UniProt functional annotation for O76083



	UniProt functional annotation for O76083

UniProt code: O76083.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Specifically hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes. Highly specific: compared to other members of the cyclic nucleotide phosphodiesterase family, has the highest affinity and selectivity for cGMP (PubMed:9624146, PubMed:18757755, PubMed:21483814). Specifically regulates natriuretic-peptide-dependent cGMP signaling in heart, acting as a regulator of cardiac hypertrophy in myocytes and muscle. Does not regulate nitric oxide-dependent cGMP in heart (PubMed:25799991). Additional experiments are required to confirm whether its ability to hydrolyze natriuretic-peptide-dependent cGMP is specific to heart or is a general feature of the protein (Probable). In brain, involved in cognitive function, such as learning and long-term memory (By similarity). {ECO:0000250|UniProtKB:Q8QZV1, ECO:0000269|PubMed:18757755, ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624146, ECO:0000305}.

Catalytic activity: Reaction=3',5'-cyclic GMP + H2O = GMP + H(+); Xref=Rhea:RHEA:16957, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57746, ChEBI:CHEBI:58115; EC=3.1.4.35; Evidence={ECO:0000269|PubMed:18757755, ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:9624146};

Cofactor: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115, ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069, ECO:0000269|PubMed:23025719, ECO:0000305|PubMed:18757755}; Note=Binds 1 Zn(2+) ion per subunit. Binds 2 divalent metal cations per subunit: site 1 preferentially binds zinc, while site 2 has a preference for magnesium. Tightly binds zinc. {ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115, ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069, ECO:0000269|PubMed:23025719, ECO:0000305|PubMed:18757755};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115, ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069, ECO:0000269|PubMed:23025719, ECO:0000305|PubMed:18757755}; Note=Binds 1 Mg(2+) ions per subunit. Binds 2 divalent metal cations per subunit: site 1 preferentially binds zinc, while site 2 has a preference for magnesium. Binds magnesium less tightly than zinc. {ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115, ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069, ECO:0000269|PubMed:23025719, ECO:0000305|PubMed:18757755};

Activity regulation: Inhibited by zaprinast; inhibitor is however not specific to PDE9A (PubMed:9624146). Specifically inhibited by BAY-73- 6691 (1-(2-chlorophenyl)-6-((2R)-3,3,3- trifluoro-2-methylpropyl)-1,5- dihydro-4H-pyrazolo(3,4-d)pyrimidine-4-one) (PubMed:16150925). BAY-73- 9961 has two enantiomers, (R) and (S), due to the presence of a chiral center, and both forms vary in their pattern of interaction (PubMed:20121115, PubMed:21483814). Specifically inhibited by PF- 4181366 (4H-Pyrazolo[3,4-d]pyrimidin-4-one, 1- cyclopentyl-1,5-dihydro- 6-[(3S,4S)-4-methyl- 1-(6-quinoxalinylmethyl)-3-pyrrolidinyl]-one) (PubMed:19919087). Specifically inhibited by PF-4449613 ((R)-6-(1-(3- phenoxyazetidin-1-yl)ethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H- pyrazolo[3,4-d]pyrimidin- 4(5H)-one) (PubMed:25799991). Specifically inhibited by inhibitor 28 (2-((1-(2-Chlorophenyl)-4-hydroxy-1Hpyrazolo[ 3,4-d]pyrimidin-6-yl)amino)-N-(4- methoxyphenyl)propanamide): inhibitor forms a hydrogen bond with Tyr-484 and Gln-513 (PubMed:22985069). Specifically inhibited by 1-Cyclopentyl-6-[(1r)-1-(3- phenoxyazetidin- 1-Yl)ethyl]-1,5-dihydro-4h-pyrazolo[3,4-D] pyrimidin- 4-one: inhibitor forms a hydrogen bond with Tyr-484 and Gln-513 (PubMed:23025719). {ECO:0000269|PubMed:16150925, ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115, ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069, ECO:0000269|PubMed:23025719, ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624146, ECO:0000303|PubMed:24746902}.

Biophysicochemical properties: Kinetic parameters: KM=0.113 uM for cGMP {ECO:0000269|PubMed:21483814}; KM=501 uM for cAMP {ECO:0000269|PubMed:21483814}; Vmax=0.285 umol/min/mg enzyme with cGMP as substrate {ECO:0000269|PubMed:21483814}; Vmax=3.7 umol/min/mg enzyme with cAMP as substrate {ECO:0000269|PubMed:21483814}; Note=kcat is 0.18 sec(-1) for cGMP. kcat is 2.37 sec(-1) for cAMP. {ECO:0000269|PubMed:21483814};

Pathway: Purine metabolism; 3',5'-cyclic GMP degradation; GMP from 3',5'-cyclic GMP: step 1/1.

Subunit: Homodimer. {ECO:0000269|PubMed:15210993, ECO:0000269|PubMed:21483814}.

Subcellular location: [Isoform PDE9A1]: Cell projection, ruffle membrane {ECO:0000269|PubMed:17090334}. Cytoplasm, perinuclear region {ECO:0000269|PubMed:17090334}. Golgi apparatus {ECO:0000269|PubMed:17090334}. Endoplasmic reticulum {ECO:0000269|PubMed:17090334}. Cell membrane, sarcolemma {ECO:0000269|PubMed:25799991}.

Subcellular location: [Isoform PDE9A2]: Cell projection, ruffle membrane {ECO:0000269|PubMed:17090334}. Cytoplasm, perinuclear region {ECO:0000269|PubMed:17090334}.

Subcellular location: [Isoform PDE9A3]: Cytoplasm {ECO:0000269|PubMed:17090334}. Endoplasmic reticulum {ECO:0000269|PubMed:17090334}.

Subcellular location: [Isoform PDE9A17]: Cytoplasm {ECO:0000269|PubMed:17090334}. Endoplasmic reticulum {ECO:0000269|PubMed:17090334}.

Tissue specificity: Expressed in all tissues examined (testis, brain, small intestine, skeletal muscle, heart, lung, thymus, spleen, placenta, kidney, liver, pancreas, ovary and prostate) except blood (PubMed:9624146). Highest levels in brain, heart, kidney, spleen, prostate and colon. Isoform PDE9A12 is found in prostate (PubMed:12565835). In brain, present in the cortex, cerebellum, and subiculum (at protein level) (PubMed:22328573). In heart, primarily localizes to myocytes (PubMed:25799991). {ECO:0000269|PubMed:12565835, ECO:0000269|PubMed:22328573, ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624146}.

Induction: Up-regulated in left ventricular hypertrophy from aortic stenosis and following heart failure with preserved ejection fraction (at protein level). {ECO:0000269|PubMed:25799991}.

Miscellaneous: PDE9A is a potential target for treatment of diseases such as stress-induced heart disease or long-term memory defects. Specific inhibitors, such as BAY-73-6691 or PF-4449613 are promising candidates for clinical tests. {ECO:0000303|PubMed:24746902, ECO:0000305|PubMed:25799991}.

Similarity: Belongs to the cyclic nucleotide phosphodiesterase family. PDE9 subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Specifically hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes. Highly specific: compared to other members of the cyclic nucleotide phosphodiesterase family, has the highest affinity and selectivity for cGMP (PubMed:9624146, PubMed:18757755, PubMed:21483814). Specifically regulates natriuretic-peptide-dependent cGMP signaling in heart, acting as a regulator of cardiac hypertrophy in myocytes and muscle. Does not regulate nitric oxide-dependent cGMP in heart (PubMed:25799991). Additional experiments are required to confirm whether its ability to hydrolyze natriuretic-peptide-dependent cGMP is specific to heart or is a general feature of the protein (Probable). In brain, involved in cognitive function, such as learning and long-term memory (By similarity). {ECO:0000250\|UniProtKB:Q8QZV1, ECO:0000269\|PubMed:18757755, ECO:0000269\|PubMed:21483814, ECO:0000269\|PubMed:25799991, ECO:0000269\|PubMed:9624146, ECO:0000305}.


Catalytic activity:		Reaction=3',5'-cyclic GMP + H2O = GMP + H(+); Xref=Rhea:RHEA:16957, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57746, ChEBI:CHEBI:58115; EC=3.1.4.35; Evidence={ECO:0000269\|PubMed:18757755, ECO:0000269\|PubMed:21483814, ECO:0000269\|PubMed:9624146};
Cofactor:		Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269\|PubMed:19919087, ECO:0000269\|PubMed:20121115, ECO:0000269\|PubMed:21483814, ECO:0000269\|PubMed:22985069, ECO:0000269\|PubMed:23025719, ECO:0000305\|PubMed:18757755}; Note=Binds 1 Zn(2+) ion per subunit. Binds 2 divalent metal cations per subunit: site 1 preferentially binds zinc, while site 2 has a preference for magnesium. Tightly binds zinc. {ECO:0000269\|PubMed:19919087, ECO:0000269\|PubMed:20121115, ECO:0000269\|PubMed:21483814, ECO:0000269\|PubMed:22985069, ECO:0000269\|PubMed:23025719, ECO:0000305\|PubMed:18757755};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:19919087, ECO:0000269\|PubMed:20121115, ECO:0000269\|PubMed:21483814, ECO:0000269\|PubMed:22985069, ECO:0000269\|PubMed:23025719, ECO:0000305\|PubMed:18757755}; Note=Binds 1 Mg(2+) ions per subunit. Binds 2 divalent metal cations per subunit: site 1 preferentially binds zinc, while site 2 has a preference for magnesium. Binds magnesium less tightly than zinc. {ECO:0000269\|PubMed:19919087, ECO:0000269\|PubMed:20121115, ECO:0000269\|PubMed:21483814, ECO:0000269\|PubMed:22985069, ECO:0000269\|PubMed:23025719, ECO:0000305\|PubMed:18757755};
Activity regulation:		Inhibited by zaprinast; inhibitor is however not specific to PDE9A (PubMed:9624146). Specifically inhibited by BAY-73- 6691 (1-(2-chlorophenyl)-6-((2R)-3,3,3- trifluoro-2-methylpropyl)-1,5- dihydro-4H-pyrazolo(3,4-d)pyrimidine-4-one) (PubMed:16150925). BAY-73- 9961 has two enantiomers, (R) and (S), due to the presence of a chiral center, and both forms vary in their pattern of interaction (PubMed:20121115, PubMed:21483814). Specifically inhibited by PF- 4181366 (4H-Pyrazolo[3,4-d]pyrimidin-4-one, 1- cyclopentyl-1,5-dihydro- 6-[(3S,4S)-4-methyl- 1-(6-quinoxalinylmethyl)-3-pyrrolidinyl]-one) (PubMed:19919087). Specifically inhibited by PF-4449613 ((R)-6-(1-(3- phenoxyazetidin-1-yl)ethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H- pyrazolo[3,4-d]pyrimidin- 4(5H)-one) (PubMed:25799991). Specifically inhibited by inhibitor 28 (2-((1-(2-Chlorophenyl)-4-hydroxy-1Hpyrazolo[ 3,4-d]pyrimidin-6-yl)amino)-N-(4- methoxyphenyl)propanamide): inhibitor forms a hydrogen bond with Tyr-484 and Gln-513 (PubMed:22985069). Specifically inhibited by 1-Cyclopentyl-6-[(1r)-1-(3- phenoxyazetidin- 1-Yl)ethyl]-1,5-dihydro-4h-pyrazolo[3,4-D] pyrimidin- 4-one: inhibitor forms a hydrogen bond with Tyr-484 and Gln-513 (PubMed:23025719). {ECO:0000269\|PubMed:16150925, ECO:0000269\|PubMed:19919087, ECO:0000269\|PubMed:20121115, ECO:0000269\|PubMed:21483814, ECO:0000269\|PubMed:22985069, ECO:0000269\|PubMed:23025719, ECO:0000269\|PubMed:25799991, ECO:0000269\|PubMed:9624146, ECO:0000303\|PubMed:24746902}.
Biophysicochemical properties:		Kinetic parameters: KM=0.113 uM for cGMP {ECO:0000269\|PubMed:21483814}; KM=501 uM for cAMP {ECO:0000269\|PubMed:21483814}; Vmax=0.285 umol/min/mg enzyme with cGMP as substrate {ECO:0000269\|PubMed:21483814}; Vmax=3.7 umol/min/mg enzyme with cAMP as substrate {ECO:0000269\|PubMed:21483814}; Note=kcat is 0.18 sec(-1) for cGMP. kcat is 2.37 sec(-1) for cAMP. {ECO:0000269\|PubMed:21483814};
Pathway:		Purine metabolism; 3',5'-cyclic GMP degradation; GMP from 3',5'-cyclic GMP: step 1/1.
Subunit:		Homodimer. {ECO:0000269\|PubMed:15210993, ECO:0000269\|PubMed:21483814}.
Subcellular location:		[Isoform PDE9A1]: Cell projection, ruffle membrane {ECO:0000269\|PubMed:17090334}. Cytoplasm, perinuclear region {ECO:0000269\|PubMed:17090334}. Golgi apparatus {ECO:0000269\|PubMed:17090334}. Endoplasmic reticulum {ECO:0000269\|PubMed:17090334}. Cell membrane, sarcolemma {ECO:0000269\|PubMed:25799991}.
Subcellular location:		[Isoform PDE9A2]: Cell projection, ruffle membrane {ECO:0000269\|PubMed:17090334}. Cytoplasm, perinuclear region {ECO:0000269\|PubMed:17090334}.
Subcellular location:		[Isoform PDE9A3]: Cytoplasm {ECO:0000269\|PubMed:17090334}. Endoplasmic reticulum {ECO:0000269\|PubMed:17090334}.
Subcellular location:		[Isoform PDE9A17]: Cytoplasm {ECO:0000269\|PubMed:17090334}. Endoplasmic reticulum {ECO:0000269\|PubMed:17090334}.
Tissue specificity:		Expressed in all tissues examined (testis, brain, small intestine, skeletal muscle, heart, lung, thymus, spleen, placenta, kidney, liver, pancreas, ovary and prostate) except blood (PubMed:9624146). Highest levels in brain, heart, kidney, spleen, prostate and colon. Isoform PDE9A12 is found in prostate (PubMed:12565835). In brain, present in the cortex, cerebellum, and subiculum (at protein level) (PubMed:22328573). In heart, primarily localizes to myocytes (PubMed:25799991). {ECO:0000269\|PubMed:12565835, ECO:0000269\|PubMed:22328573, ECO:0000269\|PubMed:25799991, ECO:0000269\|PubMed:9624146}.
Induction:		Up-regulated in left ventricular hypertrophy from aortic stenosis and following heart failure with preserved ejection fraction (at protein level). {ECO:0000269\|PubMed:25799991}.
Miscellaneous:		PDE9A is a potential target for treatment of diseases such as stress-induced heart disease or long-term memory defects. Specific inhibitors, such as BAY-73-6691 or PF-4449613 are promising candidates for clinical tests. {ECO:0000303\|PubMed:24746902, ECO:0000305\|PubMed:25799991}.
Similarity:		Belongs to the cyclic nucleotide phosphodiesterase family. PDE9 subfamily. {ECO:0000305}.