Dihydrolipoyl dehydrogenase, mitochondrial precursor

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	509 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

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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.

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Ontologies

Keywords
Cellular component	Mitochondrion
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Redox-active center Transit peptide
Ligand	FAD Flavoprotein NAD
Molecular function	Oxidoreductase
PTM	Acetylation Disulfide bond
Technical term	3D-structure
Gene Ontology (GO)
Biological process	cell redox homeostasis Inferred from electronic annotation. Source: InterPro
Cellular component	mitochondrial matrix Inferred from Experiment. Source: Reactome
Molecular function	FAD binding Inferred from electronic annotation. Source: InterPro dihydrolipoyl dehydrogenase activity Ref.12 Traceable author statement. Source: ProtInc
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 35

35

Mitochondrion

Chain

36 – 509

474

Dihydrolipoyl dehydrogenase, mitochondrial

PRO_0000030295

Regions

Nucleotide binding

71 – 80

10

FAD

Nucleotide binding

183 – 185

3

FAD

Nucleotide binding

220 – 227

8

NAD

Nucleotide binding

361 – 364

4

FAD

Sites

Active site

487

1

Proton acceptor By similarity

Binding site

89

1

FAD

Binding site

154

1

FAD; via amide nitrogen and carbonyl oxygen

Binding site

243

1

NAD

Binding site

278

1

NAD; via amide nitrogen and carbonyl oxygen

Binding site

314

1

NAD; via amide nitrogen

Binding site

355

1

FAD

Amino acid modifications

Modified residue

127

1

N6-acetyllysine By similarity

Disulfide bond

80 ↔ 85

Redox-active

Natural variations

Natural variant

72

1

K → E in DLD deficiency.

VAR_006907

Natural variant

104

1

T → K: dbSNP rs1130477. Ref.2 Ref.4 Ref.6

VAR_031922

Natural variant

229

1

G → C in DLD deficiency; carrier rate among Askenazi Jewish 1:94.

VAR_015820

Natural variant

331

1

L → V: dbSNP rs17624.

VAR_014555

Natural variant

488

1

P → L in DLD deficiency.

VAR_006908

Natural variant

495

1

R → G in DLD deficiency; loss of enzyme activity.

VAR_015821

Experimental info

Sequence conflict

154

1

G → R in AAA35764. Ref.2

Sequence conflict

209

1

L → F in BAD92940. Ref.4

Sequence conflict

493

1

A → AEA in AAB01381. Ref.3

Secondary structure

1

.

509

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

P09622-1 [UniParc].

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

509

54,150

        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

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References

	« Hide 'large scale' referencesShow '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. 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.

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Web resources

GeneReviews

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Cross-references

Sequence databases

J03490 mRNA. Translation: AAA59527.1.
J03620 mRNA. Translation: AAA35764.1.
L13761

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.

IPI

IPI00015911.

PIR

DEHULP. A92622.

UniGene

Hs.131711

3D structure databases

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1ZMC	X-ray	2.53	A/B/C/D/E/F/G/H	36-509	[»]
1ZMD	X-ray	2.08	A/B/C/D/E/F/G/H	36-509	[»]
1ZY8	X-ray	2.59	A/B/C/D/E/F/G/H/I/J	36-509	[»]
2F5Z	X-ray	2.18	A/B/C/D/E/F/G/H/I/J	36-509	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:29027N.

PTM databases

PhosphoSite

P09622.

2-D gel databases

HSC-2DPAGE

P09622.

REPRODUCTION-2DPAGE

IPI00015911.

Proteomic databases

PRIDE

P09622.

Genome annotation databases

Ensembl

ENSG00000091140. Homo sapiens. [Contig view]

Organism-specific databases

GeneCards

GC07P107318.

H-InvDB

HIX0006994.

HGNC

HGNC:2898. DLD.

MIM

238331. gene.
248600. phenotype.

Orphanet

506. Leigh syndrome.
511. Leucinosis.
2394. Lipoamide dehydrogenase deficiency.
765. Pyruvate dehydrogenase deficiency.

PharmGKB

PA27352.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

P09622.

Enzyme and pathway databases

BioCyc

MetaCyc:MON-12008.

BRENDA

1.8.1.4. 247.

Reactome

REACT_13. Metabolism of amino acids.
REACT_1505. Integration of energy metabolism.

Gene expression databases

ArrayExpress

P09622.

Bgee

P09622.

CleanEx

HS_DLD.

GermOnline

ENSG00000091140. Homo sapiens.

Family and domain databases

InterPro

IPR013027. 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]

Gene3D

G3DSA:3.30.390.30. Pyr_redox_dim. 1 hit.

PANTHER

PTHR22912:SF20. Lipoamide_DH. 1 hit.

Pfam

PF00070. Pyr_redox. 1 hit.
PF07992. Pyr_redox_2. 1 hit.
PF02852. Pyr_redox_dim. 1 hit.
[Graphical view]

PRINTS

PR00368. FADPNR.
PR00945. HGRDTASE.

ProDom

PD000139. FAD_pyr_redox. 1 hit.
[Graphical view] [Entries sharing at least one domain]

TIGRFAMs

TIGR01350. lipoamide_DH. 1 hit.

PROSITE

PS00076. PYRIDINE_REDOX_1. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00157. NADH.

SOURCE

Search...

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Entry information

Entry name

DLDH_HUMAN

Accession

Primary (citable) accession number: P09622
Secondary accession number(s): Q14131

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 status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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