* PDE1C has been shown to be a major regulator of smooth muscle proliferation, at least in human smooth muscle. Nonproliferating smooth muscle cells (SMC) exhibit only low levels of PDE1C [[Gene expression|expression]] but it is highly expressed in proliferating SMCs. It can therefore be speculated that [[Enzyme inhibitor|inhibition]] of PDE1C could produce beneficial effects due to its putative inhibition of SMC proliferation, an event that contributes importantly to the pathophysiology of [[atherosclerosis]].<ref name=Bischoff/> Another likely roles of PDE1C is in [[olfaction]] [4], to regulate sperm function and [[neuronal]] signaling.<ref name=Bischoff/>
==Regulation==
The distinguishing feature of PDE1 as a family is their regulation by calcium (Ca<sup>2+</sup>) and calmodulin (CaM).<ref name=Goraya>{{cite journal |vauthors=Goraya TA, Cooper DM |title=Ca<sup>2+</sup>-calmodulin-dependent phosphodiesterase (PDE1): current perspectives |journal=Cell. Signal. |volume=17 |issue=7 |pages=789–97 |date=July 2005 |pmid=15763421 |doi=10.1016/j.cellsig.2004.12.017 }}</ref> Calmodulin has been shown to activate cyclic nucleotide PDE in a calcium-dependent manner and the cooperative binding of four Ca<sup>2+</sup> to calmodulin is required to fully activate PDE1 [2]. The binding of one Ca<sup>2+</sup>/CaM complex per [[monomer]] to binding sites near the N-terminus stimulates hydrolysis of cyclic nucleotides. In intact cells, PDE1 is almost exclusively activated by Ca<sup>2+</sup> entering the cell from the [[extracellular]] space. The regulation of PDE1 by Ca<sup>2+</sup> and CaM has been studied in vitro and these studies have shown that eight [[methionine]] residues within the hydrophobic clefts of Ca<sup>2+</sup>-CaM are required for the binding and activation of PDE1. [[Mutations]] in the N-terminal lobe of CaM affect its ability to activate PDE1 so it is believed that the C-terminal lobe of CaM serves to target CaM to PDE1, while the N-terminal lobe activates the enzyme. The presence of an [[aromatic]] residue, usually a [[tryptophan]], in the CaM-binding region of Ca<sup>2+</sup>-CaM-regulated proteins may also be required for binding to PDE1.<ref name=Goraya/>
Between different PDE1 isozymes there is a significant difference in [[Affinity (pharmacology)|affinity]] for Ca<sup>2+</sup>/CaM. In general, the PDE1 enzymes have high affinity for the complex but the affinity can be affected by phosphorylation. [[Phosphorylation]] of PDE1A1 and PDE1A2 by protein kinase A and of PDE1B1 by CaM Kinase II decreases their sensitivity to calmodulin activation.<ref name=Lugnier/> This phosphorylation can be reversed by the phosphatase, calcineurin.<ref name=Bender/> The phosphorylation of the isozymes is accompanied by a decrease in the isozymes affinity towards CaM, as well as an increase in the Ca<sup>2+</sup> concentrations required for CaM activation of the isozymes.<ref name=Kakkar/>
==Inhibitors and their function==
PDEs have been pursued as [[Pharmacotherapy|therapeutic]] targets because of the basic [[pharmacological]] principle that regulation of degradation of any [[ligand]] or [[second messenger]] can often make a more rapid and larger percentage change in concentration than comparable rates of [[Chemical synthesis|synthesis]]. Another reason is that PDEs do not have to compete with very high levels of [[endogenous]] substrate to be effective since the levels of cAMP and cGMP in most cells are typically in the [[micromolar]] range.<ref name=Bender/>
The availability of high-resolution crystal structures of the catalytic domains of PDEs makes the development of highly potent and specific [[Enzyme inhibitor|inhibitors]] possible.<ref name=Menniti/>
Many compounds reported as PDE1 inhibitors do not interact directly with the catalytic site of PDE1 but interact during activation, either at the level of calmodulin binding sites such as compound [[KS505a]] or directly on Ca<sup>2+</sup>/calmodulin such as [[bepril]], [[flunarizine]] and [[amiodarone]].<ref name=Lugnier/>
Those inhibitors that interact with the catalytic site occupy part of the active site, primarily around the Q pocket and occasionally close to the M pocket.<ref name=Card>{{cite journal  |vauthors=Card GL, England BP, Suzuki Y, etal |title=Structural basis for the activity of drugs that inhibit phosphodiesterases |journal=Structure |volume=12 |issue=12 |pages=2233–47 |date=December 2004 |pmid=15576036 |doi=10.1016/j.str.2004.10.004 |doi-access=free }}</ref> A major point of interaction is a conserved hydrophobic pocket that is involved in orienting the substrate purine ring for interaction with a glutamine residue that is crucial for the catalytic mechanism of the PDEs.<ref name=Menniti/>
The [[Chemical reaction|interactions]] of inhibitors can be split into three major types: interactions with the metal ions mediated through water, H-bond interactions with the protein residues involved in nucleotide recognition and most importantly the interaction with the hydrophobic residues lining the cavity of the active site. All known inhibitors seem to exploit these three types of interactions and hence these interactions should guide the design of new types of inhibitors.<ref name=Card/>
Initially PDE1 inhibitors were claimed to be effective vascular relaxants. With availability of purified cloned enzymes, however, it is now known that such inhibitors are in fact equally active against PDE5.<ref name=Jeon/> Those inhibitors include e.g. [[zaprinast]], [[8-methoxymethyl IPMX]] and [[SCH 51866]].<ref name=Lugnier/>
All therapeutically effective PDE inhibitors must be incorporated into the cell because all PDEs are localized in the cytoplasm and/or on intracellular membranes.<ref name=Bischoff/>
Today, there is no real and effective specific PDE1 inhibitor that can be used to assess the functional role of PDE1 in tissues.<ref name=Lugnier/>
===Common inhibitors ===
[[File:Nimodipine structure.svg|thumb|225px|right|Chemical structure of [[nimodipine]]]]
[[File:Vinpocetine.svg|thumb|225px|right|Chemical structure of [[vinpocetine]]]]
[[Nimodipine]] is a [[dihydropyridine]] that antagonizes/blocks specifically L-type Ca<sup>2+</sup>-channel, and was first described as a PDE1 inhibitor. This effect is not related to its calcium antagonist property since it inhibits, in micromolar range, basal and calmodulin stimulated purified PDE1. Since nimodipine at lower concentrations blocks the L-type calcium channel, it can only be used to estimate PDE1 participation in tissue and cell homogenates.<ref name=Lugnier/>
[[Vinpocetine]] was described as a specific inhibitor of basal and calmodulin-activated PDE1. This effect leads to an increase of cAMP over cGMP.<ref name=Lugnier/><ref name=Vinpocetine>{{cite journal |title=Vinpocetine. Monograph |journal=Altern Med Rev |volume=7 |issue=3 |pages=240–3 |date=June 2002 |pmid=12126465 }}</ref> It is mainly used as a pharmacological tool to implicate PDE1. Vinpocetine inhibits differently the various subtypes of PDE1 (IC<sub>50</sub> from 8 to 50&nbsp;μm) and it is also able to inhibit PDE7B. It can not be used as a specific tool to investigate the functional role of PDE1 due to its direct activator effects on BK (Ca) channels.<ref name=Lugnier/> Vinpocetine crosses the blood–brain barrier and is taken up by cerebral tissue. It has been hypothesized that vinpocetine can affect voltage-dependent calcium channels.<ref name=Vinpocetine/>
[[IC224]] inhibits PDE1 (IC<sub>50</sub> = 0.08 μM) with a selective ratio of 127 (ratio of IC<sub>50</sub> value for the next most sensitive PDE and for IC<sub>50</sub> value for PDE1). It was developed by ICOS corporation. If IC224 similarly inhibits basal and calmodulin-activated PDE1 subtypes, this compound could be very helpful to characterize PDE1 activity and to clearly investigate the various roles of PDE1 in pathophysiology.<ref name=Lugnier/>
==Inhibitors in diseases==
Nearly all the phosphodiesterases are expressed in the CNS, making this gene family an attractive source of new targets for the treatment of [[psychiatric]] and [[neurodegenerative]] disorders.<ref name=Menniti/>
PDE1A2 has a potential role in neurodegenerative diseases, including:<ref name=Jeon/>
* [[Parkinson's disease]]
* [[Axonal]] [[neurofilament]] [[Chemical decomposition|degradation]]
* [[Motorneuronal degradation]]
* [[Neuronal ischemia]]
* [[Alzheimer's disease]]
* [[Epilepsy]]
PDE1C could have a role in the regulation of [[insulin]] release <ref name=Dousa/> and may target proliferating smooth muscle cells in atherosclerotic lesions or during [[restenosis]].<ref name=Jeon/><ref name= Matsumoto >{{cite journal |doi=10.1540/jsmr.39.67 |vauthors=Matsumoto T, Kobayashi T, Kamata K |title=Phosphodiesterases in the vascular system |journal=J Smooth Muscle Res |volume=39 |issue=4 |pages=67–86 |date=August 2003 |pmid=14692693 |doi-access=free }}</ref>
==References==
{{Reflist}}
== External links ==
*{{MeshName|Phosphodiesterase+I}}
{{Esterases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}
{{DEFAULTSORT:Pde1}}
[[Category:EC 3.1.4]]