UniProt functional annotation for Q96PN6



	UniProt functional annotation for Q96PN6

UniProt code: Q96PN6.

Organism: Homo sapiens (Human).

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

Function: Catalyzes the formation of the signaling molecule cAMP (PubMed:12609998, PubMed:15659711, PubMed:24616449, PubMed:25040695, PubMed:24567411). May function as sensor that mediates responses to changes in cellular bicarbonate and CO(2) levels (PubMed:15659711, PubMed:17591988). Has a critical role in mammalian spermatogenesis by producing the cAMP which regulates cAMP-responsive nuclear factors indispensable for sperm maturation in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization (By similarity). Involved in ciliary beat regulation (PubMed:17591988). {ECO:0000250|UniProtKB:Q8C0T9, ECO:0000269|PubMed:15659711, ECO:0000269|PubMed:17591988, ECO:0000269|PubMed:24567411, ECO:0000269|PubMed:24616449, ECO:0000269|PubMed:25040695}.

Catalytic activity: Reaction=ATP = 3',5'-cyclic AMP + diphosphate; Xref=Rhea:RHEA:15389, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:58165; EC=4.6.1.1; Evidence={ECO:0000269|PubMed:12609998, ECO:0000269|PubMed:15659711, ECO:0000269|PubMed:24567411, ECO:0000269|PubMed:24616449, ECO:0000269|PubMed:25040695};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:12609998, ECO:0000269|PubMed:15659711, ECO:0000269|PubMed:24567411, ECO:0000269|PubMed:25040695, ECO:0000305|PubMed:24616449}; Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000269|PubMed:12609998, ECO:0000269|PubMed:15659711, ECO:0000269|PubMed:24616449}; Note=Binds 2 magnesium ions per subunit (PubMed:25040695). Is also active with manganese (in vitro) (PubMed:12609998, PubMed:15659711, PubMed:24616449). {ECO:0000269|PubMed:12609998, ECO:0000269|PubMed:15659711, ECO:0000269|PubMed:24616449, ECO:0000305|PubMed:25040695};

Activity regulation: Activated by manganese or magnesium ions (PubMed:12609998, PubMed:24616449). In the presence of magnesium ions, the enzyme is activated by bicarbonate (PubMed:12609998, PubMed:15659711, PubMed:24567411). In the presence of manganese ions, the enzyme is inhibited by bicarbonate (PubMed:15659711). In the absence of magnesium and bicarbonate, the enzyme is weakly activated by calcium (PubMed:15659711). Calcium mildly increases the enzyme activity, also in the presence of magnesium ions (PubMed:15659711, PubMed:25040695). {ECO:0000269|PubMed:12609998, ECO:0000269|PubMed:15659711, ECO:0000269|PubMed:24567411, ECO:0000269|PubMed:24616449, ECO:0000269|PubMed:25040695}.

Biophysicochemical properties: Kinetic parameters: KM=0.8 mM for ATP-Mn(2+) {ECO:0000269|PubMed:12609998}; KM=2.41 mM for Mg(2+) {ECO:0000269|PubMed:12609998};

Subcellular location: Cell membrane {ECO:0000269|PubMed:15659711}; Peripheral membrane protein {ECO:0000269|PubMed:15659711}; Cytoplasmic side {ECO:0000269|PubMed:15659711}. Cytoplasm, cytoskeleton {ECO:0000269|PubMed:12475901, ECO:0000269|PubMed:15659711}. Cytoplasm, perinuclear region {ECO:0000269|PubMed:12475901, ECO:0000269|PubMed:15659711}. Nucleus {ECO:0000269|PubMed:12475901, ECO:0000269|PubMed:15659711}. Cell projection, cilium {ECO:0000269|PubMed:17591988}. Cytoplasm {ECO:0000269|PubMed:12475901}. Mitochondrion {ECO:0000269|PubMed:12475901}. Note=Distributed to subcellular compartments containing cAMP targets. Found as a plasma membrane-associated protein, protein concentrated in the perinuclear region and protein colocalized with actin or tubulin. {ECO:0000269|PubMed:12475901, ECO:0000269|PubMed:15659711}.

Tissue specificity: Detected in airway epithelial cells and testis (at protein level) (PubMed:17591988). Weakly expressed in multiple tissues. Expressed in brain, heart, kidney, liver, lung, pancreas, peripheral blood leukocytes, placenta, skeletal muscle, stomach, thymus, airway epithelial cells, duodenum, jejunum and ileum. Very low level of expression in bone. {ECO:0000269|PubMed:11932268, ECO:0000269|PubMed:15659711, ECO:0000269|PubMed:17591988}.

Domain: The N-terminal guanylate cyclase domains are required for enzyme activity. Fragments or isoforms containing the first 470 amino acid residues are fully active. {ECO:0000269|PubMed:24567411, ECO:0000269|PubMed:24616449, ECO:0000269|PubMed:25040695}.

Ptm: Cleavage may occur to generate the active 48 kDa form. {ECO:0000305}.

Disease: Hypercalciuria absorptive 2 (HCA2) [MIM:143870]: A common type of hypercalciuria, a condition characterized by excessive urinary calcium excretion. Absorptive hypercalciuria is due to gastrointestinal hyperabsorption of calcium and is a frequent cause of calcium oxalate nephrolithiasis. {ECO:0000269|PubMed:11932268}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity: Belongs to the adenylyl cyclase class-4/guanylyl cyclase family. {ECO:0000255|PROSITE-ProRule:PRU00099}.

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:		Catalyzes the formation of the signaling molecule cAMP (PubMed:12609998, PubMed:15659711, PubMed:24616449, PubMed:25040695, PubMed:24567411). May function as sensor that mediates responses to changes in cellular bicarbonate and CO(2) levels (PubMed:15659711, PubMed:17591988). Has a critical role in mammalian spermatogenesis by producing the cAMP which regulates cAMP-responsive nuclear factors indispensable for sperm maturation in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization (By similarity). Involved in ciliary beat regulation (PubMed:17591988). {ECO:0000250\|UniProtKB:Q8C0T9, ECO:0000269\|PubMed:15659711, ECO:0000269\|PubMed:17591988, ECO:0000269\|PubMed:24567411, ECO:0000269\|PubMed:24616449, ECO:0000269\|PubMed:25040695}.


Catalytic activity:		Reaction=ATP = 3',5'-cyclic AMP + diphosphate; Xref=Rhea:RHEA:15389, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:58165; EC=4.6.1.1; Evidence={ECO:0000269\|PubMed:12609998, ECO:0000269\|PubMed:15659711, ECO:0000269\|PubMed:24567411, ECO:0000269\|PubMed:24616449, ECO:0000269\|PubMed:25040695};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:12609998, ECO:0000269\|PubMed:15659711, ECO:0000269\|PubMed:24567411, ECO:0000269\|PubMed:25040695, ECO:0000305\|PubMed:24616449}; Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000269\|PubMed:12609998, ECO:0000269\|PubMed:15659711, ECO:0000269\|PubMed:24616449}; Note=Binds 2 magnesium ions per subunit (PubMed:25040695). Is also active with manganese (in vitro) (PubMed:12609998, PubMed:15659711, PubMed:24616449). {ECO:0000269\|PubMed:12609998, ECO:0000269\|PubMed:15659711, ECO:0000269\|PubMed:24616449, ECO:0000305\|PubMed:25040695};
Activity regulation:		Activated by manganese or magnesium ions (PubMed:12609998, PubMed:24616449). In the presence of magnesium ions, the enzyme is activated by bicarbonate (PubMed:12609998, PubMed:15659711, PubMed:24567411). In the presence of manganese ions, the enzyme is inhibited by bicarbonate (PubMed:15659711). In the absence of magnesium and bicarbonate, the enzyme is weakly activated by calcium (PubMed:15659711). Calcium mildly increases the enzyme activity, also in the presence of magnesium ions (PubMed:15659711, PubMed:25040695). {ECO:0000269\|PubMed:12609998, ECO:0000269\|PubMed:15659711, ECO:0000269\|PubMed:24567411, ECO:0000269\|PubMed:24616449, ECO:0000269\|PubMed:25040695}.
Biophysicochemical properties:		Kinetic parameters: KM=0.8 mM for ATP-Mn(2+) {ECO:0000269\|PubMed:12609998}; KM=2.41 mM for Mg(2+) {ECO:0000269\|PubMed:12609998};
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:15659711}; Peripheral membrane protein {ECO:0000269\|PubMed:15659711}; Cytoplasmic side {ECO:0000269\|PubMed:15659711}. Cytoplasm, cytoskeleton {ECO:0000269\|PubMed:12475901, ECO:0000269\|PubMed:15659711}. Cytoplasm, perinuclear region {ECO:0000269\|PubMed:12475901, ECO:0000269\|PubMed:15659711}. Nucleus {ECO:0000269\|PubMed:12475901, ECO:0000269\|PubMed:15659711}. Cell projection, cilium {ECO:0000269\|PubMed:17591988}. Cytoplasm {ECO:0000269\|PubMed:12475901}. Mitochondrion {ECO:0000269\|PubMed:12475901}. Note=Distributed to subcellular compartments containing cAMP targets. Found as a plasma membrane-associated protein, protein concentrated in the perinuclear region and protein colocalized with actin or tubulin. {ECO:0000269\|PubMed:12475901, ECO:0000269\|PubMed:15659711}.
Tissue specificity:		Detected in airway epithelial cells and testis (at protein level) (PubMed:17591988). Weakly expressed in multiple tissues. Expressed in brain, heart, kidney, liver, lung, pancreas, peripheral blood leukocytes, placenta, skeletal muscle, stomach, thymus, airway epithelial cells, duodenum, jejunum and ileum. Very low level of expression in bone. {ECO:0000269\|PubMed:11932268, ECO:0000269\|PubMed:15659711, ECO:0000269\|PubMed:17591988}.
Domain:		The N-terminal guanylate cyclase domains are required for enzyme activity. Fragments or isoforms containing the first 470 amino acid residues are fully active. {ECO:0000269\|PubMed:24567411, ECO:0000269\|PubMed:24616449, ECO:0000269\|PubMed:25040695}.
Ptm:		Cleavage may occur to generate the active 48 kDa form. {ECO:0000305}.
Disease:		Hypercalciuria absorptive 2 (HCA2) [MIM:143870]: A common type of hypercalciuria, a condition characterized by excessive urinary calcium excretion. Absorptive hypercalciuria is due to gastrointestinal hyperabsorption of calcium and is a frequent cause of calcium oxalate nephrolithiasis. {ECO:0000269\|PubMed:11932268}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Similarity:		Belongs to the adenylyl cyclase class-4/guanylyl cyclase family. {ECO:0000255\|PROSITE-ProRule:PRU00099}.