UniProt functional annotation for P9WKI7



	UniProt functional annotation for P9WKI7

UniProt code: P9WKI7.

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

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

Function: Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth (PubMed:20491506, PubMed:21081761). Does not catalyze the reverse reaction, i.e. the conversion of XMP to IMP (PubMed:21081761). Appears to be essential for the optimal growth of M.tuberculosis (PubMed:12657046). {ECO:0000255|HAMAP-Rule:MF_01964, ECO:0000269|PubMed:12657046, ECO:0000269|PubMed:20491506, ECO:0000269|PubMed:21081761}.

Catalytic activity: Reaction=H2O + IMP + NAD(+) = H(+) + NADH + XMP; Xref=Rhea:RHEA:11708, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57464, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:58053; EC=1.1.1.205; Evidence={ECO:0000255|HAMAP-Rule:MF_01964, ECO:0000269|PubMed:20491506, ECO:0000269|PubMed:21081761};

Cofactor: Name=K(+); Xref=ChEBI:CHEBI:29103; Evidence={ECO:0000255|HAMAP-Rule:MF_01964, ECO:0000269|PubMed:21081761};

Activity regulation: Mycophenolic acid (MPA) is a non-competitive inhibitor that prevents formation of the closed enzyme conformation by binding to the same site as the amobile flap. In contrast, mizoribine monophosphate (MZP) is a competitive inhibitor that induces the closed conformation. MPA is a potent inhibitor of mammalian IMPDHs but a poor inhibitor of the bacterial enzymes. MZP is a more potent inhibitor of bacterial IMPDH (By similarity). Inhibited by the products XMP and NADH. Significantly inhibited in vitro by a panel of diphenyl urea- based derivatives and a series of novel classes of inhibitors, which are also potent anti-mycobacterial agents against M.tuberculosis and M.smegmatis (PubMed:21081761) (PubMed:22479467). Is also inhibited by a mycophenolic adenine dinucleotide (MAD) derivative in which a 1,2,3- triazole linker was incorporated as isosteric replacement of the pyrophosphate linker, thereby mimicking NAD (PubMed:20491506). Other inhibitors with modular structures consisting of two aromatic moieties connected by different linkers (such as urea and amide) have been identified and shown to exhibit antitubercular activity (PubMed:26440283). {ECO:0000255|HAMAP-Rule:MF_01964, ECO:0000269|PubMed:20491506, ECO:0000269|PubMed:21081761, ECO:0000269|PubMed:22479467, ECO:0000269|PubMed:26440283}.

Biophysicochemical properties: Kinetic parameters: KM=78 uM for inosine 5'-phosphate {ECO:0000269|PubMed:20491506}; KM=1005 uM for NAD(+) {ECO:0000269|PubMed:20491506}; KM=128.1 uM for inosine 5'-phosphate {ECO:0000269|PubMed:21081761}; KM=610.5 uM for NAD(+) {ECO:0000269|PubMed:21081761}; Note=kcat is 0.53 sec(-1). {ECO:0000269|PubMed:20491506}; pH dependence: Optimum pH is 8-8.5. {ECO:0000269|PubMed:21081761}; Temperature dependence: Optimum temperature is 37 degrees Celsius. {ECO:0000269|PubMed:21081761};

Pathway: Purine metabolism; XMP biosynthesis via de novo pathway; XMP from IMP: step 1/1. {ECO:0000255|HAMAP-Rule:MF_01964}.

Subunit: Homotetramer. {ECO:0000255|HAMAP-Rule:MF_01964, ECO:0000305|PubMed:26440283}.

Disruption phenotype: Cells lacking this gene display impaired growth. {ECO:0000269|PubMed:12657046}.

Similarity: Belongs to the IMPDH/GMPR family. {ECO:0000255|HAMAP- Rule:MF_01964}.

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 conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth (PubMed:20491506, PubMed:21081761). Does not catalyze the reverse reaction, i.e. the conversion of XMP to IMP (PubMed:21081761). Appears to be essential for the optimal growth of M.tuberculosis (PubMed:12657046). {ECO:0000255\|HAMAP-Rule:MF_01964, ECO:0000269\|PubMed:12657046, ECO:0000269\|PubMed:20491506, ECO:0000269\|PubMed:21081761}.


Catalytic activity:		Reaction=H2O + IMP + NAD(+) = H(+) + NADH + XMP; Xref=Rhea:RHEA:11708, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57464, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:58053; EC=1.1.1.205; Evidence={ECO:0000255\|HAMAP-Rule:MF_01964, ECO:0000269\|PubMed:20491506, ECO:0000269\|PubMed:21081761};
Cofactor:		Name=K(+); Xref=ChEBI:CHEBI:29103; Evidence={ECO:0000255\|HAMAP-Rule:MF_01964, ECO:0000269\|PubMed:21081761};
Activity regulation:		Mycophenolic acid (MPA) is a non-competitive inhibitor that prevents formation of the closed enzyme conformation by binding to the same site as the amobile flap. In contrast, mizoribine monophosphate (MZP) is a competitive inhibitor that induces the closed conformation. MPA is a potent inhibitor of mammalian IMPDHs but a poor inhibitor of the bacterial enzymes. MZP is a more potent inhibitor of bacterial IMPDH (By similarity). Inhibited by the products XMP and NADH. Significantly inhibited in vitro by a panel of diphenyl urea- based derivatives and a series of novel classes of inhibitors, which are also potent anti-mycobacterial agents against M.tuberculosis and M.smegmatis (PubMed:21081761) (PubMed:22479467). Is also inhibited by a mycophenolic adenine dinucleotide (MAD) derivative in which a 1,2,3- triazole linker was incorporated as isosteric replacement of the pyrophosphate linker, thereby mimicking NAD (PubMed:20491506). Other inhibitors with modular structures consisting of two aromatic moieties connected by different linkers (such as urea and amide) have been identified and shown to exhibit antitubercular activity (PubMed:26440283). {ECO:0000255\|HAMAP-Rule:MF_01964, ECO:0000269\|PubMed:20491506, ECO:0000269\|PubMed:21081761, ECO:0000269\|PubMed:22479467, ECO:0000269\|PubMed:26440283}.
Biophysicochemical properties:		Kinetic parameters: KM=78 uM for inosine 5'-phosphate {ECO:0000269\|PubMed:20491506}; KM=1005 uM for NAD(+) {ECO:0000269\|PubMed:20491506}; KM=128.1 uM for inosine 5'-phosphate {ECO:0000269\|PubMed:21081761}; KM=610.5 uM for NAD(+) {ECO:0000269\|PubMed:21081761}; Note=kcat is 0.53 sec(-1). {ECO:0000269\|PubMed:20491506}; pH dependence: Optimum pH is 8-8.5. {ECO:0000269\|PubMed:21081761}; Temperature dependence: Optimum temperature is 37 degrees Celsius. {ECO:0000269\|PubMed:21081761};
Pathway:		Purine metabolism; XMP biosynthesis via de novo pathway; XMP from IMP: step 1/1. {ECO:0000255\|HAMAP-Rule:MF_01964}.
Subunit:		Homotetramer. {ECO:0000255\|HAMAP-Rule:MF_01964, ECO:0000305\|PubMed:26440283}.
Disruption phenotype:		Cells lacking this gene display impaired growth. {ECO:0000269\|PubMed:12657046}.
Similarity:		Belongs to the IMPDH/GMPR family. {ECO:0000255\|HAMAP- Rule:MF_01964}.