UniProt functional annotation for P9WHK7



	UniProt functional annotation for P9WHK7

UniProt code: P9WHK7.

Organism: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).

Taxonomy: Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae; Mycobacterium; Mycobacterium tuberculosis complex.

Function: Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as the source of nitrogen. Is essential for M.tuberculosis growth in vitro and ex vivo (PubMed:26097035). Regulates intracellular CTP levels through interactions with the four ribonucleotide triphosphates (By similarity). {ECO:0000255|HAMAP- Rule:MF_01227, ECO:0000269|PubMed:26097035}.

Catalytic activity: Reaction=ATP + H2O + L-glutamine + UTP = ADP + CTP + 2 H(+) + L- glutamate + phosphate; Xref=Rhea:RHEA:26426, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:29985, ChEBI:CHEBI:30616, ChEBI:CHEBI:37563, ChEBI:CHEBI:43474, ChEBI:CHEBI:46398, ChEBI:CHEBI:58359, ChEBI:CHEBI:456216; EC=6.3.4.2; Evidence={ECO:0000255|HAMAP-Rule:MF_01227, ECO:0000269|PubMed:26097035};

Activity regulation: Allosterically activated by GTP, when glutamine is the substrate; GTP has no effect on the reaction when ammonia is the substrate. The allosteric effector GTP functions by stabilizing the protein conformation that binds the tetrahedral intermediate(s) formed during glutamine hydrolysis. Inhibited by the product CTP, via allosteric rather than competitive inhibition (By similarity). Is inhibited by the EthA-activated metabolites of compounds 7947882 (5- methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl- N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide), that have been shown to have anti-tubercular activity against M.tuberculosis in its replicating, non-replicating, and intracellular states; active metabolites of 7947882 correspond to the S-dioxide and S-monoxide derivatives (PubMed:26097035). One active metabolite was shown to behave as a competitive inhibitor toward the ATP-binding site of PyrG (PubMed:26097035). Direct inhibition of PyrG decreases CTP levels, leading to disruption of the nucleotide metabolic network, characterized by increased levels of several intermediates in the biosynthesis of pyrimidines and purines (PubMed:26097035). {ECO:0000255|HAMAP-Rule:MF_01227, ECO:0000269|PubMed:26097035}.

Biophysicochemical properties: Kinetic parameters: KM=0.18 mM for ATP {ECO:0000269|PubMed:26097035}; KM=0.14 mM for UTP {ECO:0000269|PubMed:26097035}; Note=kcat is 22.9 sec(-1). {ECO:0000269|PubMed:26097035};

Pathway: Pyrimidine metabolism; CTP biosynthesis via de novo pathway; CTP from UDP: step 2/2. {ECO:0000255|HAMAP-Rule:MF_01227}.

Subunit: Homotetramer. {ECO:0000255|HAMAP-Rule:MF_01227, ECO:0000269|PubMed:26097035}.

Miscellaneous: CTPSs have evolved a hybrid strategy for distinguishing between UTP and CTP. The overlapping regions of the product feedback inhibitory and substrate sites recognize a common feature in both compounds, the triphosphate moiety. To differentiate isosteric substrate and product pyrimidine rings, an additional pocket far from the expected kinase/ligase catalytic site, specifically recognizes the cytosine and ribose portions of the product inhibitor. {ECO:0000255|HAMAP-Rule:MF_01227}.

Similarity: Belongs to the CTP synthase family. {ECO:0000255|HAMAP- Rule:MF_01227}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
Taxonomy:		Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae; Mycobacterium; Mycobacterium tuberculosis complex.



Function:		Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as the source of nitrogen. Is essential for M.tuberculosis growth in vitro and ex vivo (PubMed:26097035). Regulates intracellular CTP levels through interactions with the four ribonucleotide triphosphates (By similarity). {ECO:0000255\|HAMAP- Rule:MF_01227, ECO:0000269\|PubMed:26097035}.


Catalytic activity:		Reaction=ATP + H2O + L-glutamine + UTP = ADP + CTP + 2 H(+) + L- glutamate + phosphate; Xref=Rhea:RHEA:26426, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:29985, ChEBI:CHEBI:30616, ChEBI:CHEBI:37563, ChEBI:CHEBI:43474, ChEBI:CHEBI:46398, ChEBI:CHEBI:58359, ChEBI:CHEBI:456216; EC=6.3.4.2; Evidence={ECO:0000255\|HAMAP-Rule:MF_01227, ECO:0000269\|PubMed:26097035};
Activity regulation:		Allosterically activated by GTP, when glutamine is the substrate; GTP has no effect on the reaction when ammonia is the substrate. The allosteric effector GTP functions by stabilizing the protein conformation that binds the tetrahedral intermediate(s) formed during glutamine hydrolysis. Inhibited by the product CTP, via allosteric rather than competitive inhibition (By similarity). Is inhibited by the EthA-activated metabolites of compounds 7947882 (5- methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl- N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide), that have been shown to have anti-tubercular activity against M.tuberculosis in its replicating, non-replicating, and intracellular states; active metabolites of 7947882 correspond to the S-dioxide and S-monoxide derivatives (PubMed:26097035). One active metabolite was shown to behave as a competitive inhibitor toward the ATP-binding site of PyrG (PubMed:26097035). Direct inhibition of PyrG decreases CTP levels, leading to disruption of the nucleotide metabolic network, characterized by increased levels of several intermediates in the biosynthesis of pyrimidines and purines (PubMed:26097035). {ECO:0000255\|HAMAP-Rule:MF_01227, ECO:0000269\|PubMed:26097035}.
Biophysicochemical properties:		Kinetic parameters: KM=0.18 mM for ATP {ECO:0000269\|PubMed:26097035}; KM=0.14 mM for UTP {ECO:0000269\|PubMed:26097035}; Note=kcat is 22.9 sec(-1). {ECO:0000269\|PubMed:26097035};
Pathway:		Pyrimidine metabolism; CTP biosynthesis via de novo pathway; CTP from UDP: step 2/2. {ECO:0000255\|HAMAP-Rule:MF_01227}.
Subunit:		Homotetramer. {ECO:0000255\|HAMAP-Rule:MF_01227, ECO:0000269\|PubMed:26097035}.
Miscellaneous:		CTPSs have evolved a hybrid strategy for distinguishing between UTP and CTP. The overlapping regions of the product feedback inhibitory and substrate sites recognize a common feature in both compounds, the triphosphate moiety. To differentiate isosteric substrate and product pyrimidine rings, an additional pocket far from the expected kinase/ligase catalytic site, specifically recognizes the cytosine and ribose portions of the product inhibitor. {ECO:0000255\|HAMAP-Rule:MF_01227}.
Similarity:		Belongs to the CTP synthase family. {ECO:0000255\|HAMAP- Rule:MF_01227}.