EzCatDB: T00017
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DB codeT00017
CATH domainDomain 13.50.50.60 : FAD/NAD(P)-binding domainCatalytic domain
Domain 23.50.50.60 : FAD/NAD(P)-binding domain
Domain 33.30.390.30 : Enolase-like; domain 1Catalytic domain
E.C.1.8.1.4

CATH domainRelated DB codes (homologues)
3.30.390.30 : Enolase-like; domain 1M00163,T00213,T00233,T00242
3.50.50.60 : FAD/NAD(P)-binding domainM00163,D00015,D00041,D00042,D00045,D00064,D00071,T00004,T00015,T00025,T00211,T00213,T00233,T00242

Enzyme Name
UniProtKBKEGG

P11959P14218P09063P18925P66004
Protein nameDihydrolipoyl dehydrogenaseDihydrolipoyl dehydrogenaseDihydrolipoyl dehydrogenaseDihydrolipoyl dehydrogenaseDihydrolipoyl dehydrogenasedihydrolipoyl dehydrogenase
LDP-Glc
LDP-Val
dehydrolipoate dehydrogenase
diaphorase
dihydrolipoamide dehydrogenase
dihydrolipoamide:NAD+ oxidoreductase
dihydrolipoic dehydrogenase
dihydrothioctic dehydrogenase
lipoamide dehydrogenase (NADH)
lipoamide oxidoreductase (NADH)
lipoamide reductase
lipoamide reductase (NADH)
lipoate dehydrogenase
lipoic acid dehydrogenase
lipoyl dehydrogenase
protein-6-N-(dihydrolipoyl)lysine:NAD+ oxidoreductase
SynonymsEC 1.8.1.4
Dihydrolipoamide dehydrogenase
E3 component of pyruvate complex
EC 1.8.1.4
Dihydrolipoamide dehydrogenase
E3 component of 2-oxoglutarate dehydrogenase complex
EC 1.8.1.4
Dihydrolipoamide dehydrogenase
LPD-Val
E3 component of branched-chain alpha-keto acid dehydrogenase complex
EC 1.8.1.4
Dihydrolipoamide dehydrogenase
E3 component of pyruvate complex
EC 1.8.1.4
Dihydrolipoamide dehydrogenase
E3 component of alpha keto acid dehydrogenase complexes
RefSeq



NP_214976.1 (Protein)
NC_000962.3 (DNA/RNA sequence)
NP_334888.1 (Protein)
NC_002755.2 (DNA/RNA sequence)
YP_006513791.1 (Protein)
NC_018143.1 (DNA/RNA sequence)
PfamPF00070 (Pyr_redox)
PF07992 (Pyr_redox_2)
PF02852 (Pyr_redox_dim)
[Graphical view]
PF00070 (Pyr_redox)
PF07992 (Pyr_redox_2)
PF02852 (Pyr_redox_dim)
[Graphical view]
PF00070 (Pyr_redox)
PF07992 (Pyr_redox_2)
PF02852 (Pyr_redox_dim)
[Graphical view]
PF00070 (Pyr_redox)
PF07992 (Pyr_redox_2)
PF02852 (Pyr_redox_dim)
[Graphical view]
PF00070 (Pyr_redox)
PF07992 (Pyr_redox_2)
PF02852 (Pyr_redox_dim)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00010Glycolysis / Gluconeogenesis
MAP00020Citrate cycle (TCA cycle)
MAP00260Glycine, serine and threonine metabolism
MAP00280Valine, leucine and isoleucine degradation
MAP00620Pyruvate metabolism

UniProtKB:Accession NumberP11959P14218P09063P18925P66004
Entry nameDLDH1_BACSTDLDH_PSEFLDLDH1_PSEPUDLDH_AZOVIDLDH_MYCTU
ActivityProtein N(6)-(dihydrolipoyl)lysine + NAD(+) = protein N(6)-(lipoyl)lysine + NADH.Protein N(6)-(dihydrolipoyl)lysine + NAD(+) = protein N(6)-(lipoyl)lysine + NADH.Protein N(6)-(dihydrolipoyl)lysine + NAD(+) = protein N(6)-(lipoyl)lysine + NADH.Protein N(6)-(dihydrolipoyl)lysine + NAD(+) = protein N(6)-(lipoyl)lysine + NADH.Protein N(6)-(dihydrolipoyl)lysine + NAD(+) = protein N(6)-(lipoyl)lysine + NADH.
SubunitHomodimer. Identified in a complex with pdhC.Homodimer.Homodimer.Homodimer.Homodimer.
Subcellular locationCytoplasm.Cytoplasm.Cytoplasm.Cytoplasm.Cytoplasm (Potential).
CofactorBinds 1 FAD per subunit.Binds 1 FAD per subunit.Binds 1 FAD per subunit (By similarity).Binds 1 FAD per subunit.Binds 1 FAD per subunit.

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00016C00003C02972C00004C02051C00080
CompoundFADNAD+DihydrolipoylproteinNADHLipoylproteinH+
Typeamide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carbohydrate,nucleotideamide group,amine group,nucleotidecarbohydrate,lipid,peptide/protein,sulfhydryl groupamide group,amine group,nucleotidedisulfide bond,lipid,peptide/proteinothers
ChEBI16238
15846

16908

15378
PubChem643975
5893

439153

1038
              
1ebdA01Bound:FADUnboundUnboundUnboundUnbound 
1ebdB01Bound:FADUnboundUnboundUnboundUnbound 
1lpfA01Bound:FADUnboundUnboundUnboundUnbound 
1lpfB01Bound:FADUnboundUnboundUnboundUnbound 
1lvlA01Bound:FADUnboundUnboundUnboundUnbound 
3ladA01Bound:FADUnboundUnboundUnboundUnbound 
3ladB01Bound:FADUnboundUnboundUnboundUnbound 
2a8xA01Bound:FADUnboundUnboundUnboundUnbound 
2a8xB01Bound:FADUnboundUnboundUnboundUnbound 
1ebdA02UnboundUnboundUnboundUnboundUnbound 
1ebdB02UnboundUnboundUnboundUnboundUnbound 
1lpfA02UnboundUnboundUnboundUnboundUnbound 
1lpfB02UnboundUnboundUnboundUnboundUnbound 
1lvlA02UnboundBound:NADUnboundUnboundUnbound 
3ladA02UnboundUnboundUnboundUnboundUnbound 
3ladB02UnboundUnboundUnboundUnboundUnbound 
2a8xA02UnboundUnboundUnboundUnboundUnbound 
2a8xB02UnboundUnboundUnboundUnboundUnbound 
1ebdA03UnboundUnboundUnboundUnboundUnbound 
1ebdB03UnboundUnboundUnboundUnboundUnbound 
1lpfA03UnboundUnboundUnboundUnboundUnbound 
1lpfB03UnboundUnboundUnboundUnboundUnbound 
1lvlA03UnboundUnboundUnboundUnboundUnbound 
3ladA03UnboundUnboundUnboundUnboundUnbound 
3ladB03UnboundUnboundUnboundUnboundUnbound 
2a8xA03UnboundUnboundUnboundUnboundUnbound 
2a8xB03UnboundUnboundUnboundUnboundUnbound 

Active-site residues
resource
Swiss-prot;P11959, P09063, P18925, P14218 & literature [19], [36]
pdbCatalytic residuescomment
          
1ebdA01TYR 22;CYS 47;CYS 52
 
1ebdB01TYR 22;CYS 47;CYS 52
 
1lpfA01TYR 16;CYS 48;CYS 53
 
1lpfB01TYR 16;CYS 48;CYS 53
 
1lvlA01TYR 18;CYS 43;CYS 48
 
3ladA01TYR 16;CYS 48;CYS 53
 
3ladB01TYR 16;CYS 48;CYS 53
 
2a8xA01TYR 16;CYS 41;CYS 46
 
2a8xB01TYR 16;CYS 41;CYS 46
 
1ebdA02 
 
1ebdB02 
 
1lpfA02 
 
1lpfB02 
 
1lvlA02 
 
3ladA02 
 
3ladB02 
 
2a8xA02 
 
2a8xB02 
 
1ebdA03HIS 446;       
invisible H466
1ebdB03HIS 446;       
invisible H466
1lpfA03HIS 450;HIS 470
 
1lpfB03HIS 450;HIS 470
 
1lvlA03HIS 437;HIS 457
 
3ladA03HIS 450;HIS 470
 
3ladB03HIS 450;HIS 470
 
2a8xA03HIS 443;ASN 463
 
2a8xB03HIS 443;ASN 463
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[2]Scheme I, Scheme II
[7]Scheme 2
[10]p.989
[12]Scheme I, Scheme II, p.3070-3072
[13]Scheme 1, Scheme 2
[17]

[19]

[36]Scheme 1, Scheme 5

references
[1]
PubMed ID6894226
JournalArch Biochem Biophys
Year1981
Volume206
Pages77-86
AuthorsTsai CS, Templeton DM, Wand AJ
TitleMultifunctionality of lipoamide dehydrogenase: activities of chemically trapped monomeric and dimeric enzymes.
[2]
PubMed ID6688532
JournalBiochemistry
Year1983
Volume22
Pages3792-6
AuthorsO'Donnell ME, Johnson FA, Williams CH Jr
TitleProton nuclear magnetic resonance investigation of the mechanism of flavin C-4a adduct formation induced by oxidized nicotinamide adenine dinucleotide binding to monoalkylated pig heart lipoamide dehydrogenase.
[3]
PubMed ID6546954
JournalJ Mol Biol
Year1984
Volume174
Pages483-96
AuthorsRice DW, Schulz GE, Guest JR
TitleStructural relationship between glutathione reductase and lipoamide dehydrogenase.
[4]
PubMed ID3292518
JournalJ Biochem (Tokyo)
Year1988
Volume103
Pages463-9
AuthorsTakenaka A, Kizawa K, Hata T, Sato S, Misaka E, Tamura C, Sasada Y
TitleX-ray study of baker's yeast lipoamide dehydrogenase at 4.5 A resolution by molecular replacement method.
[5]
PubMed ID2716052
JournalJ Mol Biol
Year1989
Volume206
Pages365-79
AuthorsSchierbeek AJ, Swarte MB, Dijkstra BW, Vriend G, Read RJ, Hol WG, Drenth J, Betzel C
TitleX-ray structure of lipoamide dehydrogenase from Azotobacter vinelandii determined by a combination of molecular and isomorphous replacement techniques.
[6]
PubMed ID2176163
JournalFEBS Lett
Year1990
Volume276
Pages189-91
AuthorsShi XL, Dalal NS
TitleNADPH-dependent flavoenzymes catalyze one electron reduction of metal ions and molecular oxygen and generate hydroxyl radicals.
[7]
PubMed ID1684937
JournalEur J Biochem
Year1991
Volume202
Pages863-72
AuthorsBenen J, van Berkel W, Zak Z, Visser T, Veeger C, de Kok A
TitleLipoamide dehydrogenase from Azotobacter vinelandii: site-directed mutagenesis of the His450-Glu455 diad. Spectral properties of wild type and mutated enzymes.
[8]
PubMed ID1765065
JournalEur J Biochem
Year1991
Volume202
Pages1049-55
Authorsvan Berkel WJ, Regelink AG, Beintema JJ, de Kok A
TitleThe conformational stability of the redox states of lipoamide dehydrogenase from Azotobacter vinelandii.
[9]
PubMed ID1652585
JournalJ Biochem (Tokyo)
Year1991
Volume109
Pages450-4
AuthorsBando Y, Aki K
TitleMechanisms of generation of oxygen radicals and reductive mobilization of ferritin iron by lipoamide dehydrogenase.
[10]
CommentsX-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS).
Medline ID91350192
PubMed ID1880807
JournalJ Mol Biol
Year1991
Volume220
Pages975-94
AuthorsMattevi A, Schierbeek AJ, Hol WG
TitleRefined crystal structure of lipoamide dehydrogenase from Azotobacter vinelandii at 2.2 A resolution. A comparison with the structure of glutathione reductase.
Related PDB3lad
Related UniProtKBP18925
[11]
PubMed ID1456954
JournalBiochem Int
Year1992
Volume28
Pages323-34
AuthorsSreider CM, Grinblat L, Stoppani AO
TitleReduction of nitrofuran compounds by heart lipoamide dehydrogenase: role of flavin and the reactive disulfide groups.
[12]
PubMed ID1554695
JournalBiochemistry
Year1992
Volume31
Pages3065-72
AuthorsLeichus BN, Blanchard JS
TitlePig heart lipoamide dehydrogenase: solvent equilibrium and kinetic isotope effects.
[13]
PubMed ID1633804
JournalEur J Biochem
Year1992
Volume207
Pages487-97
AuthorsBenen J, van Berkel W, Dieteren N, Arscott D, Williams C Jr, Veeger C, de Kok A
TitleLipoamide dehydrogenase from Azotobacter vinelandii: site-directed mutagenesis of the His450-Glu455 diad. Kinetics of wild-type and mutated enzymes.
[14]
PubMed ID1633805
JournalEur J Biochem
Year1992
Volume207
Pages499-505
AuthorsBenen J, van Berkel W, Veeger C, de Kok A
TitleLipoamide dehydrogenase from Azotobacter vinelandii. The role of the C-terminus in catalysis and dimer stabilization.
[15]
PubMed ID1451916
JournalInt J Biochem
Year1992
Volume24
Pages1801-6
AuthorsTsai CS, Wand AJ
TitlepH dependent kinetic studies of lipoamide dehydrogenase catalysis.
[16]
PubMed ID1347528
JournalJ Biol Chem
Year1992
Volume267
Pages5128-32
AuthorsKim H, Patel MS
TitleCharacterization of two site-specifically mutated human dihydrolipoamide dehydrogenases (His-452----Gln and Glu-457----Gln).
[17]
CommentsX-RAY CRYSTALLOGRAPHY (2.45 ANGSTROMS).
Medline ID92390345
PubMed ID1325638
JournalProteins
Year1992
Volume13
Pages336-51
AuthorsMattevi A, Obmolova G, Sokatch JR, Betzel C, Hol WG
TitleThe refined crystal structure of Pseudomonas putida lipoamide dehydrogenase complexed with NAD+ at 2.45 A resolution.
Related PDB1lvl
Related UniProtKBP09063
[18]
PubMed ID8385902
JournalArch Biochem Biophys
Year1993
Volume302
Pages300-3
AuthorsShi X, Dalal NS
TitleOne-electron reduction of vanadium(V) by flavoenzymes/NADPH.
[19]
CommentsX-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS).
Medline ID93253780
PubMed ID8487301
JournalJ Mol Biol
Year1993
Volume230
Pages1200-15
AuthorsMattevi A, Obmolova G, Kalk KH, van Berkel WJ, Hol WG
TitleThree-dimensional structure of lipoamide dehydrogenase from Pseudomonas fluorescens at 2.8 A resolution. Analysis of redox and thermostability properties.
Related PDB1lpf
Related UniProtKBP14218
[20]
PubMed ID8575446
JournalEur J Biochem
Year1995
Volume234
Pages861-70
AuthorsWestphal AH, Fabisz-Kijowska A, Kester H, Obels PP, de Kok A
TitleThe interaction between lipoamide dehydrogenase and the peripheral-component-binding domain from the Azotobacter vinelandii pyruvate dehydrogenase complex.
[21]
PubMed ID7672506
JournalFASEB J
Year1995
Volume9
Pages1138-46
AuthorsKrauth-Siegel RL, Schoneck R
TitleFlavoprotein structure and mechanism. 5. Trypanothione reductase and lipoamide dehydrogenase as targets for a structure-based drug design.
[22]
PubMed ID7499374
JournalJ Biol Chem
Year1995
Volume270
Pages28586-94
AuthorsMurthy YV, Massey V
TitleChemical modification of the N-10 ribityl side chain of flavins. Effects on properties of flavoprotein disulfide oxidoreductases.
[23]
CommentsX-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
Medline ID96398614
PubMed ID8805537
JournalStructure
Year1996
Volume4
Pages277-86
AuthorsMande SS, Sarfaty S, Allen MD, Perham RN, Hol WG
TitleProtein-protein interactions in the pyruvate dehydrogenase multienzyme complex: dihydrolipoamide dehydrogenase complexed with the binding domain of dihydrolipoamide acetyltransferase.
Related PDB1ebd
Related UniProtKBP11959
[24]
PubMed ID9143318
JournalArch Biochem Biophys
Year1997
Volume340
Pages168-76
AuthorsMarcinkeviciene J, Blanchard JS
TitleCatalytic properties of lipoamide dehydrogenase from Mycobacterium smegmatis.
[25]
PubMed ID9278141
JournalBiol Chem
Year1997
Volume378
Pages617-34
AuthorsBerg A, de Kok A
Title2-Oxo acid dehydrogenase multienzyme complexes. The central role of the lipoyl domain.
[26]
PubMed ID9193005
JournalJ Mol Biol
Year1997
Volume269
Pages129-41
AuthorsLi de la Sierra I, Pernot L, Prange T, Saludjian P, Schiltz M, Fourme R, Padron G
TitleMolecular structure of the lipoamide dehydrogenase domain of a surface antigen from Neisseria meningitidis.
[27]
PubMed ID10047833
JournalBiochem Soc Trans
Year1998
Volume26
PagesS319
AuthorsRice L, Phoenix DA, Wainwright M, Waring JJ
TitleEffect of increasing methylation on the ability of methylene blue to cause diaphorase-catalysed oxidation of NADH.
[28]
PubMed ID9538259
JournalJ Biochem (Tokyo)
Year1998
Volume123
Pages668-74
AuthorsToyoda T, Suzuki K, Sekiguchi T, Reed LJ, Takenaka A
TitleCrystal structure of eucaryotic E3, lipoamide dehydrogenase from yeast.
Related PDB1jeh
[29]
PubMed ID10806386
JournalEur J Biochem
Year2000
Volume267
Pages2890-8
AuthorsFaure M, Bourguignon J, Neuburger M, MacHerel D, Sieker L, Ober R, Kahn R, Cohen-Addad C, Douce R
TitleInteraction between the lipoamide-containing H-protein and the lipoamide dehydrogenase (L-protein) of the glycine decarboxylase multienzyme system 2. Crystal structures of H- and L-proteins.
Related PDB1dxl
[30]
PubMed ID10806385
JournalEur J Biochem
Year2000
Volume267
Pages2882-9
AuthorsNeuburger M, Polidori AM, Pietre E, Faure M, Jourdain A, Bourguignon J, Pucci B, Douce R
TitleInteraction between the lipoamide-containing H-protein and the lipoamide dehydrogenase (L-protein) of the glycine decarboxylase multienzyme system. 1. Biochemical studies.
[31]
PubMed ID10970889
JournalJ Biol Chem
Year2000
Volume275
Pages36665-70
AuthorsLindsay H, Beaumont E, Richards SD, Kelly SM, Sanderson SJ, Price NC, Lindsay JG
TitleFAD insertion is essential for attaining the assembly competence of the dihydrolipoamide dehydrogenase (E3) monomer from Escherichia coli.
[32]
PubMed ID11390211
JournalBiosens Bioelectron
Year2001
Volume16
Pages245-52
AuthorsEicher I, Schmidt HL
TitleElectrocatalytic reduction of lipoic acid and electroenzymatic reduction of NAD(P)(+) for integrated dehydrogenase biosensors.
[33]
PubMed ID11559360
JournalEur J Biochem
Year2001
Volume268
Pages4908-17
AuthorsTozawa K, Broadhurst RW, Raine AR, Fuller C, Alvarez A, Guillen G, Padron G, Perham RN
TitleSolution structure of the lipoyl domain of the chimeric dihydrolipoyl dehydrogenase P64K from Neisseria meningitidis.
[34]
PubMed ID11170645
JournalJ Med Chem
Year2001
Volume44
Pages548-65
AuthorsSalmon-Chemin L, Buisine E, Yardley V, Kohler S, Debreu MA, Landry V, Sergheraert C, Croft SL, Krauth-Siegel RL, Davioud-Charvet E
Title2- and 3-substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: synthesis and correlation between redox cycling activities and in vitro cytotoxicity.
[35]
PubMed ID12200115
JournalBiochem Biophys Res Commun
Year2002
Volume296
Pages779-84
AuthorsBhushan B, Halasz A, Spain JC, Hawari J
TitleDiaphorase catalyzed biotransformation of RDX via N-denitration mechanism.
[36]
PubMed ID12463758
JournalBiochemistry
Year2002
Volume41
Pages14580-90
AuthorsArgyrou A, Blanchard JS, Palfey BA
TitleThe lipoamide dehydrogenase from Mycobacterium tuberculosis permits the direct observation of flavin intermediates in catalysis.
[37]
PubMed ID11799204
JournalScience
Year2002
Volume295
Pages1073-7
AuthorsBryk R, Lima CD, Erdjument-Bromage H, Tempst P, Nathan C
TitleMetabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein.
[38]
PubMed ID16093239
JournalJ Biol Chem
Year2005
Volume280
Pages33977-83
AuthorsRajashankar KR, Bryk R, Kniewel R, Buglino JA, Nathan CF, Lima CD
TitleCrystal structure and functional analysis of lipoamide dehydrogenase from Mycobacterium tuberculosis.
Related PDB2a8x
[39]
PubMed ID15946682
JournalJ Mol Biol
Year2005
Volume350
Pages543-52
AuthorsBrautigam CA, Chuang JL, Tomchick DR, Machius M, Chuang DT
TitleCrystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations.
Related PDB1zmc,1zmd

comments
This enzyme is one of the component of the pyruvate dehydrogenase multienzyme complex which is composed of dihydrolipoamide acetyltransferase(E1), pyruvate decarboxylase(E2), and dihydrolipoamide dehydrogenase(E3). Moreover, it is homologous to the L protein of glycine cleavage system (M00163 in EzCatDB).
According to the literature [36], this enzyme catalyzes the following reactions:
(A) Hydride transfer from NADH to FAD, giving reduced flavin (FADH2):
(B) Electron transfer from FADH2 to the redox-active disulfide bond (Cys-Cys), giving the oxidized flavin (FAD):
(C) Electron transfer from the active site cysteine residues to lipoamide substrate, giving dihyrolipoamide and the disulfide bond of the cysteine residues.
In the so-called reductive half-reaction, the reactions, (A) and (B), occur.
In the so-called oxidative half-reaction, the reaction, (C), occurs subsequently.

createdupdated
2004-12-222009-03-12


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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