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Reviewed, UniProtKB/Swiss-Prot P09622 (DLDH_HUMAN)

Last modified June 16, 2009. Version 126. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Dihydrolipoyl dehydrogenase, mitochondrial
    EC=1.8.1.4
Alternative name(s):
    Dihydrolipoamide dehydrogenase
    Glycine cleavage system L protein
Gene names
Name: DLD
Synonyms: GCSL, LAD, PHE3
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length509 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

Lipoamide dehydrogenase is a component of the glycine cleavage system as well as of the alpha-ketoacid dehydrogenase complexes.

Catalytic activity

Protein N(6)-(dihydrolipoyl)lysine + NAD+ = protein N(6)-(lipoyl)lysine + NADH.

Cofactor

Binds 1 FAD per subunit By similarity.

Subunit structure

Homodimer. Eukaryotic pyruvate dehydrogenase complexes are organized about a core consisting of the oligomeric dihydrolipoamide acetyl-transferase, around which are arranged multiple copies of pyruvate dehydrogenase, dihydrolipoamide dehydrogenase and protein X bound by non-covalent bonds. Ref.9

Subcellular location

Mitochondrion matrix.

Involvement in disease

Defects in DLD are a cause of congenital infantile lactic acidosis.

Defects in DLD are a cause of maple syrup urine disease (MSUD) [MIM:248600]. MSUD is characterized by mental and physical retardation, feeding problems and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine, resulting from a block in oxidative decarboxylation.

Miscellaneous

The active site is a redox-active disulfide bond.

Sequence similarities

Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family.

Ontologies

Keywords
   Cellular componentMitochondrion
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
   DomainRedox-active center
Transit peptide
   LigandFAD
Flavoprotein
NAD
   Molecular functionOxidoreductase
   PTMAcetylation
Disulfide bond
   Technical term3D-structure
Gene Ontology (GO)
   Biological processcell redox homeostasis

Inferred from electronic annotation. Source: InterPro

   Cellular componentmitochondrial matrix

Inferred from Experiment. Source: Reactome

   Molecular functionFAD binding

Inferred from electronic annotation. Source: InterPro

dihydrolipoyl dehydrogenase activity Ref.12

Traceable author statement. Source: ProtInc

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 3535Mitochondrion
Chain36 – 509474Dihydrolipoyl dehydrogenase, mitochondrial
PRO_0000030295

Regions

Nucleotide binding71 – 8010FAD
Nucleotide binding183 – 1853FAD
Nucleotide binding220 – 2278NAD
Nucleotide binding361 – 3644FAD

Sites

Active site4871Proton acceptor By similarity
Binding site891FAD
Binding site1541FAD; via amide nitrogen and carbonyl oxygen
Binding site2431NAD
Binding site2781NAD; via amide nitrogen and carbonyl oxygen
Binding site3141NAD; via amide nitrogen
Binding site3551FAD

Amino acid modifications

Modified residue1271N6-acetyllysine By similarity
Disulfide bond80 ↔ 85Redox-active

Natural variations

Natural variant721K → E in DLD deficiency.
VAR_006907
Natural variant1041T → K: dbSNP rs1130477. Ref.2 Ref.4 Ref.6
VAR_031922
Natural variant2291G → C in DLD deficiency; carrier rate among Askenazi Jewish 1:94.
VAR_015820
Natural variant3311L → V: dbSNP rs17624.
VAR_014555
Natural variant4881P → L in DLD deficiency.
VAR_006908
Natural variant4951R → G in DLD deficiency; loss of enzyme activity.
VAR_015821

Experimental info

Sequence conflict1541G → R in AAA35764. Ref.2
Sequence conflict2091L → F in BAD92940. Ref.4
Sequence conflict4931A → AEA in AAB01381. Ref.3

Secondary structure

..................................................................................... 509
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P09622-1 [UniParc].

Last modified July 1, 1989. Version 1.
Checksum: BD10006B52F4369B

FASTA50954,150
        10         20         30         40         50         60 
MQSWSRVYCS LAKRGHFNRI SHGLQGLSAV PLRTYADQPI DADVTVIGSG PGGYVAAIKA 

        70         80         90        100        110        120 
AQLGFKTVCI EKNETLGGTC LNVGCIPSKA LLNNSHYYHM AHGTDFASRG IEMSEVRLNL 

       130        140        150        160        170        180 
DKMMEQKSTA VKALTGGIAH LFKQNKVVHV NGYGKITGKN QVTATKADGG TQVIDTKNIL 

       190        200        210        220        230        240 
IATGSEVTPF PGITIDEDTI VSSTGALSLK KVPEKMVVIG AGVIGVELGS VWQRLGADVT 

       250        260        270        280        290        300 
AVEFLGHVGG VGIDMEISKN FQRILQKQGF KFKLNTKVTG ATKKSDGKID VSIEAASGGK 

       310        320        330        340        350        360 
AEVITCDVLL VCIGRRPFTK NLGLEELGIE LDPRGRIPVN TRFQTKIPNI YAIGDVVAGP 

       370        380        390        400        410        420 
MLAHKAEDEG IICVEGMAGG AVHIDYNCVP SVIYTHPEVA WVGKSEEQLK EEGIEYKVGK 

       430        440        450        460        470        480 
FPFAANSRAK TNADTDGMVK ILGQKSTDRV LGAHILGPGA GEMVNEAALA LEYGASCEDI 

       490        500 
ARVCHAHPTL SEAFREANLA ASFGKSINF 

« Hide

References

« Hide 'large scale' references
[1]"Isolation and sequence determination of cDNA clones for porcine and human lipoamide dehydrogenase. Homology to other disulfide oxidoreductases."
Otulakowski G., Robinson B.H.
J. Biol. Chem. 262:17313-17318(1987) [PubMed: 3693355] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"Cloning and cDNA sequence of the dihydrolipoamide dehydrogenase component human alpha-ketoacid dehydrogenase complexes."
Pons G., Raefsky-Estrin C., Carothers D.J., Pepin R.A., Javed A.A., Jesse B.W., Ganapathi M.K., Samols D., Patel M.S.
Proc. Natl. Acad. Sci. U.S.A. 85:1422-1426(1988) [PubMed: 3278312] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT LYS-104.
[3]"The structure of the human dihydrolipoamide dehydrogenase gene (DLD) and its upstream elements."
Feigenbaum A.S., Robinson B.H.
Genomics 17:376-381(1993) [PubMed: 8406489] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Tissue: Liver.
[4]Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., Ohara O., Nagase T., Kikuno R.F.
Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT LYS-104.
Tissue: Brain.
[5]"Human chromosome 7: DNA sequence and biology."
Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., Kanematsu E., Gentles S. expand/collapse author list , Christopoulos C.C., Choufani S., Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., Adams M.D., Tsui L.-C.
Science 300:767-772(2003) [PubMed: 12690205] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT LYS-104.
Tissue: Ovary.
[7]"Characterization of the transcriptional regulatory region of the human dihydrolipoamide dehydrogenase gene."
Johanning G.L., Morris J.I., Madhusudhan K.T., Samols D., Patel M.S.
Proc. Natl. Acad. Sci. U.S.A. 89:10964-10968(1992) [PubMed: 1332063] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-13.
[8]Colinge J., Superti-Furga G., Bennett K.L.
Submitted (OCT-2008) to UniProtKB
Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[9]"Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations."
Brautigam C.A., Chuang J.L., Tomchick D.R., Machius M., Chuang D.T.
J. Mol. Biol. 350:543-552(2005) [PubMed: 15946682] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.08 ANGSTROMS) OF 36-509 IN COMPLEXES WITH NAD AND FAD, SUBUNIT.
[10]"How dihydrolipoamide dehydrogenase-binding protein binds dihydrolipoamide dehydrogenase in the human pyruvate dehydrogenase complex."
Ciszak E.M., Makal A., Hong Y.S., Vettaikkorumakankauv A.K., Korotchkina L.G., Patel M.S.
J. Biol. Chem. 281:648-655(2006) [PubMed: 16263718] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.59 ANGSTROMS) OF 36-509.
[11]"Structural insight into interactions between dihydrolipoamide dehydrogenase (E3) and E3 binding protein of human pyruvate dehydrogenase complex."
Brautigam C.A., Wynn R.M., Chuang J.L., Machius M., Tomchick D.R., Chuang D.T.
Structure 14:611-621(2006) [PubMed: 16442803] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.18 ANGSTROMS) OF 36-509 IN COMPLEX WITH PDHX, CHARACTERIZATION OF VARIANT DLD DEFICIENCY GLY-495.
[12]"Identification of two missense mutations in a dihydrolipoamide dehydrogenase-deficient patient."
Liu T.-C., Kim H., Arizmendi C., Kitano A., Patel M.S.
Proc. Natl. Acad. Sci. U.S.A. 90:5186-5190(1993) [PubMed: 8506365] [Abstract]
Cited for: VARIANTS DLD DEFICIENCY GLU-72 AND LEU-488.
[13]"Identification of two mutations in a compound heterozygous child with dihydrolipoamide dehydrogenase deficiency."
Hong Y.S., Kerr D.S., Craigen W.J., Tan J., Pan Y., Lusk M., Patel M.S.
Hum. Mol. Genet. 5:1925-1930(1996) [PubMed: 8968745] [Abstract]
Cited for: VARIANT DLD DEFICIENCY GLY-495.
[14]"Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews."
Shaag A., Saada A., Berger I., Mandel H., Joseph A., Feigenbaum A., Elpeleg O.N.
Am. J. Med. Genet. 82:177-182(1999) [PubMed: 9934985] [Abstract]
Cited for: VARIANT DLD DEFICIENCY CYS-229.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

J03490 mRNA. Translation: AAA59527.1.
J03620 mRNA. Translation: AAA35764.1.
L13761 expand/collapse EMBL AC list , L13749, L13750, L13751, L13752, L13753, L13754, L13748, L13755, L13759, L13760, L13756, L13757, L13758 Genomic DNA. Translation: AAB01381.1.
AB209703 mRNA. Translation: BAD92940.1. Different initiation.
CH236947 Genomic DNA. Translation: EAL24389.1.
BC018648 mRNA. Translation: AAH18648.1.
BC018696 mRNA. Translation: AAH18696.1.
M99384 Genomic DNA. Translation: AAA35759.1.
IPIIPI00015911.
PIRDEHULP. A92622.
UniGeneHs.131711

3D structure databases

EntryMethodResolution (Å)ChainPositionsPDBsum
1ZMCX-ray2.53A/B/C/D/E/F/G/H36-509[»]
1ZMDX-ray2.08A/B/C/D/E/F/G/H36-509[»]
1ZY8X-ray2.59A/B/C/D/E/F/G/H/I/J36-509[»]
2F5ZX-ray2.18A/B/C/D/E/F/G/H/I/J36-509[»]
ModBaseSearch...

Protein-protein interaction databases

DIPDIP:29027N.

PTM databases

PhosphoSiteP09622.

2-D gel databases

HSC-2DPAGEP09622.
REPRODUCTION-2DPAGEIPI00015911.

Proteomic databases

PRIDEP09622.

Genome annotation databases

EnsemblENSG00000091140. Homo sapiens. [Contig view]

Organism-specific databases

GeneCardsGC07P107318.
H-InvDBHIX0006994.
HGNCHGNC:2898. DLD.
MIM238331. gene.
248600. phenotype.
Orphanet506. Leigh syndrome.
511. Leucinosis.
2394. Lipoamide dehydrogenase deficiency.
765. Pyruvate dehydrogenase deficiency.
PharmGKBPA27352.
GenAtlasSearch...

Phylogenomic databases

HOVERGENP09622.

Enzyme and pathway databases

BioCycMetaCyc:MON-12008.
BRENDA1.8.1.4. 247.
ReactomeREACT_13. Metabolism of amino acids.
REACT_1505. Integration of energy metabolism.

Gene expression databases

ArrayExpressP09622.
BgeeP09622.
CleanExHS_DLD.
GermOnlineENSG00000091140. Homo sapiens.

Family and domain databases

InterProIPR013027. FAD_pyr_nucl-diS_OxRdtase.
IPR000815. Hg_reductase.
IPR006258. Lipoamide_DH.
IPR004099. Pyr_nucl-diS_OxRdtase_dimer.
IPR012999. Pyr_OxRdtase_I_AS.
IPR001327. Pyr_OxRdtase_NAD_bd.
[Graphical view]
Gene3DG3DSA:3.30.390.30. Pyr_redox_dim. 1 hit.
PANTHERPTHR22912:SF20. Lipoamide_DH. 1 hit.
PfamPF00070. Pyr_redox. 1 hit.
PF07992. Pyr_redox_2. 1 hit.
PF02852. Pyr_redox_dim. 1 hit.
[Graphical view]
PRINTSPR00368. FADPNR.
PR00945. HGRDTASE.
ProDomPD000139. FAD_pyr_redox. 1 hit.
[Graphical view] [Entries sharing at least one domain]
TIGRFAMsTIGR01350. lipoamide_DH. 1 hit.
PROSITEPS00076. PYRIDINE_REDOX_1. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

DrugBankDB00157. NADH.
SOURCESearch...

Entry information

Entry nameDLDH_HUMAN
AccessionPrimary (citable) accession number: P09622
Secondary accession number(s): Q14131 expand/collapse secondary AC list , Q14167, Q59EV8, Q8WTS4
Entry history
Integrated into UniProtKB/Swiss-Prot: July 1, 1989
Last sequence update: July 1, 1989
Last modified: June 16, 2009
This is version 126 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)

Relevant documents

Human chromosome 7

Human chromosome 7: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents