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Protein

cGMP-specific 3',5'-cyclic phosphodiesterase

Gene

PDE5A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP (PubMed:9714779, PubMed:15489334). Specifically regulates nitric-oxide-generated cGMP (PubMed:15489334).2 Publications

Caution

Was initially thought to act as a major regulator of cardiac hypertrophy in myocytes and muscle and investigations have been made on selective PDE5A inhibitors that could protect against cardiovascular disease. However, while PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signaling is often depressed by heart disease, limiting its effect. Moreover, clinical trial using PDE5A inhibitors were disappointing.1 Publication

Catalytic activityi

Guanosine 3',5'-cyclic phosphate + H2O = guanosine 5'-phosphate.1 Publication

Cofactori

Protein has several cofactor binding sites:

Activity regulationi

Sildenafil (Viagra) is a highly selective and potent inhibitor of PDE5A and is effective in the treatment of penile erectile dysfunction. Also inhibited by zaprinast.1 Publication

Pathwayi: 3',5'-cyclic GMP degradation

This protein is involved in step 1 of the subpathway that synthesizes GMP from 3',5'-cyclic GMP.
Proteins known to be involved in this subpathway in this organism are:
  1. cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A (PDE10A), High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A), cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A)
This subpathway is part of the pathway 3',5'-cyclic GMP degradation, which is itself part of Purine metabolism.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes GMP from 3',5'-cyclic GMP, the pathway 3',5'-cyclic GMP degradation and in Purine metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei613Proton donorBy similarity1
Metal bindingi617Zinc; via tele nitrogen1 Publication1
Metal bindingi653Zinc; via tele nitrogen1 Publication1
Metal bindingi654Magnesium1 Publication1
Metal bindingi654Zinc1 Publication1
Metal bindingi764Zinc1 Publication1
Binding sitei817cGMP1 Publication1

GO - Molecular functioni

  • 3',5'-cyclic-GMP phosphodiesterase activity Source: UniProtKB
  • 3',5'-cyclic-nucleotide phosphodiesterase activity Source: UniProtKB
  • cGMP binding Source: UniProtKB
  • metal ion binding Source: UniProtKB-KW

GO - Biological processi

Keywordsi

Molecular functionAllosteric enzyme, Hydrolase
LigandcGMP, cGMP-binding, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi3.1.4.35 2681
ReactomeiR-HSA-418457 cGMP effects
SIGNORiO76074
UniPathwayi
UPA00763;UER00748

Names & Taxonomyi

Protein namesi
Recommended name:
cGMP-specific 3',5'-cyclic phosphodiesterase (EC:3.1.4.351 Publication)
Alternative name(s):
cGMP-binding cGMP-specific phosphodiesterase
Short name:
CGB-PDE
Gene namesi
Name:PDE5A
Synonyms:PDE5
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 4

Organism-specific databases

EuPathDBiHostDB:ENSG00000138735.15
HGNCiHGNC:8784 PDE5A
MIMi603310 gene
neXtProtiNX_O76074

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Pathology & Biotechi

Organism-specific databases

DisGeNETi8654
OpenTargetsiENSG00000138735
PharmGKBiPA33132

Chemistry databases

ChEMBLiCHEMBL1827
DrugBankiDB07954 3-isobutyl-1-methyl-7H-xanthine
DB06237 Avanafil
DB00201 Caffeine
DB04272 Citric Acid
DB00975 Dipyridamole
DB03597 Gamma-Glutamyl[S-(2-Iodobenzyl)Cysteinyl]Glycine
DB01972 Guanosine-5'-Monophosphate
DB05415 OSI-461
DB00806 Pentoxifylline
DB00203 Sildenafil
DB00820 Tadalafil
DB00277 Theophylline
DB06267 Udenafil
DB00862 Vardenafil
GuidetoPHARMACOLOGYi1304

Polymorphism and mutation databases

BioMutaiPDE5A

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001988231 – 875cGMP-specific 3',5'-cyclic phosphodiesteraseAdd BLAST875

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei102PhosphoserineSequence analysis1

Post-translational modificationi

Phosphorylation is regulated by binding of cGMP to the two allosteric sites (By similarity). Phosphorylation by PRKG1 leads to its activation.By similarity1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiO76074
MaxQBiO76074
PaxDbiO76074
PeptideAtlasiO76074
PRIDEiO76074
ProteomicsDBi50374
50375 [O76074-2]

PTM databases

iPTMnetiO76074
PhosphoSitePlusiO76074

Expressioni

Tissue specificityi

Expressed in aortic smooth muscle cells, heart, placenta, skeletal muscle and pancreas and, to a much lesser extent, in brain, liver and lung.

Gene expression databases

BgeeiENSG00000138735 Expressed in 189 organ(s), highest expression level in intestine
CleanExiHS_PDE5A
ExpressionAtlasiO76074 baseline and differential
GenevisibleiO76074 HS

Organism-specific databases

HPAiHPA004729
HPA012873

Interactioni

Binary interactionsi

WithEntry#Exp.IntActNotes
PRKG1Q139764EBI-9023531,EBI-3952014

Protein-protein interaction databases

BioGridi114205, 8 interactors
DIPiDIP-46287N
IntActiO76074, 5 interactors
STRINGi9606.ENSP00000347046

Chemistry databases

BindingDBiO76074

Structurei

Secondary structure

1875
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliO76074
SMRiO76074
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO76074

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini164 – 314GAF 1Add BLAST151
Domaini346 – 503GAF 2Add BLAST158
Domaini536 – 860PDEasePROSITE-ProRule annotationAdd BLAST325

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi10 – 24Poly-GlnAdd BLAST15

Domaini

Composed of a C-terminal catalytic domain containing two putative divalent metal sites and an N-terminal regulatory domain which contains two homologous allosteric cGMP-binding regions, A and B.

Sequence similaritiesi

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG3689 Eukaryota
ENOG410XRI7 LUCA
GeneTreeiENSGT00760000119066
HOVERGENiHBG101207
KOiK13762
OMAiVQRCTIF
OrthoDBiEOG091G04JU
PhylomeDBiO76074
TreeFamiTF316499

Family and domain databases

CDDicd00077 HDc, 1 hit
Gene3Di1.10.1300.10, 1 hit
3.30.450.40, 2 hits
InterProiView protein in InterPro
IPR003018 GAF
IPR029016 GAF-like_dom_sf
IPR003607 HD/PDEase_dom
IPR023088 PDEase
IPR002073 PDEase_catalytic_dom
IPR036971 PDEase_catalytic_dom_sf
IPR023174 PDEase_CS
PfamiView protein in Pfam
PF01590 GAF, 2 hits
PF00233 PDEase_I, 1 hit
PRINTSiPR00387 PDIESTERASE1
SMARTiView protein in SMART
SM00065 GAF, 2 hits
SM00471 HDc, 1 hit
PROSITEiView protein in PROSITE
PS00126 PDEASE_I_1, 1 hit
PS51845 PDEASE_I_2, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 3 potential isoforms that are computationally mapped.Show allAlign All

Isoform PDE5A1 (identifier: O76074-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MERAGPSFGQ QRQQQQPQQQ KQQQRDQDSV EAWLDDHWDF TFSYFVRKAT
60 70 80 90 100
REMVNAWFAE RVHTIPVCKE GIRGHTESCS CPLQQSPRAD NSAPGTPTRK
110 120 130 140 150
ISASEFDRPL RPIVVKDSEG TVSFLSDSEK KEQMPLTPPR FDHDEGDQCS
160 170 180 190 200
RLLELVKDIS SHLDVTALCH KIFLHIHGLI SADRYSLFLV CEDSSNDKFL
210 220 230 240 250
ISRLFDVAEG STLEEVSNNC IRLEWNKGIV GHVAALGEPL NIKDAYEDPR
260 270 280 290 300
FNAEVDQITG YKTQSILCMP IKNHREEVVG VAQAINKKSG NGGTFTEKDE
310 320 330 340 350
KDFAAYLAFC GIVLHNAQLY ETSLLENKRN QVLLDLASLI FEEQQSLEVI
360 370 380 390 400
LKKIAATIIS FMQVQKCTIF IVDEDCSDSF SSVFHMECEE LEKSSDTLTR
410 420 430 440 450
EHDANKINYM YAQYVKNTME PLNIPDVSKD KRFPWTTENT GNVNQQCIRS
460 470 480 490 500
LLCTPIKNGK KNKVIGVCQL VNKMEENTGK VKPFNRNDEQ FLEAFVIFCG
510 520 530 540 550
LGIQNTQMYE AVERAMAKQM VTLEVLSYHA SAAEEETREL QSLAAAVVPS
560 570 580 590 600
AQTLKITDFS FSDFELSDLE TALCTIRMFT DLNLVQNFQM KHEVLCRWIL
610 620 630 640 650
SVKKNYRKNV AYHNWRHAFN TAQCMFAALK AGKIQNKLTD LEILALLIAA
660 670 680 690 700
LSHDLDHRGV NNSYIQRSEH PLAQLYCHSI MEHHHFDQCL MILNSPGNQI
710 720 730 740 750
LSGLSIEEYK TTLKIIKQAI LATDLALYIK RRGEFFELIR KNQFNLEDPH
760 770 780 790 800
QKELFLAMLM TACDLSAITK PWPIQQRIAE LVATEFFDQG DRERKELNIE
810 820 830 840 850
PTDLMNREKK NKIPSMQVGF IDAICLQLYE ALTHVSEDCF PLLDGCRKNR
860 870
QKWQALAEQQ EKMLINGESG QAKRN
Length:875
Mass (Da):99,985
Last modified:January 11, 2011 - v2
Checksum:i9E30C6C182F13388
GO
Isoform PDE5A2 (identifier: O76074-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-49: MERAGPSFGQQRQQQQPQQQKQQQRDQDSVEAWLDDHWDFTFSYFVRKA → MLPFGDK

Show »
Length:833
Mass (Da):94,805
Checksum:i41D0B4B1BAB57D6D
GO

Computationally mapped potential isoform sequencesi

There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
G5E9C5G5E9C5_HUMAN
Phosphodiesterase
PDE5A hCG_38154
823Annotation score:
H0YA14H0YA14_HUMAN
cGMP-specific 3',5'-cyclic phosphod...
PDE5A
185Annotation score:
C9JGT3C9JGT3_HUMAN
cGMP-specific 3',5'-cyclic phosphod...
PDE5A
224Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti159I → V in AAP31235 (PubMed:10393044).Curated1
Sequence conflicti310C → G in AAP31235 (PubMed:10393044).Curated1
Sequence conflicti381S → F in AAP31235 (PubMed:10393044).Curated1
Sequence conflicti406K → R in AAP31235 (PubMed:10393044).Curated1
Sequence conflicti642E → G in BAA81667 (Ref. 4) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02777593A → V5 PublicationsCorresponds to variant dbSNP:rs3733526Ensembl.1
Natural variantiVAR_027776181S → A. Corresponds to variant dbSNP:rs17051276Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0045911 – 49MERAG…FVRKA → MLPFGDK in isoform PDE5A2. 3 PublicationsAdd BLAST49

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF043731 mRNA Translation: AAC63967.1
AF043732 mRNA Translation: AAC63968.1
AB001635 Genomic DNA Translation: BAA33372.2
D89094 mRNA Translation: BAA28945.1
AJ004865 mRNA Translation: CAA06170.1
AB015656 mRNA Translation: BAA81667.1
AY264918 mRNA Translation: AAP21809.1
AK290189 mRNA Translation: BAF82878.1
AC093752 Genomic DNA No translation available.
AC080089 Genomic DNA No translation available.
BC126233 mRNA Translation: AAI26234.1
AY266363 mRNA Translation: AAP31235.1
CCDSiCCDS34055.1 [O76074-2]
CCDS3713.1 [O76074-1]
PIRiJW0106
RefSeqiNP_001074.2, NM_001083.3 [O76074-1]
NP_236914.2, NM_033430.2 [O76074-2]
NP_246273.2, NM_033437.3
UniGeneiHs.647971

Genome annotation databases

EnsembliENST00000264805; ENSP00000264805; ENSG00000138735 [O76074-2]
ENST00000354960; ENSP00000347046; ENSG00000138735 [O76074-1]
GeneIDi8654
KEGGihsa:8654
UCSCiuc003idf.4 human [O76074-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF043731 mRNA Translation: AAC63967.1
AF043732 mRNA Translation: AAC63968.1
AB001635 Genomic DNA Translation: BAA33372.2
D89094 mRNA Translation: BAA28945.1
AJ004865 mRNA Translation: CAA06170.1
AB015656 mRNA Translation: BAA81667.1
AY264918 mRNA Translation: AAP21809.1
AK290189 mRNA Translation: BAF82878.1
AC093752 Genomic DNA No translation available.
AC080089 Genomic DNA No translation available.
BC126233 mRNA Translation: AAI26234.1
AY266363 mRNA Translation: AAP31235.1
CCDSiCCDS34055.1 [O76074-2]
CCDS3713.1 [O76074-1]
PIRiJW0106
RefSeqiNP_001074.2, NM_001083.3 [O76074-1]
NP_236914.2, NM_033430.2 [O76074-2]
NP_246273.2, NM_033437.3
UniGeneiHs.647971

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1RKPX-ray2.05A535-860[»]
1T9RX-ray2.10A531-875[»]
1T9SX-ray2.00A/B534-858[»]
1TBFX-ray1.30A534-858[»]
1UDTX-ray2.30A537-860[»]
1UDUX-ray2.83A/B537-860[»]
1UHOX-ray2.50A537-860[»]
1XOZX-ray1.37A534-875[»]
1XP0X-ray1.79A534-875[»]
2CHMX-ray1.60A534-656[»]
A682-858[»]
2H40X-ray1.85A535-860[»]
2H42X-ray2.30A/B/C535-860[»]
2H44X-ray1.80A535-860[»]
2XSSX-ray2.50A/B346-509[»]
3B2RX-ray2.07A/B535-860[»]
3BJCX-ray2.00A1-875[»]
3HC8X-ray1.79A536-657[»]
A682-858[»]
3HDZX-ray1.80A536-657[»]
A682-858[»]
3JWQX-ray2.87A/B/C/D535-786[»]
A/B/C/D827-860[»]
3JWRX-ray2.99A/B535-786[»]
A/B827-860[»]
3LFVX-ray2.80A/B98-518[»]
3MF0X-ray3.10A/B89-518[»]
3SHYX-ray2.65A535-860[»]
3SHZX-ray2.45A535-860[»]
3SIEX-ray1.93A/B535-860[»]
3TGEX-ray1.96A534-656[»]
A682-858[»]
3TGGX-ray1.91A534-660[»]
A662-858[»]
4G2WX-ray2.28A535-860[»]
4G2YX-ray2.40A535-860[»]
4I9ZX-ray2.08A535-860[»]
4IA0X-ray2.17A535-860[»]
4MD6X-ray2.00A535-860[»]
4OEWX-ray2.44A535-860[»]
4OEXX-ray2.14A535-860[»]
5JO3X-ray1.49B534-858[»]
5ZZ2X-ray2.60A535-860[»]
6ACBX-ray2.80A535-860[»]
ProteinModelPortaliO76074
SMRiO76074
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114205, 8 interactors
DIPiDIP-46287N
IntActiO76074, 5 interactors
STRINGi9606.ENSP00000347046

Chemistry databases

BindingDBiO76074
ChEMBLiCHEMBL1827
DrugBankiDB07954 3-isobutyl-1-methyl-7H-xanthine
DB06237 Avanafil
DB00201 Caffeine
DB04272 Citric Acid
DB00975 Dipyridamole
DB03597 Gamma-Glutamyl[S-(2-Iodobenzyl)Cysteinyl]Glycine
DB01972 Guanosine-5'-Monophosphate
DB05415 OSI-461
DB00806 Pentoxifylline
DB00203 Sildenafil
DB00820 Tadalafil
DB00277 Theophylline
DB06267 Udenafil
DB00862 Vardenafil
GuidetoPHARMACOLOGYi1304

PTM databases

iPTMnetiO76074
PhosphoSitePlusiO76074

Polymorphism and mutation databases

BioMutaiPDE5A

Proteomic databases

EPDiO76074
MaxQBiO76074
PaxDbiO76074
PeptideAtlasiO76074
PRIDEiO76074
ProteomicsDBi50374
50375 [O76074-2]

Protocols and materials databases

DNASUi8654
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000264805; ENSP00000264805; ENSG00000138735 [O76074-2]
ENST00000354960; ENSP00000347046; ENSG00000138735 [O76074-1]
GeneIDi8654
KEGGihsa:8654
UCSCiuc003idf.4 human [O76074-1]

Organism-specific databases

CTDi8654
DisGeNETi8654
EuPathDBiHostDB:ENSG00000138735.15
GeneCardsiPDE5A
HGNCiHGNC:8784 PDE5A
HPAiHPA004729
HPA012873
MIMi603310 gene
neXtProtiNX_O76074
OpenTargetsiENSG00000138735
PharmGKBiPA33132
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3689 Eukaryota
ENOG410XRI7 LUCA
GeneTreeiENSGT00760000119066
HOVERGENiHBG101207
KOiK13762
OMAiVQRCTIF
OrthoDBiEOG091G04JU
PhylomeDBiO76074
TreeFamiTF316499

Enzyme and pathway databases

UniPathwayi
UPA00763;UER00748

BRENDAi3.1.4.35 2681
ReactomeiR-HSA-418457 cGMP effects
SIGNORiO76074

Miscellaneous databases

ChiTaRSiPDE5A human
EvolutionaryTraceiO76074
GeneWikiiCGMP-specific_phosphodiesterase_type_5
GenomeRNAii8654
PROiPR:O76074
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000138735 Expressed in 189 organ(s), highest expression level in intestine
CleanExiHS_PDE5A
ExpressionAtlasiO76074 baseline and differential
GenevisibleiO76074 HS

Family and domain databases

CDDicd00077 HDc, 1 hit
Gene3Di1.10.1300.10, 1 hit
3.30.450.40, 2 hits
InterProiView protein in InterPro
IPR003018 GAF
IPR029016 GAF-like_dom_sf
IPR003607 HD/PDEase_dom
IPR023088 PDEase
IPR002073 PDEase_catalytic_dom
IPR036971 PDEase_catalytic_dom_sf
IPR023174 PDEase_CS
PfamiView protein in Pfam
PF01590 GAF, 2 hits
PF00233 PDEase_I, 1 hit
PRINTSiPR00387 PDIESTERASE1
SMARTiView protein in SMART
SM00065 GAF, 2 hits
SM00471 HDc, 1 hit
PROSITEiView protein in PROSITE
PS00126 PDEASE_I_1, 1 hit
PS51845 PDEASE_I_2, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiPDE5A_HUMAN
AccessioniPrimary (citable) accession number: O76074
Secondary accession number(s): A0AV69
, A8K2C4, O75026, O75887, Q86UI0, Q86V66, Q9Y6Z6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: January 11, 2011
Last modified: November 7, 2018
This is version 181 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human chromosome 4
    Human chromosome 4: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  7. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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