Reviewed, UniProtKB/Swiss-Prot O76074 (PDE5A_HUMAN)

Names and origin

Protein names

Recommended name:
    cGMP-specific 3',5'-cyclic phosphodiesterase
    EC=3.1.4.35
Alternative name(s):
    cGMP-binding cGMP-specific phosphodiesterase
      Short name=CGB-PDE

Gene names

Name:	PDE5A
Synonyms:	PDE5

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	875 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	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.
Catalytic activity	Guanosine 3',5'-cyclic phosphate + H2O = guanosine 5'-phosphate.
Cofactor	Divalent cations. Zinc ions yields maximum activity. Manganese, magnesium and cobalt also support catalysis but at much higher concentrations.
Enzyme regulation	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.
Pathway	Purine metabolism; cGMP degradation; GMP from cGMP: step 1/1.
Tissue specificity	Expressed in aortic smooth muscle cells, heart, placenta, skeletal muscle and pancreas and, to a much lesser extent, in brain, liver and lung.
Domain	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.
Post-translational modification	Phosphorylation is regulated by binding of cGMP to the two allosteric sites By similarity.
Sequence similarities	Belongs to the cyclic nucleotide phosphodiesterase family. Contains 2 GAF domains.

Ontologies

Keywords
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Repeat
Ligand	Magnesium Metal-binding Nucleotide-binding Zinc cGMP cGMP-binding
Molecular function	Hydrolase
PTM	Phosphoprotein
Technical term	3D-structure Allosteric enzyme
Gene Ontology (GO)
Biological process	cyclic nucleotide metabolic process Non-traceable author statement. Source: UniProtKB signal transduction Non-traceable author statement. Source: UniProtKB
Cellular component	cytoplasm Inferred from direct assay. Source: HPA
Molecular function	3',5'-cyclic-GMP phosphodiesterase activity Inferred from electronic annotation. Source: EC cGMP binding Inferred from electronic annotation. Source: UniProtKB-KW magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW zinc ion binding Non-traceable author statement. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform PDE5A1 (identifier: O76074-1)

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.

Isoform PDE5A2 (identifier: O76074-2)

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

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 875

875

cGMP-specific 3',5'-cyclic phosphodiesterase

PRO_0000198823

Regions

Domain

164 – 314

151

GAF 1

Domain

346 – 503

158

GAF 2

Region

588 – 853

266

Catalytic By similarity

Compositional bias

10 – 24

15

Poly-Gln

Sites

Metal binding

617

1

Zinc

Metal binding

653

1

Zinc

Metal binding

654

1

Magnesium

Metal binding

654

1

Zinc

Metal binding

657

1

Magnesium

Metal binding

682

1

Magnesium

Metal binding

764

1

Zinc

Binding site

817

1

cGMP

Amino acid modifications

Modified residue

102

1

Phosphoserine Potential

Natural variations

Alternative sequence

1 – 49

49

MERAG…FVRKA → MLPFGDK in isoform PDE5A2.

VSP_004591

Natural variant

93

1

V → A: dbSNP rs3733526. Ref.5 Ref.7

VAR_027775

Natural variant

181

1

S → A: dbSNP rs17051276.

VAR_027776

Experimental info

Sequence conflict

159

1

I → V in AAP31235. Ref.8

Sequence conflict

310

1

C → G in AAP31235. Ref.8

Sequence conflict

381

1

S → F in AAP31235. Ref.8

Sequence conflict

406

1

K → R in AAP31235. Ref.8

Sequence conflict

642

1

E → G in BAA81667. Ref.4

Secondary structure

1

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875

Helix Strand Turn

Details...

Helix

535 – 545

11

Helix

551 – 554

4

Turn

555 – 557

3

Helix

568 – 581

14

Helix

584 – 587

4

Helix

592 – 604

13

Beta strand

610 – 614

5

Helix

615 – 630

16

Helix

635 – 637

3

Helix

640 – 652

13

Turn

653 – 656

4

Helix

662 – 667

6

Helix

671 – 675

5

Helix

680 – 694

15

Turn

700 – 703

4

Helix

706 – 722

17

Helix

725 – 740

16

Helix

749 – 764

16

Helix

766 – 769

4

Helix

772 – 796

25

Helix

803 – 805

3

Helix

807 – 812

6

Helix

813 – 823

11

Helix

825 – 835

11

Helix

837 – 839

3

Helix

840 – 857

18

Sequences

	Sequence		Length	Mass (Da)
	Isoform PDE5A1 [UniParc]. Last modified November 1, 1998. Version 1. Checksum: 91EA8C33B6CD254D	FASTA	875	100,013
	10 20 30 40 50 60 MERAGPSFGQ QRQQQQPQQQ KQQQRDQDSV EAWLDDHWDF TFSYFVRKAT REMVNAWFAE 70 80 90 100 110 120 RVHTIPVCKE GIRGHTESCS CPLQQSPRAD NSVPGTPTRK ISASEFDRPL RPIVVKDSEG 130 140 150 160 170 180 TVSFLSDSEK KEQMPLTPPR FDHDEGDQCS RLLELVKDIS SHLDVTALCH KIFLHIHGLI 190 200 210 220 230 240 SADRYSLFLV CEDSSNDKFL ISRLFDVAEG STLEEVSNNC IRLEWNKGIV GHVAALGEPL 250 260 270 280 290 300 NIKDAYEDPR FNAEVDQITG YKTQSILCMP IKNHREEVVG VAQAINKKSG NGGTFTEKDE 310 320 330 340 350 360 KDFAAYLAFC GIVLHNAQLY ETSLLENKRN QVLLDLASLI FEEQQSLEVI LKKIAATIIS 370 380 390 400 410 420 FMQVQKCTIF IVDEDCSDSF SSVFHMECEE LEKSSDTLTR EHDANKINYM YAQYVKNTME 430 440 450 460 470 480 PLNIPDVSKD KRFPWTTENT GNVNQQCIRS LLCTPIKNGK KNKVIGVCQL VNKMEENTGK 490 500 510 520 530 540 VKPFNRNDEQ FLEAFVIFCG LGIQNTQMYE AVERAMAKQM VTLEVLSYHA SAAEEETREL 550 560 570 580 590 600 QSLAAAVVPS AQTLKITDFS FSDFELSDLE TALCTIRMFT DLNLVQNFQM KHEVLCRWIL 610 620 630 640 650 660 SVKKNYRKNV AYHNWRHAFN TAQCMFAALK AGKIQNKLTD LEILALLIAA LSHDLDHRGV 670 680 690 700 710 720 NNSYIQRSEH PLAQLYCHSI MEHHHFDQCL MILNSPGNQI LSGLSIEEYK TTLKIIKQAI 730 740 750 760 770 780 LATDLALYIK RRGEFFELIR KNQFNLEDPH QKELFLAMLM TACDLSAITK PWPIQQRIAE 790 800 810 820 830 840 LVATEFFDQG DRERKELNIE PTDLMNREKK NKIPSMQVGF IDAICLQLYE ALTHVSEDCF 850 860 870 PLLDGCRKNR QKWQALAEQQ EKMLINGESG QAKRN
	Isoform PDE5A2. Checksum: 4E0AFE438E896BA8	FASTA	833	94,834
	10 20 30 40 50 60 MLPFGDKTRE MVNAWFAERV HTIPVCKEGI RGHTESCSCP LQQSPRADNS VPGTPTRKIS 70 80 90 100 110 120 ASEFDRPLRP IVVKDSEGTV SFLSDSEKKE QMPLTPPRFD HDEGDQCSRL LELVKDISSH 130 140 150 160 170 180 LDVTALCHKI FLHIHGLISA DRYSLFLVCE DSSNDKFLIS RLFDVAEGST LEEVSNNCIR 190 200 210 220 230 240 LEWNKGIVGH VAALGEPLNI KDAYEDPRFN AEVDQITGYK TQSILCMPIK NHREEVVGVA 250 260 270 280 290 300 QAINKKSGNG GTFTEKDEKD FAAYLAFCGI VLHNAQLYET SLLENKRNQV LLDLASLIFE 310 320 330 340 350 360 EQQSLEVILK KIAATIISFM QVQKCTIFIV DEDCSDSFSS VFHMECEELE KSSDTLTREH 370 380 390 400 410 420 DANKINYMYA QYVKNTMEPL NIPDVSKDKR FPWTTENTGN VNQQCIRSLL CTPIKNGKKN 430 440 450 460 470 480 KVIGVCQLVN KMEENTGKVK PFNRNDEQFL EAFVIFCGLG IQNTQMYEAV ERAMAKQMVT 490 500 510 520 530 540 LEVLSYHASA AEEETRELQS LAAAVVPSAQ TLKITDFSFS DFELSDLETA LCTIRMFTDL 550 560 570 580 590 600 NLVQNFQMKH EVLCRWILSV KKNYRKNVAY HNWRHAFNTA QCMFAALKAG KIQNKLTDLE 610 620 630 640 650 660 ILALLIAALS HDLDHRGVNN SYIQRSEHPL AQLYCHSIME HHHFDQCLMI LNSPGNQILS 670 680 690 700 710 720 GLSIEEYKTT LKIIKQAILA TDLALYIKRR GEFFELIRKN QFNLEDPHQK ELFLAMLMTA 730 740 750 760 770 780 CDLSAITKPW PIQQRIAELV ATEFFDQGDR ERKELNIEPT DLMNREKKNK IPSMQVGFID 790 800 810 820 830 AICLQLYEAL THVSEDCFPL LDGCRKNRQK WQALAEQQEK MLINGESGQA KRN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation and characterization of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3',5'-cyclic nucleotide phosphodiesterase." Loughney K., Hill T.R., Florio V.A., Uher L., Rosman G.J., Wolda S.L., Jones B.A., Howard M.L., McAllister-Lucas L.M., Sonnenburg W.K., Francis S.H., Corbin J.D., Beavo J.A., Ferguson K. Gene 216:139-147(1998) [PubMed: 9714779] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS PDE5A1 AND PDE5A2).
[2]	"Expression, structure and chromosomal localization of the human cGMP-binding cGMP-specific phosphodiesterase PDE5A gene." Yanaka N., Kotera J., Ohtsuka A., Akatsuka H., Imai Y., Michibata H., Fujishige K., Kawai E., Takebayashi S., Okumura K., Omori K. Eur. J. Biochem. 255:391-399(1998) [PubMed: 9716380] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM PDE5A1). Tissue: Lung and Placenta.
[3]	"Molecular cloning and expression of human cGMP-binding cGMP-specific phosphodiesterase." Stacey P., Rulten S., Dapling A., Phillips S.C. Biochem. Biophys. Res. Commun. 247:249-254(1998) [PubMed: 9642111] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE5A1). Tissue: Prostate and Skeletal muscle.
[4]	"Molecular cloning and characterization of human cGMP-specific phosphodiesterase 5A2 cDNA." Kotera J., Imai Y., Omori K. Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE5A2). Tissue: Lung.
[5]	"PDE5A splice variants in T84 cells." Sopory S., Visweswariah S.S. Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE5A2), VARIANT ALA-93. Tissue: Colon carcinoma.
[6]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PDE5A1). Tissue: Thalamus.
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PDE5A1), VARIANT ALA-93.
[8]	"Multiple cyclic nucleotide phosphodiesterases in human trabecular meshwork cells." Zhou L., Thompson W.J., Potter D.E. Invest. Ophthalmol. Vis. Sci. 40:1745-1752(1999) [PubMed: 10393044] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 157-411. Tissue: Trabecular meshwork.
[9]	"Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules." Sung B.-J., Hwang K.Y., Jeon Y.H., Lee J.I., Heo Y.-S., Kim J.H., Moon J., Yoon J.M., Hyun Y.-L., Kim E., Eum S.J., Park S.-Y., Lee J.-O., Lee T.G., Ro S., Cho J.M. Nature 425:98-102(2003) [PubMed: 12955149] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 537-860 IN COMPLEX WITH THE INHIBITORS SILDENAFIL; TADALAFIL AND VARDENAFIL, METAL-BINDING.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

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.
BC126233 mRNA. Translation: AAI26234.1.
AY266363 mRNA. Translation: AAP31235.1.

IPI

IPI00294595.
IPI00306123.

PIR

JW0106.

RefSeq

NP_001074.2.
NP_236914.2.
NP_246273.2.

UniGene

Hs.587281
Hs.647971

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1RKP	X-ray	2.05	A	535-860	[»]
1T9R	X-ray	2.10	A	531-875	[»]
1T9S	X-ray	2.00	A/B	534-858	[»]
1TBF	X-ray	1.30	A	534-858	[»]
1UDT	X-ray	2.30	A	537-860	[»]
1UDU	X-ray	2.83	A/B	537-860	[»]
1UHO	X-ray	2.50	A	537-860	[»]
1XOZ	X-ray	1.37	A	534-875	[»]
1XP0	X-ray	1.79	A	534-875	[»]
2CHM	X-ray	1.60	A	534-858	[»]
2H40	X-ray	1.85	A	535-860	[»]
2H42	X-ray	2.30	A/B/C	535-860	[»]
2H44	X-ray	1.80	A	535-860	[»]
3B2R	X-ray	2.07	A/B	535-860	[»]
3BJC	X-ray	2.00	A	1-875	[»]

ModBase

Search...

PTM databases

PhosphoSite

O76074.

Proteomic databases

PRIDE

O76074.

Genome annotation databases

Ensembl

ENSG00000138735. Homo sapiens. [Contig view]

GeneID

8654.

KEGG

hsa:8654.

Organism-specific databases

GeneCards

GC04M120698.

H-InvDB

HIX0031341.

HGNC

HGNC:8784. PDE5A.

HPA

HPA004729.
HPA012873.

MIM

603310. gene.

PharmGKB

PA33132.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

O76074.

Enzyme and pathway databases

BRENDA

3.1.4.35. 247.

Gene expression databases

ArrayExpress

O76074.

Bgee

O76074.

CleanEx

HS_PDE5A.

GermOnline

ENSG00000138735. Homo sapiens.

Family and domain databases

InterPro

IPR003018. GAF.
IPR003607. Met-dep_phosphohydro_HD.
IPR002073. PDEase.
[Graphical view]

Pfam

PF01590. GAF. 2 hits.
PF00233. PDEase_I. 1 hit.
[Graphical view]

PRINTS

PR00387. PDIESTERASE1.

SMART

SM00065. GAF. 2 hits.
SM00471. HDc. 1 hit.
[Graphical view]

PROSITE

PS00126. PDEASE_I. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00975. Dipyridamole.
DB00806. Pentoxifylline.
DB00203. Sildenafil.
DB00820. Tadalafil.
DB00277. Theophylline.
DB00862. Vardenafil.

NextBio

32453.

SOURCE

Search...

Entry information

Entry name

PDE5A_HUMAN

Accession

Primary (citable) accession number: O76074
Secondary accession number(s): A0AV69 , A8K2C4, O75026, O75887, Q86UI0, Q86V66, Q9Y6Z6

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	November 1, 1998
Last modified:	May 26, 2009
This is version 97 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)