Names & Taxonomy

Uniprot ID:
O76083
Entry Name:
PDE9A_HUMAN
Status:
reviewed
Protein Names:
High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (EC 3.1.4.35)
Gene Names:
PDE9A
Gene Names Primary:
PDE9A
Organism:
Homo sapiens (Human)

Structure

Length:
593
Sequence:
MGSGSSSYRPKAIYLDIDGRIQKVIFSKYCNSSDIMDLFCIATGLPRNTTISLLTTDDAMVSIDPTMPANSERTPYKVRPVAIKQLSAGVEDKRTTSRGQSAERPLRDRRVVGLEQPRREGAFESGQVEPRPREPQGCYQEGQRIPPEREELIQSVLAQVAEQFSRAFKINELKAEVANHLAVLEKRVELEGLKVVEIEKCKSDIKKMREELAARSSRTNCPCKYSFLDNHKKLTPRRDVPTYPKYLLSPETIEALRKPTFDVWLWEPNEMLSCLEHMYHDLGLVRDFSINPVTLRRWLFCVHDNYRNNPFHNFRHCFCVAQMMYSMVWLCSLQEKFSQTDILILMTAAICHDLDHPGYNNTYQINARTELAVRYNDISPLENHHCAVAFQILAEPECNIFSNIPPDGFKQIRQGMITLILATDMARHAEIMDSFKEKMENFDYSNEEHMTLLKMILIKCCDISNEVRPMEVAEPWVDCLLEEYFMQSDREKSEGLPVAPFMDRDKVTKATAQIGFIKFVLIPMFETVTKLFPMVEEIMLQPLWESRDRYEELKRIDDAMKELQKKTDSLTSGATEKSRERSRDVKNSEGDCA
Proteomes:
UP000005640

Subcellular location

Subcellular Location:
Isoform PDE9A1: Cell projection, ruffle membrane

Function

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).
Pathway:
Purine metabolism; 3',5'-cyclic GMP degradation; GMP from 3',5'-cyclic GMP: step 1/1.
Catalytic Activity:
Guanosine 3',5'-cyclic phosphate + H(2)O = guanosine 5'-phosphate.
Cofactor:
COFACTOR: Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
Kinetics:
BIOPHYSICOCHEMICAL PROPERTIES: ; Kinetic parameters: KM=0.113 uM for cGMP
Enzyme Regulation:
ENZYME 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-Pyrazolopyrimidin-4-one, 1- cyclopentyl-1,5-dihydro-6--one) (PubMed:19919087). Specifically inhibited by PF-4449613 ((R)-6-(1-(3-phenoxyazetidin-1-yl)ethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolopyrimidin- 4(5H)-one) (PubMed:25799991). Specifically inhibited by inhibitor 28 (2-((1-(2-Chlorophenyl)-4-hydroxy-1Hpyrazolopyrimidin-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--1,5-dihydro-4h-pyrazolo pyrimidin-4-one: inhibitor forms a hydrogen bond with Tyr-484 and Gln-513 (PubMed:23025719).
Active Site:
ACT_SITE 312 312 Proton donor.
Cross Reference Drug Bank:
DB00201
Gene Ontology Go:
cytosol
endoplasmic reticulum
Golgi apparatus
perikaryon
perinuclear region of cytoplasm
ruffle membrane
sarcolemma
3',5'-cyclic-GMP phosphodiesterase activity
3',5'-cyclic-nucleotide phosphodiesterase activity
metal ion binding
blood coagulation
cGMP catabolic process
cGMP metabolic process
cGMP-mediated signaling
positive regulation of cardiac muscle hypertrophy
signal transduction
Gene Ontology Biological Process:
blood coagulation
cGMP catabolic process
cGMP-mediated signaling
cGMP metabolic process
positive regulation of cardiac muscle hypertrophy
signal transduction
Gene Ontology Molecular Function:
3',5'-cyclic-GMP phosphodiesterase activity
3',5'-cyclic-nucleotide phosphodiesterase activity
metal ion binding
Gene Ontology Cellular Component:
cytosol
endoplasmic reticulum
Golgi apparatus
perikaryon
perinuclear region of cytoplasm
ruffle membrane
sarcolemma
Keywords:
3D-structure
Alternative splicing
Cell membrane
Cell projection
Complete proteome
Cytoplasm
Endoplasmic reticulum
Golgi apparatus
Hydrolase
Magnesium
Membrane
Metal-binding
Phosphoprotein
Reference proteome
Zinc
cGMP
Interacts With:
O95817; A2RU00; P49759; Q49AN0; Q9H8Y8; P60410; Q9BYR5; Q9BYQ4; Q14657; P25791; Q9BRA0; Q7Z3S9; Q96FC7-2; P49888; Q13049; Q9BRU9; Q9Y260

Publication

PubMed ID:
9624146 9856478 12565835 14527714 17090334 14702039 10830953 15489334 16150925 22328573 24746902 25799991 15210993 18757755 19919087 20121115 21483814 22985069 23025719