UniProt functional annotation for P9WHT9



	UniProt functional annotation for P9WHT9

UniProt code: P9WHT9.

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

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

Function: Component of the proteasome core, a large protease complex with broad specificity involved in protein degradation. The M.tuberculosis proteasome is able to cleave oligopeptides not only after hydrophobic but also after basic, acidic and small neutral residues (PubMed:16468985). In complex with the ATPase Mpa, degrades protein targets conjugated to a prokaryotic ubiquitin-like protein (Pup). Among the identified substrates of the M.tuberculosis proteasome are the pupylated FabD, PanB and Mpa proteins (PubMed:17082771). One function of the proteasome is to contribute to M.tuberculosis ability to resist killing by host macrophages, since the core proteasome is essential for persistence of the pathogen during the chronic phase of infection in mice (PubMed:18059281). Likely functions to recycle amino acids under nutrient starvation, thereby enabling the cell to maintain basal metabolic activities (PubMed:20711362) (By similarity). The mechanism of protection against bactericidal chemistries of the host's immune response probably involves the degradation of proteins that are irreversibly oxidized, nitrated, or nitrosated. A proteolysis- independent activity of the proteasome core is required for optimal growth of M.tuberculosis in mouse lungs and for RNI resistance; in contrast, long-term survival of M.tuberculosis in stationary phase and during starvation in vitro and in the chronic phase of mouse infection required a proteolytically active proteasome (PubMed:20711362). {ECO:0000250|UniProtKB:A0QZ47, ECO:0000255|HAMAP-Rule:MF_02113, ECO:0000269|PubMed:16468985, ECO:0000269|PubMed:17082771, ECO:0000269|PubMed:18059281, ECO:0000269|PubMed:20711362}.

Catalytic activity: Reaction=Cleavage of peptide bonds with very broad specificity.; EC=3.4.25.1; Evidence={ECO:0000255|HAMAP-Rule:MF_02113, ECO:0000269|PubMed:16468985};

Activity regulation: The formation of the proteasomal ATPase ARC-20S proteasome complex, likely via the docking of the C-termini of ARC into the intersubunit pockets in the alpha-rings, may trigger opening of the gate for substrate entry. Interconversion between the open-gate and close-gate conformations leads to a dynamic regulation of the 20S proteasome proteolysis activity. In vitro, chymotryptic and tryptic activities of the proteasome are both completely inhibited by epoxomicin and by the peptidyl boronate inhibitor MLN-273. Also inhibited by Mg(2+), Ca(2+) and SDS. It was also shown that certain oxathiazol-2-one compounds can act as selective suicide-substrate inhibitors of the M.tuberculosis proteasome by irreversibly cyclocarbonylating its active site threonine. Proteasome activity is potently inhibited by fellutamide B (Ki=6.8 nM), a lipopeptide aldehyde that forms a reversible bond with the beta-OH of the active site threonine (PubMed:20558127). {ECO:0000255|HAMAP-Rule:MF_02113, ECO:0000269|PubMed:16468985, ECO:0000269|PubMed:19759536, ECO:0000269|PubMed:20558127}.

Biophysicochemical properties: Kinetic parameters: KM=56 uM for succinyl-LLVY-7-amino-4-methylcoumarin {ECO:0000269|PubMed:16468985}; Vmax=0.24 nmol/min/mg enzyme with succinyl-LLVY-7-amino-4- methylcoumarin as substrate {ECO:0000269|PubMed:16468985};

Pathway: Protein degradation; proteasomal Pup-dependent pathway. {ECO:0000255|HAMAP-Rule:MF_02113}.

Subunit: The 20S proteasome core is composed of 14 alpha and 14 beta subunits that assemble into four stacked heptameric rings, resulting in a barrel-shaped structure. The two inner rings, each composed of seven catalytic beta subunits, are sandwiched by two outer rings, each composed of seven alpha subunits. The catalytic chamber with the active sites is on the inside of the barrel. Has a gated structure, the ends of the cylinder being occluded by the N-termini of the alpha-subunits. Is capped by the proteasome-associated ATPase, ARC (Mpa). {ECO:0000255|HAMAP-Rule:MF_02113, ECO:0000269|PubMed:16468985, ECO:0000269|PubMed:16468986, ECO:0000269|PubMed:20085764, ECO:0000269|PubMed:20461058}.

Subcellular location: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_02113}.

Domain: In contrast to Rhodococus, the M.tuberculosis proteasome does not require the propeptide of PrcB for correct folding and assembly. {ECO:0000269|PubMed:16468985}.

Ptm: The unprocessed form of PrcB is phosphorylated by PknA. Processing of PrcB is greatly retarded in the presence of H(2)O(2). {ECO:0000269|PubMed:25224505}.

Disruption phenotype: Cells lacking the core proteasome prcBA subunits exhibit reduced growth and persistence in mice. They are also attenuated in interferon-gamma-deficient mice. They also display increased sensitivity to reactive nitrogen intermediates (RNI) and increased resistance to oxidative stress. {ECO:0000269|PubMed:18059281, ECO:0000269|PubMed:20711362}.

Biotechnology: In the course of search for new antibiotics, a class of oxathiazol-2-one compounds has been identified that selectively inhibits the M.tuberculosis proteasome over the human proteasome and that kills non-replicating M.tuberculosis. {ECO:0000269|PubMed:19759536}.

Similarity: Belongs to the peptidase T1B family. {ECO:0000255|HAMAP- Rule:MF_02113}.

Annotations taken from UniProtKB at the EBI.


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



Function:		Component of the proteasome core, a large protease complex with broad specificity involved in protein degradation. The M.tuberculosis proteasome is able to cleave oligopeptides not only after hydrophobic but also after basic, acidic and small neutral residues (PubMed:16468985). In complex with the ATPase Mpa, degrades protein targets conjugated to a prokaryotic ubiquitin-like protein (Pup). Among the identified substrates of the M.tuberculosis proteasome are the pupylated FabD, PanB and Mpa proteins (PubMed:17082771). One function of the proteasome is to contribute to M.tuberculosis ability to resist killing by host macrophages, since the core proteasome is essential for persistence of the pathogen during the chronic phase of infection in mice (PubMed:18059281). Likely functions to recycle amino acids under nutrient starvation, thereby enabling the cell to maintain basal metabolic activities (PubMed:20711362) (By similarity). The mechanism of protection against bactericidal chemistries of the host's immune response probably involves the degradation of proteins that are irreversibly oxidized, nitrated, or nitrosated. A proteolysis- independent activity of the proteasome core is required for optimal growth of M.tuberculosis in mouse lungs and for RNI resistance; in contrast, long-term survival of M.tuberculosis in stationary phase and during starvation in vitro and in the chronic phase of mouse infection required a proteolytically active proteasome (PubMed:20711362). {ECO:0000250\|UniProtKB:A0QZ47, ECO:0000255\|HAMAP-Rule:MF_02113, ECO:0000269\|PubMed:16468985, ECO:0000269\|PubMed:17082771, ECO:0000269\|PubMed:18059281, ECO:0000269\|PubMed:20711362}.


Catalytic activity:		Reaction=Cleavage of peptide bonds with very broad specificity.; EC=3.4.25.1; Evidence={ECO:0000255\|HAMAP-Rule:MF_02113, ECO:0000269\|PubMed:16468985};
Activity regulation:		The formation of the proteasomal ATPase ARC-20S proteasome complex, likely via the docking of the C-termini of ARC into the intersubunit pockets in the alpha-rings, may trigger opening of the gate for substrate entry. Interconversion between the open-gate and close-gate conformations leads to a dynamic regulation of the 20S proteasome proteolysis activity. In vitro, chymotryptic and tryptic activities of the proteasome are both completely inhibited by epoxomicin and by the peptidyl boronate inhibitor MLN-273. Also inhibited by Mg(2+), Ca(2+) and SDS. It was also shown that certain oxathiazol-2-one compounds can act as selective suicide-substrate inhibitors of the M.tuberculosis proteasome by irreversibly cyclocarbonylating its active site threonine. Proteasome activity is potently inhibited by fellutamide B (Ki=6.8 nM), a lipopeptide aldehyde that forms a reversible bond with the beta-OH of the active site threonine (PubMed:20558127). {ECO:0000255\|HAMAP-Rule:MF_02113, ECO:0000269\|PubMed:16468985, ECO:0000269\|PubMed:19759536, ECO:0000269\|PubMed:20558127}.
Biophysicochemical properties:		Kinetic parameters: KM=56 uM for succinyl-LLVY-7-amino-4-methylcoumarin {ECO:0000269\|PubMed:16468985}; Vmax=0.24 nmol/min/mg enzyme with succinyl-LLVY-7-amino-4- methylcoumarin as substrate {ECO:0000269\|PubMed:16468985};
Pathway:		Protein degradation; proteasomal Pup-dependent pathway. {ECO:0000255\|HAMAP-Rule:MF_02113}.
Subunit:		The 20S proteasome core is composed of 14 alpha and 14 beta subunits that assemble into four stacked heptameric rings, resulting in a barrel-shaped structure. The two inner rings, each composed of seven catalytic beta subunits, are sandwiched by two outer rings, each composed of seven alpha subunits. The catalytic chamber with the active sites is on the inside of the barrel. Has a gated structure, the ends of the cylinder being occluded by the N-termini of the alpha-subunits. Is capped by the proteasome-associated ATPase, ARC (Mpa). {ECO:0000255\|HAMAP-Rule:MF_02113, ECO:0000269\|PubMed:16468985, ECO:0000269\|PubMed:16468986, ECO:0000269\|PubMed:20085764, ECO:0000269\|PubMed:20461058}.
Subcellular location:		Cytoplasm {ECO:0000255\|HAMAP-Rule:MF_02113}.
Domain:		In contrast to Rhodococus, the M.tuberculosis proteasome does not require the propeptide of PrcB for correct folding and assembly. {ECO:0000269\|PubMed:16468985}.
Ptm:		The unprocessed form of PrcB is phosphorylated by PknA. Processing of PrcB is greatly retarded in the presence of H(2)O(2). {ECO:0000269\|PubMed:25224505}.
Disruption phenotype:		Cells lacking the core proteasome prcBA subunits exhibit reduced growth and persistence in mice. They are also attenuated in interferon-gamma-deficient mice. They also display increased sensitivity to reactive nitrogen intermediates (RNI) and increased resistance to oxidative stress. {ECO:0000269\|PubMed:18059281, ECO:0000269\|PubMed:20711362}.
Biotechnology:		In the course of search for new antibiotics, a class of oxathiazol-2-one compounds has been identified that selectively inhibits the M.tuberculosis proteasome over the human proteasome and that kills non-replicating M.tuberculosis. {ECO:0000269\|PubMed:19759536}.
Similarity:		Belongs to the peptidase T1B family. {ECO:0000255\|HAMAP- Rule:MF_02113}.