DLD (dihydrolipoamide dehydrogenase)

Gene

• Entrez ID: 1738
• Gene name: Dihydrolipoamide dehydrogenase
• Gene symbol: DLD
• Synonyms: DLDD, DLDH, E3, GCSL, LAD, OGDC-E3, PHE3
• Chromosome: 7
• Chromosome location: 7q31.1
• Summary: This gene encodes a member of the class-I pyridine nucleotide-disulfide oxidoreductase family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In homodimeric form, the encoded protein functions as a dehydrogenase and is found in several multi-enzyme complexes that regulate energy metabolism. However, as a monomer, this protein can function as a protease. Mutations in this gene have been identified in patients with E3-deficient maple syrup urine disease and lipoamide dehydrogenase deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs111257462	G>A,C	Likely-pathogenic	Splice donor variant
rs121964987	A>G	Pathogenic	Missense variant, intron variant, coding sequence variant
rs121964988	C>T	Pathogenic	Missense variant, coding sequence variant
rs121964989	A>G	Pathogenic	Missense variant, coding sequence variant
rs121964990	G>C,T	Pathogenic	Missense variant, coding sequence variant
rs121964991	T>C	Pathogenic	Missense variant, coding sequence variant
rs121964992	G>A	Pathogenic, likely-pathogenic	Missense variant, coding sequence variant
rs121964993	A>G	Pathogenic	Missense variant, coding sequence variant
rs148873419	A>T	Conflicting-interpretations-of-pathogenicity	Coding sequence variant, missense variant
rs397514649	A>T	Pathogenic	Missense variant, coding sequence variant
rs397514650	A>G	Pathogenic	Missense variant, coding sequence variant
rs397514651	T>C	Pathogenic	Missense variant, coding sequence variant, intron variant
rs533405046	A>C,T	Conflicting-interpretations-of-pathogenicity, uncertain-significance	Missense variant, coding sequence variant
rs747810875	C>G,T	Likely-pathogenic, likely-benign	5 prime UTR variant, coding sequence variant, stop gained, synonymous variant
rs753234219	->A	Likely-pathogenic	5 prime UTR variant, coding sequence variant, stop gained
rs763303046	A>G,T	Likely-pathogenic, uncertain-significance	Intron variant, coding sequence variant, missense variant
rs764611160	AG>-	Likely-pathogenic, pathogenic	Coding sequence variant, frameshift variant
rs764704217	T>-,TT	Likely-pathogenic	Coding sequence variant, 5 prime UTR variant, frameshift variant
rs777884525	TCAA>-	Likely-pathogenic	Coding sequence variant, frameshift variant
rs780025714	G>T	Likely-pathogenic	Splice donor variant
rs796051947	C>T	Likely-pathogenic	Coding sequence variant, intron variant, missense variant
rs796051948	A>G	Likely-pathogenic	Coding sequence variant, intron variant, missense variant
rs1040811473	A>-,AA	Likely-pathogenic	Frameshift variant, coding sequence variant
rs1057516698	C>T	Uncertain-significance, likely-pathogenic	Stop gained, 5 prime UTR variant, coding sequence variant
rs1057517214	->A	Likely-pathogenic	Frameshift variant, coding sequence variant, intron variant
rs1328820332	G>A	Likely-pathogenic	Splice donor variant
rs1554396895	C>-	Pathogenic	5 prime UTR variant, coding sequence variant, stop gained
rs1554396908	G>T	Likely-pathogenic	Splice donor variant
rs1554398193	G>A	Likely-pathogenic	Intron variant, splice donor variant
rs1554398264	G>A	Likely-pathogenic	Splice acceptor variant, intron variant
rs1554398461	A>G	Likely-pathogenic	Splice acceptor variant
rs1554398624	AG>T	Likely-pathogenic	Splice acceptor variant
rs1554398625	A>-	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1554400179	->A	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1554400483	G>T	Likely-pathogenic	Splice donor variant
rs1554400699	G>-	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1554400704	TGTG>-	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1554400713	AG>-	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1562908173	G>A	Pathogenic	Coding sequence variant, 5 prime UTR variant, stop gained

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT031565	hsa-miR-16-5p	Proteomics	18668040
MIRT048620	hsa-miR-99a-5p	CLASH	23622248

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0004148	Function	Dihydrolipoyl dehydrogenase activity	IBA	21873635
GO:0004148	Function	Dihydrolipoyl dehydrogenase activity	IDA	16442803
GO:0005515	Function	Protein binding	IPI	16263718, 16442803, 28514442, 29128334, 32296183, 32814053
GO:0005634	Component	Nucleus	IDA	29211711
GO:0005739	Component	Mitochondrion	HDA	20833797
GO:0005739	Component	Mitochondrion	IBA	21873635
GO:0005739	Component	Mitochondrion	IDA	29211711
GO:0005759	Component	Mitochondrial matrix	TAS
GO:0006090	Process	Pyruvate metabolic process	TAS
GO:0006099	Process	Tricarboxylic acid cycle	TAS
GO:0006103	Process	2-oxoglutarate metabolic process	IEA
GO:0006120	Process	Mitochondrial electron transport, NADH to ubiquinone	IEA
GO:0006508	Process	Proteolysis	IEA
GO:0006554	Process	Lysine catabolic process	TAS
GO:0007369	Process	Gastrulation	IEA
GO:0007568	Process	Aging	IEA
GO:0009083	Process	Branched-chain amino acid catabolic process	TAS
GO:0009106	Process	Lipoate metabolic process	IEA
GO:0031514	Component	Motile cilium	IEA
GO:0034604	Function	Pyruvate dehydrogenase (NAD+) activity	IDA	9242632
GO:0042391	Process	Regulation of membrane potential	IEA
GO:0043159	Component	Acrosomal matrix	IEA
GO:0043544	Function	Lipoamide binding	IEA
GO:0045252	Component	Oxoglutarate dehydrogenase complex	IBA	21873635
GO:0045252	Component	Oxoglutarate dehydrogenase complex	IDA	29211711
GO:0045254	Component	Pyruvate dehydrogenase complex	IDA	9242632
GO:0045454	Process	Cell redox homeostasis	IEA
GO:0048240	Process	Sperm capacitation	IEA
GO:0050660	Function	Flavin adenine dinucleotide binding	IBA	21873635
GO:0051068	Process	Dihydrolipoamide metabolic process	IEA
GO:0051287	Function	NAD binding	IEA
GO:0061732	Process	Mitochondrial acetyl-CoA biosynthetic process from pyruvate	IC	9242632
GO:0106077	Process	Histone succinylation	IDA	29211711

Other IDs

• MIM: 238331
• HGNC: 2898
• e!Ensembl: ENSG00000091140

Protein

• UniProt ID: P09622
• Protein name: Dihydrolipoyl dehydrogenase, mitochondrial (EC 1.8.1.4) (Dihydrolipoamide dehydrogenase) (Glycine cleavage system L protein)
• Protein 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).
• PDB: 1ZMC, 1ZMD, 1ZY8, 2F5Z, 3RNM, 5J5Z, 5NHG, 6HG8, 6I4P, 6I4Q, 6I4R, 6I4S, 6I4T, 6I4U, 6I4Z
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF07992	Pyr_redox_2	42 → 370	Pyridine nucleotide-disulphide oxidoreductase	Domain
  PF02852	Pyr_redox_dim	389 → 498	Pyridine nucleotide-disulphide oxidoreductase, dimerisation domain	Domain

• Sequence:

  MQSWSRVYCSLAKRGHFNRISHGLQGLSAVPLRTYADQPIDADVTVIGSGPGGYVAAIKA
  AQLGFKTVCIEKNETLGGTCLNVGCIPSKALLNNSHYYHMAHGKDFASRGIEMSEVRLNL
  DKMMEQKSTAVKALTGGIAHLFKQNKVVHVNGYGKITGKNQVTATKADGGTQVIDTKNIL
  IATGSEVTPFPGITIDEDTIVSSTGALSLKKVPEKMVVIGAGVIGVELGSVWQRLGADVT
  AVEFLGHVGGVGIDMEISKNFQRILQKQGFKFKLNTKVTGATKKSDGKIDVSIEAASGGK
  AEVITCDVLLVCIGRRPFTKNLGLEELGIELDPRGRIPVNTRFQTKIPNIYAIGDVVAGP
  MLAHKAEDEGIICVEGMAGGAVHIDYNCVPSVIYTHPEVAWVGKSEEQLKEEGIEYKVGK
  FPFAANSRAKTNADTDGMVKILGQKSTDRVLGAHILGPGAGEMVNEAALALEYGASCEDI
  ARVCHAHPTLSEAFREANLAASFGKSINF

• Sequence length: 509