UniProt functional annotation for P09622



	UniProt functional annotation for P09622

UniProt code: P09622.

Organism: Homo sapiens (Human).

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

Function: Lipoamide dehydrogenase is a component of the glycine cleavage system as well as an E3 component of three alpha-ketoacid dehydrogenase complexes (pyruvate-, alpha-ketoglutarate-, and branched- chain amino acid-dehydrogenase complex) (PubMed:15712224, PubMed:16442803, PubMed:16770810, PubMed:17404228, PubMed:20160912, PubMed:20385101). The 2-oxoglutarate dehydrogenase complex is mainly active in the mitochondrion (PubMed:29211711). A fraction of the 2- oxoglutarate dehydrogenase complex also localizes in the nucleus and is required for lysine succinylation of histones: associates with KAT2A on chromatin and provides succinyl-CoA to histone succinyltransferase KAT2A (PubMed:29211711). In monomeric form may have additional moonlighting function as serine protease (PubMed:17404228). Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction (By similarity). {ECO:0000250|UniProtKB:Q811C4, ECO:0000269|PubMed:15712224, ECO:0000269|PubMed:16442803, ECO:0000269|PubMed:16770810, ECO:0000269|PubMed:17404228, ECO:0000269|PubMed:20160912, ECO:0000269|PubMed:20385101, ECO:0000269|PubMed:29211711}.

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:15712224, ECO:0000269|PubMed:16442803, ECO:0000269|PubMed:16770810, ECO:0000269|PubMed:17404228, ECO:0000269|PubMed:20160912, ECO:0000269|PubMed:20385101};

Cofactor: Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000269|PubMed:15946682, ECO:0000269|PubMed:16442803}; Note=Binds 1 FAD per subunit. {ECO:0000269|PubMed:15946682, ECO:0000269|PubMed:16442803};

Activity regulation: Disruption of native heterodimer state inhibits primary dihydrolipoamide dehydrogenase activity and induces serine protease activity. {ECO:0000269|PubMed:17404228}.

Subunit: Homodimer (PubMed:15946682). Part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (subunits PDHA (PDHA1 or PDHA2) and PDHB, E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (PubMed:14638692). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules (by non covalent bonds) (PubMed:14638692, PubMed:20361979). The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2) and DLD (dihydrolipoamide dehydrogenase; E3). It contains multiple copies of the three enzymatic components (E1, E2 and E3). In the nucleus, the 2-oxoglutarate dehydrogenase complex associates with KAT2A (PubMed:29211711). Interacts with PDHX (PubMed:20385101, PubMed:16442803, PubMed:20160912, PubMed:20361979). {ECO:0000269|PubMed:14638692, ECO:0000269|PubMed:15946682, ECO:0000269|PubMed:16442803, ECO:0000269|PubMed:20160912, ECO:0000269|PubMed:20361979, ECO:0000269|PubMed:20385101, ECO:0000269|PubMed:29211711}.

Subcellular location: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. Nucleus {ECO:0000269|PubMed:29211711}. Cell projection, cilium, flagellum {ECO:0000250|UniProtKB:Q811C4}. Cytoplasmic vesicle, secretory vesicle, acrosome {ECO:0000269|PubMed:15888450}. Note=Mainly localizes in the mitochondrion. A small fraction localizes to the nucleus, where the 2- oxoglutarate dehydrogenase complex is required for histone succinylation. {ECO:0000269|PubMed:29211711}.

Ptm: Tyrosine phosphorylated. {ECO:0000250|UniProtKB:Q811C4}.

Disease: Dihydrolipoamide dehydrogenase deficiency (DLDD) [MIM:246900]: An autosomal recessive metabolic disorder characterized biochemically by a combined deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC), and alpha-ketoglutarate dehydrogenase complex (KGDC). Clinically, affected individuals have lactic acidosis and neurologic deterioration due to sensitivity of the central nervous system to defects in oxidative metabolism. {ECO:0000269|PubMed:10448086, ECO:0000269|PubMed:11687750, ECO:0000269|PubMed:12925875, ECO:0000269|PubMed:15712224, ECO:0000269|PubMed:16442803, ECO:0000269|PubMed:16770810, ECO:0000269|PubMed:17404228, ECO:0000269|PubMed:20160912, ECO:0000269|PubMed:8506365, ECO:0000269|PubMed:8968745, ECO:0000269|PubMed:9540846, ECO:0000269|PubMed:9934985}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: The active site is a redox-active disulfide bond. {ECO:0000250|UniProtKB:P09624}.

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

Sequence caution: Sequence=BAD92940.1; 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:		Lipoamide dehydrogenase is a component of the glycine cleavage system as well as an E3 component of three alpha-ketoacid dehydrogenase complexes (pyruvate-, alpha-ketoglutarate-, and branched- chain amino acid-dehydrogenase complex) (PubMed:15712224, PubMed:16442803, PubMed:16770810, PubMed:17404228, PubMed:20160912, PubMed:20385101). The 2-oxoglutarate dehydrogenase complex is mainly active in the mitochondrion (PubMed:29211711). A fraction of the 2- oxoglutarate dehydrogenase complex also localizes in the nucleus and is required for lysine succinylation of histones: associates with KAT2A on chromatin and provides succinyl-CoA to histone succinyltransferase KAT2A (PubMed:29211711). In monomeric form may have additional moonlighting function as serine protease (PubMed:17404228). Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction (By similarity). {ECO:0000250\|UniProtKB:Q811C4, ECO:0000269\|PubMed:15712224, ECO:0000269\|PubMed:16442803, ECO:0000269\|PubMed:16770810, ECO:0000269\|PubMed:17404228, ECO:0000269\|PubMed:20160912, ECO:0000269\|PubMed:20385101, ECO:0000269\|PubMed:29211711}.


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:15712224, ECO:0000269\|PubMed:16442803, ECO:0000269\|PubMed:16770810, ECO:0000269\|PubMed:17404228, ECO:0000269\|PubMed:20160912, ECO:0000269\|PubMed:20385101};
Cofactor:		Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000269\|PubMed:15946682, ECO:0000269\|PubMed:16442803}; Note=Binds 1 FAD per subunit. {ECO:0000269\|PubMed:15946682, ECO:0000269\|PubMed:16442803};
Activity regulation:		Disruption of native heterodimer state inhibits primary dihydrolipoamide dehydrogenase activity and induces serine protease activity. {ECO:0000269\|PubMed:17404228}.
Subunit:		Homodimer (PubMed:15946682). Part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (subunits PDHA (PDHA1 or PDHA2) and PDHB, E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (PubMed:14638692). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules (by non covalent bonds) (PubMed:14638692, PubMed:20361979). The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2) and DLD (dihydrolipoamide dehydrogenase; E3). It contains multiple copies of the three enzymatic components (E1, E2 and E3). In the nucleus, the 2-oxoglutarate dehydrogenase complex associates with KAT2A (PubMed:29211711). Interacts with PDHX (PubMed:20385101, PubMed:16442803, PubMed:20160912, PubMed:20361979). {ECO:0000269\|PubMed:14638692, ECO:0000269\|PubMed:15946682, ECO:0000269\|PubMed:16442803, ECO:0000269\|PubMed:20160912, ECO:0000269\|PubMed:20361979, ECO:0000269\|PubMed:20385101, ECO:0000269\|PubMed:29211711}.
Subcellular location:		Mitochondrion matrix {ECO:0000305\|PubMed:29211711, ECO:0000305\|PubMed:3693355}. Nucleus {ECO:0000269\|PubMed:29211711}. Cell projection, cilium, flagellum {ECO:0000250\|UniProtKB:Q811C4}. Cytoplasmic vesicle, secretory vesicle, acrosome {ECO:0000269\|PubMed:15888450}. Note=Mainly localizes in the mitochondrion. A small fraction localizes to the nucleus, where the 2- oxoglutarate dehydrogenase complex is required for histone succinylation. {ECO:0000269\|PubMed:29211711}.
Ptm:		Tyrosine phosphorylated. {ECO:0000250\|UniProtKB:Q811C4}.
Disease:		Dihydrolipoamide dehydrogenase deficiency (DLDD) [MIM:246900]: An autosomal recessive metabolic disorder characterized biochemically by a combined deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC), and alpha-ketoglutarate dehydrogenase complex (KGDC). Clinically, affected individuals have lactic acidosis and neurologic deterioration due to sensitivity of the central nervous system to defects in oxidative metabolism. {ECO:0000269\|PubMed:10448086, ECO:0000269\|PubMed:11687750, ECO:0000269\|PubMed:12925875, ECO:0000269\|PubMed:15712224, ECO:0000269\|PubMed:16442803, ECO:0000269\|PubMed:16770810, ECO:0000269\|PubMed:17404228, ECO:0000269\|PubMed:20160912, ECO:0000269\|PubMed:8506365, ECO:0000269\|PubMed:8968745, ECO:0000269\|PubMed:9540846, ECO:0000269\|PubMed:9934985}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		The active site is a redox-active disulfide bond. {ECO:0000250\|UniProtKB:P09624}.
Similarity:		Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family. {ECO:0000305}.
Sequence caution:		Sequence=BAD92940.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};