UniProt functional annotation for P31327



	UniProt functional annotation for P31327

UniProt code: P31327.

Organism: Homo sapiens (Human).

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

Function: Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.

Catalytic activity: Reaction=2 ATP + hydrogencarbonate + NH4(+) = 2 ADP + carbamoyl phosphate + 2 H(+) + phosphate; Xref=Rhea:RHEA:18029, ChEBI:CHEBI:15378, ChEBI:CHEBI:17544, ChEBI:CHEBI:28938, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:58228, ChEBI:CHEBI:456216; EC=6.3.4.16; Evidence={ECO:0000269|PubMed:23649895, ECO:0000269|PubMed:24813853};

Activity regulation: Requires N-acetyl-L-glutamate (NAG) as an allosteric activator. Activated by glycerol in the absence of NAG, whereas in the presence of NAG it is inhibited by increasing concentrations of glycerol. {ECO:0000269|PubMed:19754428, ECO:0000269|PubMed:23649895}.

Biophysicochemical properties: Kinetic parameters: KM=0.47 mM for ATP {ECO:0000269|PubMed:23649895}; KM=4.0 mM for HCO(3)(-) {ECO:0000269|PubMed:23649895}; KM=1.00 mM for NH(4)(+) {ECO:0000269|PubMed:23649895}; Vmax=1.22 umol/min/mg enzyme for ATP {ECO:0000269|PubMed:23649895}; Vmax=1.23 umol/min/mg enzyme for HCO(3)(-) {ECO:0000269|PubMed:23649895}; Vmax=1.19 umol/min/mg enzyme for NH(4)(+) {ECO:0000269|PubMed:23649895};

Subunit: Can form homooligomers (monomers as predominant form and dimers). {ECO:0000269|PubMed:23649895}.

Subcellular location: Mitochondrion {ECO:0000269|PubMed:22002106}. Nucleus, nucleolus {ECO:0000269|PubMed:22002106}.

Tissue specificity: Primarily in the liver and small intestine.

Domain: The type-1 glutamine amidotransferase domain is defective.

Ptm: Undergoes proteolytic cleavage in the C-terminal region corresponding to the loss of approximately 12 AA residues from the C- terminus. {ECO:0000269|PubMed:23649895}.

Ptm: Succinylated at Lys-287 and Lys-1291. Desuccinylated at Lys-1291 by SIRT5, leading to activation (By similarity). {ECO:0000250|UniProtKB:Q8C196}.

Ptm: Glutarylated. Glutarylation levels increase during fasting. Deglutarylated by SIRT5 at Lys-55, Lys-219, Lys-412, Lys-889, Lys-892, Lys-915, Lys-1360 and Lys-1486, leading to activation. {ECO:0000269|PubMed:24703693}.

Disease: Carbamoyl phosphate synthetase 1 deficiency (CPS1D) [MIM:237300]: An autosomal recessive disorder of the urea cycle causing hyperammonemia. It can present as a devastating metabolic disease dominated by severe hyperammonemia in neonates or as a more insidious late-onset condition, generally manifesting as life-threatening hyperammonemic crises under catabolic situations. Clinical features include protein intolerance, intermittent ataxia, seizures, lethargy, developmental delay and mental retardation. {ECO:0000269|PubMed:11388595, ECO:0000269|PubMed:11474210, ECO:0000269|PubMed:12655559, ECO:0000269|PubMed:12955727, ECO:0000269|PubMed:15164414, ECO:0000269|PubMed:15617192, ECO:0000269|PubMed:16737834, ECO:0000269|PubMed:17310273, ECO:0000269|PubMed:20578160, ECO:0000269|PubMed:21120950, ECO:0000269|PubMed:22173106, ECO:0000269|PubMed:23649895, ECO:0000269|PubMed:24813853, ECO:0000269|PubMed:26440671, ECO:0000269|PubMed:9711878}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Pulmonary hypertension, neonatal (PHN) [MIM:615371]: A disease characterized by elevated pulmonary artery pressure. Pulmonary hypertension in the neonate is associated with multiple underlying problems such as respiratory distress syndrome, meconium aspiration syndrome, congenital diaphragmatic hernia, bronchopulmonary dysplasia, sepsis, or congenital heart disease. {ECO:0000269|PubMed:11407344}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. CPS1 variants influence the availability of precursors for nitric oxide (NO) synthesis and play a role in clinical situations where endogenous NO production is critically important, such as neonatal pulmonary hypertension, increased pulmonary artery pressure following surgical repair of congenital heart defects or hepatovenocclusive disease following bone marrow transplantation. Infants with neonatal pulmonary hypertension homozygous for Thr-1406 have lower L-arginine concentrations than neonates homozygous for Asn-1406 (PubMed:11407344). {ECO:0000269|PubMed:11407344}.

Sequence caution: Sequence=BAD92037.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={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:		Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.


Catalytic activity:		Reaction=2 ATP + hydrogencarbonate + NH4(+) = 2 ADP + carbamoyl phosphate + 2 H(+) + phosphate; Xref=Rhea:RHEA:18029, ChEBI:CHEBI:15378, ChEBI:CHEBI:17544, ChEBI:CHEBI:28938, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:58228, ChEBI:CHEBI:456216; EC=6.3.4.16; Evidence={ECO:0000269\|PubMed:23649895, ECO:0000269\|PubMed:24813853};
Activity regulation:		Requires N-acetyl-L-glutamate (NAG) as an allosteric activator. Activated by glycerol in the absence of NAG, whereas in the presence of NAG it is inhibited by increasing concentrations of glycerol. {ECO:0000269\|PubMed:19754428, ECO:0000269\|PubMed:23649895}.
Biophysicochemical properties:		Kinetic parameters: KM=0.47 mM for ATP {ECO:0000269\|PubMed:23649895}; KM=4.0 mM for HCO(3)(-) {ECO:0000269\|PubMed:23649895}; KM=1.00 mM for NH(4)(+) {ECO:0000269\|PubMed:23649895}; Vmax=1.22 umol/min/mg enzyme for ATP {ECO:0000269\|PubMed:23649895}; Vmax=1.23 umol/min/mg enzyme for HCO(3)(-) {ECO:0000269\|PubMed:23649895}; Vmax=1.19 umol/min/mg enzyme for NH(4)(+) {ECO:0000269\|PubMed:23649895};
Subunit:		Can form homooligomers (monomers as predominant form and dimers). {ECO:0000269\|PubMed:23649895}.
Subcellular location:		Mitochondrion {ECO:0000269\|PubMed:22002106}. Nucleus, nucleolus {ECO:0000269\|PubMed:22002106}.
Tissue specificity:		Primarily in the liver and small intestine.
Domain:		The type-1 glutamine amidotransferase domain is defective.
Ptm:		Undergoes proteolytic cleavage in the C-terminal region corresponding to the loss of approximately 12 AA residues from the C- terminus. {ECO:0000269\|PubMed:23649895}.
Ptm:		Succinylated at Lys-287 and Lys-1291. Desuccinylated at Lys-1291 by SIRT5, leading to activation (By similarity). {ECO:0000250\|UniProtKB:Q8C196}.
Ptm:		Glutarylated. Glutarylation levels increase during fasting. Deglutarylated by SIRT5 at Lys-55, Lys-219, Lys-412, Lys-889, Lys-892, Lys-915, Lys-1360 and Lys-1486, leading to activation. {ECO:0000269\|PubMed:24703693}.
Disease:		Carbamoyl phosphate synthetase 1 deficiency (CPS1D) [MIM:237300]: An autosomal recessive disorder of the urea cycle causing hyperammonemia. It can present as a devastating metabolic disease dominated by severe hyperammonemia in neonates or as a more insidious late-onset condition, generally manifesting as life-threatening hyperammonemic crises under catabolic situations. Clinical features include protein intolerance, intermittent ataxia, seizures, lethargy, developmental delay and mental retardation. {ECO:0000269\|PubMed:11388595, ECO:0000269\|PubMed:11474210, ECO:0000269\|PubMed:12655559, ECO:0000269\|PubMed:12955727, ECO:0000269\|PubMed:15164414, ECO:0000269\|PubMed:15617192, ECO:0000269\|PubMed:16737834, ECO:0000269\|PubMed:17310273, ECO:0000269\|PubMed:20578160, ECO:0000269\|PubMed:21120950, ECO:0000269\|PubMed:22173106, ECO:0000269\|PubMed:23649895, ECO:0000269\|PubMed:24813853, ECO:0000269\|PubMed:26440671, ECO:0000269\|PubMed:9711878}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Pulmonary hypertension, neonatal (PHN) [MIM:615371]: A disease characterized by elevated pulmonary artery pressure. Pulmonary hypertension in the neonate is associated with multiple underlying problems such as respiratory distress syndrome, meconium aspiration syndrome, congenital diaphragmatic hernia, bronchopulmonary dysplasia, sepsis, or congenital heart disease. {ECO:0000269\|PubMed:11407344}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. CPS1 variants influence the availability of precursors for nitric oxide (NO) synthesis and play a role in clinical situations where endogenous NO production is critically important, such as neonatal pulmonary hypertension, increased pulmonary artery pressure following surgical repair of congenital heart defects or hepatovenocclusive disease following bone marrow transplantation. Infants with neonatal pulmonary hypertension homozygous for Thr-1406 have lower L-arginine concentrations than neonates homozygous for Asn-1406 (PubMed:11407344). {ECO:0000269\|PubMed:11407344}.
Sequence caution:		Sequence=BAD92037.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};