UniProt functional annotation for P9WHH9



	UniProt functional annotation for P9WHH9

UniProt code: P9WHH9.

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

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

Function: Lipoamide dehydrogenase is an essential component of the alpha-ketoacid dehydrogenase complexes, namely the pyruvate dehydrogenase (PDH) complex, the branched-chain alpha-ketoacid dehydrogenase (BCKADH) complex, and likely also the 2-oxoglutarate dehydrogenase (ODH) complex. Catalyzes the reoxidation of dihydrolipoyl groups which are covalently attached to the lipoate acyltransferase components (E2) of the complexes. Is also able to catalyze the transhydrogenation of NADH and thio-NAD(+) in the absence of D,L- lipoamide, and the NADH-dependent reduction of quinones in vitro.

Function: Together with AhpC, AhpD and DlaT, Lpd constitutes an NADH- dependent peroxidase active against hydrogen and alkyl peroxides as well as serving as a peroxynitrite reductase, thus protecting the bacterium against reactive nitrogen intermediates and oxidative stress generated by the host immune system.

Function: Appears to be essential for Mtb pathogenesis.

Catalytic activity: Reaction=(R)-N(6)-dihydrolipoyl-L-lysyl-[protein] + NAD(+) = (R)-N(6)- lipoyl-L-lysyl-[protein] + H(+) + NADH; Xref=Rhea:RHEA:15045, Rhea:RHEA-COMP:10474, Rhea:RHEA-COMP:10475, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:83099, ChEBI:CHEBI:83100; EC=1.8.1.4; Evidence={ECO:0000269|PubMed:11560483};

Cofactor: Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000269|PubMed:11560483}; Note=Binds 1 FAD per subunit. {ECO:0000269|PubMed:11560483};

Activity regulation: Triazaspirodimethoxybenzoyls are high-nanomolar inhibitors of M.tuberculosis Lpd and are non-competitive versus NADH, NAD(+), and lipoamide and >100-fold selective compared to human Lpd. {ECO:0000269|PubMed:20078138}.

Biophysicochemical properties: Kinetic parameters: KM=66 uM for NAD(+) {ECO:0000269|PubMed:11560483, ECO:0000269|PubMed:16045627}; KM=7.3 uM for NADH {ECO:0000269|PubMed:11560483, ECO:0000269|PubMed:16045627}; KM=110 uM for thio-NADH {ECO:0000269|PubMed:11560483, ECO:0000269|PubMed:16045627}; KM=16 mM for D,L-lipoamide {ECO:0000269|PubMed:11560483, ECO:0000269|PubMed:16045627}; KM=120 mM for D,L-lipoate {ECO:0000269|PubMed:11560483, ECO:0000269|PubMed:16045627}; pH dependence: Optimum pH is 8.0 for PDH complex activity. Half-maximal activity is observed at pH 7.0 and pH 9.0. Activity is abolished at pH < 5. {ECO:0000269|PubMed:16045627};

Subunit: Homodimer. Identified in a complex with AhpC, AhpD and DlaT. Also is part of the PDH complex, consisting of multiple copies of AceE (E1), DlaT (E2) and Lpd (E3), and of the BCKADH complex, consisting of multiple copies of BkdA/BkdB (E1), BkdC (E2) and Lpd (E3). {ECO:0000269|PubMed:11560483, ECO:0000269|PubMed:11799204, ECO:0000269|PubMed:16045627, ECO:0000269|PubMed:16093239, ECO:0000269|PubMed:20078138, ECO:0000269|PubMed:21238944}.

Subcellular location: Cytoplasm {ECO:0000305}.

Disruption phenotype: Cells lacking this gene grow, albeit poorly, in standard medium with dextrose, glycerol, and fatty acids as carbon sources, but fail to grow on carbohydrates. They are less resistant than wild-type to exposition to mildly acidified nitrite, but are more resistant to oxidative stress in the form of H(2)O(2) in vitro. Lpd- deficient strains are severely attenuated in wild-type and immunodeficient mice. In contrast to wild-type or DlaT lacking strains, strains lacking Lpd are unable to grow on leucine or isoleucine. Disruption of this gene also leads to extraordinary accumulations of pyruvate and branched chain amino and keto acids. {ECO:0000269|PubMed:21238944}.

Miscellaneous: The active site is a redox-active disulfide bond.

Similarity: Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


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



Function:		Lipoamide dehydrogenase is an essential component of the alpha-ketoacid dehydrogenase complexes, namely the pyruvate dehydrogenase (PDH) complex, the branched-chain alpha-ketoacid dehydrogenase (BCKADH) complex, and likely also the 2-oxoglutarate dehydrogenase (ODH) complex. Catalyzes the reoxidation of dihydrolipoyl groups which are covalently attached to the lipoate acyltransferase components (E2) of the complexes. Is also able to catalyze the transhydrogenation of NADH and thio-NAD(+) in the absence of D,L- lipoamide, and the NADH-dependent reduction of quinones in vitro.



Function:		Together with AhpC, AhpD and DlaT, Lpd constitutes an NADH- dependent peroxidase active against hydrogen and alkyl peroxides as well as serving as a peroxynitrite reductase, thus protecting the bacterium against reactive nitrogen intermediates and oxidative stress generated by the host immune system.



Function:		Appears to be essential for Mtb pathogenesis.


Catalytic activity:		Reaction=(R)-N(6)-dihydrolipoyl-L-lysyl-[protein] + NAD(+) = (R)-N(6)- lipoyl-L-lysyl-[protein] + H(+) + NADH; Xref=Rhea:RHEA:15045, Rhea:RHEA-COMP:10474, Rhea:RHEA-COMP:10475, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:83099, ChEBI:CHEBI:83100; EC=1.8.1.4; Evidence={ECO:0000269\|PubMed:11560483};
Cofactor:		Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000269\|PubMed:11560483}; Note=Binds 1 FAD per subunit. {ECO:0000269\|PubMed:11560483};
Activity regulation:		Triazaspirodimethoxybenzoyls are high-nanomolar inhibitors of M.tuberculosis Lpd and are non-competitive versus NADH, NAD(+), and lipoamide and >100-fold selective compared to human Lpd. {ECO:0000269\|PubMed:20078138}.
Biophysicochemical properties:		Kinetic parameters: KM=66 uM for NAD(+) {ECO:0000269\|PubMed:11560483, ECO:0000269\|PubMed:16045627}; KM=7.3 uM for NADH {ECO:0000269\|PubMed:11560483, ECO:0000269\|PubMed:16045627}; KM=110 uM for thio-NADH {ECO:0000269\|PubMed:11560483, ECO:0000269\|PubMed:16045627}; KM=16 mM for D,L-lipoamide {ECO:0000269\|PubMed:11560483, ECO:0000269\|PubMed:16045627}; KM=120 mM for D,L-lipoate {ECO:0000269\|PubMed:11560483, ECO:0000269\|PubMed:16045627}; pH dependence: Optimum pH is 8.0 for PDH complex activity. Half-maximal activity is observed at pH 7.0 and pH 9.0. Activity is abolished at pH < 5. {ECO:0000269\|PubMed:16045627};
Subunit:		Homodimer. Identified in a complex with AhpC, AhpD and DlaT. Also is part of the PDH complex, consisting of multiple copies of AceE (E1), DlaT (E2) and Lpd (E3), and of the BCKADH complex, consisting of multiple copies of BkdA/BkdB (E1), BkdC (E2) and Lpd (E3). {ECO:0000269\|PubMed:11560483, ECO:0000269\|PubMed:11799204, ECO:0000269\|PubMed:16045627, ECO:0000269\|PubMed:16093239, ECO:0000269\|PubMed:20078138, ECO:0000269\|PubMed:21238944}.
Subcellular location:		Cytoplasm {ECO:0000305}.
Disruption phenotype:		Cells lacking this gene grow, albeit poorly, in standard medium with dextrose, glycerol, and fatty acids as carbon sources, but fail to grow on carbohydrates. They are less resistant than wild-type to exposition to mildly acidified nitrite, but are more resistant to oxidative stress in the form of H(2)O(2) in vitro. Lpd- deficient strains are severely attenuated in wild-type and immunodeficient mice. In contrast to wild-type or DlaT lacking strains, strains lacking Lpd are unable to grow on leucine or isoleucine. Disruption of this gene also leads to extraordinary accumulations of pyruvate and branched chain amino and keto acids. {ECO:0000269\|PubMed:21238944}.
Miscellaneous:		The active site is a redox-active disulfide bond.
Similarity:		Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family. {ECO:0000305}.