EzCatDB: S00319
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DB codeS00319
RLCP classification9.1050.440000.8010 : Hydride transfer
9.5010.536200.8010 : Hydride transfer
CATH domainDomain 13.40.50.720 : Rossmann foldCatalytic domain
E.C.1.1.1.1
MACiEM0255

CATH domainRelated DB codes (homologues)
3.40.50.720 : Rossmann foldS00543,S00551,S00552,S00553,S00602,S00604,S00605,S00608,S00610,S00625,S00328,S00329,S00330,S00331,S00332,D00456,D00457,D00458,S00324,S00320,S00325,S00326,S00327,D00459,S00335,S00336,S00334,T00219,S00339,D00513,D00001,D00002,D00003,D00005,D00007,D00008,D00010,D00012,D00017,D00018,D00023,D00027,D00028,D00031,D00032,D00033,D00034,D00035,D00037,D00048,D00071,D00476,D00481,D00482,D00490,D00492,D00494,D00545,D00601,D00603,D00604,D00605,D00615,D00845,D00857,D00858,M00161,M00171,M00210,T00002,T00010,T00011,T00015,T00227,T00247,T00408,T00414,D00827,D00262,D00274,D00275,M00035,T00109

Enzyme Name
UniProtKBKEGG

P10807P00334
Protein nameAlcohol dehydrogenaseAlcohol dehydrogenasealcohol dehydrogenase
aldehyde reductase
ADH
alcohol dehydrogenase (NAD)
aliphatic alcohol dehydrogenase
ethanol dehydrogenase
NAD-dependent alcohol dehydrogenase
NAD-specific aromatic alcohol dehydrogenase
NADH-alcohol dehydrogenase
NADH-aldehyde dehydrogenase
primary alcohol dehydrogenase
yeast alcohol dehydrogenase
SynonymsEC 1.1.1.1
EC 1.1.1.1
RefSeq
NP_001027266.1 (Protein)
NM_001032095.1 (DNA/RNA sequence)
NP_001027267.1 (Protein)
NM_001032096.1 (DNA/RNA sequence)
NP_001027268.1 (Protein)
NM_001032097.1 (DNA/RNA sequence)
NP_001027269.1 (Protein)
NM_001032098.1 (DNA/RNA sequence)
NP_001027270.1 (Protein)
NM_001032099.1 (DNA/RNA sequence)
PfamPF00106 (adh_short)
[Graphical view]
PF00106 (adh_short)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00010Glycolysis / Gluconeogenesis
MAP00071Fatty acid metabolism
MAP00120Bile acid biosynthesis
MAP00260Glycine, serine and threonine metabolism
MAP00350Tyrosine metabolism
MAP006241- and 2-Methylnaphthalene degradation
MAP006413-Chloroacrylic acid degradation
MAP00830Retinol metabolism
MAP00980Metabolism of xenobiotics by cytochrome P450
MAP00982Drug metabolism - cytochrome P450

UniProtKB:Accession NumberP10807P00334
Entry nameADH_DROLEADH_DROME
ActivityAn alcohol + NAD(+) = an aldehyde or ketone + NADH.An alcohol + NAD(+) = an aldehyde or ketone + NADH.
SubunitHomodimer.Homodimer.
Subcellular location

Cofactor


Compound table: links to PDB-related databases & PoSSuM

SubstratesProducts
KEGG-idC00003C00069C00004C00071C00709C00080
CompoundNAD+AlcoholNADHAldehydeKetoneH+
Typeamide group,amine group,nucleotidecarbohydrateamide group,amine group,nucleotidecarbohydratecarbohydrateothers
ChEBI15846

16908


15378
PubChem5893

439153


1038
              
1a4uAUnboundUnboundUnboundUnboundUnbound 
1a4uBUnboundUnboundUnboundUnboundUnbound 
1b14ABound:NADUnboundUnboundUnboundUnbound 
1b14BBound:NADUnboundUnboundUnboundUnbound 
1b15AAnalogue:NAE(NAD-Ketone)UnboundUnboundUnboundAnalogue:NAE(NAD-Ketone) 
1b15BAnalogue:NAE(NAD-Ketone)UnboundUnboundUnboundAnalogue:NAE(NAD-Ketone) 
1b16AAnalogue:NAQ(NAD-Ketone)UnboundUnboundUnboundAnalogue:NAQ(NAD-Ketone) 
1b16BAnalogue:NAQ(NAD-Ketone)UnboundUnboundUnboundAnalogue:NAQ(NAD-Ketone) 
1b2lAAnalogue:NDC(NAD-Ketone)UnboundUnboundUnboundAnalogue:NDC(NAD-Ketone) 
1sbyABound:NADAnalogue:ETFUnboundUnboundUnbound 
1sbyBBound:NADAnalogue:ETFUnboundUnboundUnbound 
1mg5ABound:NADUnboundUnboundUnboundAnalogue:ACT 
1mg5BBound:NADUnboundUnboundUnboundAnalogue:ACT 

Active-site residues
resource
PDB;1a4u & Swiss-prot;P10807
pdbCatalytic residues
         
1a4uASER 138;TYR 151;LYS 155
1a4uBSER 138;TYR 151;LYS 155
1b14ASER 138;TYR 151;LYS 155
1b14BSER 138;TYR 151;LYS 155
1b15ASER 138;TYR 151;LYS 155
1b15BSER 138;TYR 151;LYS 155
1b16ASER 138;TYR 151;LYS 155
1b16BSER 138;TYR 151;LYS 155
1b2lASER 138;TYR 151;LYS 155
1sbyASER 138;TYR 151;LYS 155
1sbyBSER 138;TYR 151;LYS 155
1mg5ASER 139;TYR 152;LYS 156
1mg5BSER 139;TYR 152;LYS 156

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[10]Fig.5, p.3345-33462
[11]p.7054
[12]p.84
[16]p.193
[18]p.389-391
[20]Fig.10, p.346-348
[21]Fig.5, p.608-611
[25]p.296-298
[28]Fig.7, p.3927-3930

references
[1]
PubMed ID6821373
JournalBiochem J
Year1980
Volume187
Pages875-83
AuthorsThatcher DR
TitleThe complete amino acid sequence of three alcohol dehydrogenase alleloenzymes (AdhN-11, AdhS and AdhUF) from the fruitfly Drosophila melanogaster.
[2]
PubMed ID6821374
JournalBiochem J
Year1980
Volume187
Pages884-6
AuthorsThatcher DR, Sawyer L
TitleSecondary-structure prediction from the sequence of Drosophila melanogaster (fruitfly) alcohol dehydrogenase.
[3]
PubMed ID6789320
JournalProc Natl Acad Sci U S A
Year1981
Volume78
Pages2717-21
AuthorsBenyajati C, Place AR, Powers DA, Sofer W
TitleAlcohol dehydrogenase gene of Drosophila melanogaster: relationship of intervening sequences to functional domains in the protein.
[4]
PubMed ID3160338
JournalBiochem Genet
Year1985
Volume23
Pages205-16
AuthorsWinberg JO, Hovik R, McKinley-McKee JS
TitleThe alcohol dehydrogenase alleloenzymes AdhS and AdhF from the fruitfly Drosophila melanogaster: an enzymatic rate assay to determine the active-site concentration.
[5]
PubMed ID1804107
JournalBiochem Int
Year1991
Volume25
Pages879-85
AuthorsMcKinley-McKee JS, Winberg JO, Pettersson G
TitleMechanism of action of Drosophila melanogaster alcohol dehydrogenase.
[6]
PubMed ID1904719
JournalBiochem J
Year1991
Volume276
Pages433-8
AuthorsRibas De Pouplana L, Atrian S, Gonzalex-Duarte R, Fothergill-Gilmore LA, Kelly SM, Price NC
TitleStructural properties of long- and short-chain alcohol dehydrogenases. Contribution of NAD+ to stability.
[7]
PubMed ID1733784
JournalInt J Biochem
Year1992
Volume24
Pages169-81
AuthorsWinberg JO, McKinley-McKee JS
TitleKinetic interpretations of active site topologies and residue exchanges in Drosophila alcohol dehydrogenases.
[8]
PubMed ID1522600
JournalJ Mol Biol
Year1992
Volume227
Pages356-8
AuthorsGordon EJ, Bury SM, Sawyer L, Atrian S, Gonzalez-Duarte R
TitlePreliminary X-ray crystallographic studies on alcohol dehydrogenase from Drosophila.
[9]
PubMed ID1508206
JournalMol Cell Biol
Year1992
Volume12
Pages4093-103
AuthorsFalb D, Maniatis T
TitleDrosophila transcriptional repressor protein that binds specifically to negative control elements in fat body enhancers.
[10]
PubMed ID8461298
JournalBiochemistry
Year1993
Volume32
Pages3342-6
AuthorsChen Z, Jiang JC, Lin ZG, Lee WR, Baker ME, Chang SH
TitleSite-specific mutagenesis of Drosophila alcohol dehydrogenase: evidence for involvement of tyrosine-152 and lysine-156 in catalysis.
[11]
PubMed ID8003469
JournalBiochemistry
Year1994
Volume33
Pages7047-55
AuthorsRibas de Pouplana L, Fothergill-Gilmore LA
TitleThe active site architecture of a short-chain dehydrogenase defined by site-directed mutagenesis and structure modeling.
[12]
PubMed ID7988726
JournalFEBS Lett
Year1994
Volume356
Pages81-5
AuthorsChen Z, Tsigelny I, Lee WR, Baker ME, Chang SH
TitleAdding a positive charge at residue 46 of Drosophila alcohol dehydrogenase increases cofactor specificity for NADP+.
[13]
PubMed ID7772022
JournalBiochem J
Year1995
Volume308
Pages419-23
AuthorsChenevert SW, Fossett NG, Chang SH, Tsigelny I, Baker ME, Lee WR
TitleAmino acids important in enzyme activity and dimer stability for Drosophila alcohol dehydrogenase.
[14]
PubMed ID7588794
JournalEur J Biochem
Year1995
Volume233
Pages498-505
AuthorsAlbalat R, Valls M, Fibla J, Atrian S, Gonzalez-Duarte R
TitleInvolvement of the C-terminal tail in the activity of Drosophila alcohol dehydrogenase. Evaluation of truncated proteins constructed by site-directed mutagenesis.
[15]
PubMed ID8547186
JournalJ Steroid Biochem Mol Biol
Year1995
Volume55
Pages589-600
AuthorsTsigelny I, Baker ME
TitleStructures important in mammalian 11 beta- and 17 beta-hydroxysteroid dehydrogenases.
[16]
PubMed ID9280279
JournalFEBS Lett
Year1997
Volume413
Pages191-3
AuthorsCols N, Atrian S, Benach J, Ladenstein R, Gonzalez-Duarte R
TitleDrosophila alcohol dehydrogenase: evaluation of Ser139 site-directed mutants.
[17]
PubMed ID9562905
JournalBiochem Genet
Year1998
Volume36
Pages37-49
AuthorsSmilda T, Reinders P, Beintema JJ
TitleModeling studies of conformational changes in the substrate-binding loop in Drosophila alcohol dehydrogenase.
[18]
CommentsX-RAY CRYSTALLOGRAPHY (1.92 ANGSTROMS).
Medline ID98407982
PubMed ID9735295
JournalJ Mol Biol
Year1998
Volume282
Pages383-99
AuthorsBenach J, Atrian S, Gonzalez-Duarte R, Ladenstein R
TitleThe refined crystal structure of Drosophila lebanonensis alcohol dehydrogenase at 1.9 A resolution.
Related PDB1a4u,1b14
Related UniProtKBP10807
[19]
PubMed ID9694670
JournalJ Mol Evol
Year1998
Volume47
Pages211-21
AuthorsAtrian S, Sanchez-Pulido L, Gonzalez-Duarte R, Valencia A
TitleShaping of Drosophila alcohol dehydrogenase through evolution: relationship with enzyme functionality.
[20]
CommentsX-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS).
Medline ID99296633
PubMed ID10366509
JournalJ Mol Biol
Year1999
Volume289
Pages335-55
AuthorsBenach J, Atrian S, Gonzalez-Duarte R, Ladenstein R
TitleThe catalytic reaction and inhibition mechanism of Drosophila alcohol dehydrogenase: observation of an enzyme-bound NAD-ketone adduct at 1.4 A resolution by X-ray crystallography.
Related PDB1b15,1b16,1b2l
Related UniProtKBP10807
[21]
PubMed ID10610783
JournalJ Mol Biol
Year1999
Volume294
Pages601-16
AuthorsWinberg JO, Brendskag MK, Sylte I, Lindstad RI, McKinley-McKee JS
TitleThe catalytic triad in Drosophila alcohol dehydrogenase: pH, temperature and molecular modelling studies.
[22]
PubMed ID10093214
JournalJ Mol Evol
Year1999
Volume48
Pages262-3
AuthorsAtrian S, Gonzalez-Duarte R
TitleThe Drosophila virilis alcohol dehydrogenase catalytic residues are conserved.
[23]
PubMed ID10848978
JournalEur J Biochem
Year2000
Volume267
Pages3613-22
AuthorsBenach J, Atrian S, Fibla J, Gonzalez-Duarte R, Ladenstein R
TitleStructure-function relationships in Drosophila melanogaster alcohol dehydrogenase allozymes ADH(S), ADH(F) and ADH(UF), and distantly related forms.
[24]
PubMed ID11443349
JournalJ Mol Evol
Year2001
Volume52
Pages457-66
AuthorsSmilda T, Kamminga AH, Reinders P, Baron W, van Hylckama Vlieg JE, Beintema JJ
TitleEnzymic and structural studies on Drosophila alcohol dehydrogenase and other short-chain dehydrogenases/reductases.
[25]
PubMed ID12660997
JournalProteins
Year2003
Volume51
Pages289-98
AuthorsKoumanov A, Benach J, Atrian S, Gonzalez-Duarte R, Karshikoff A, Ladenstein R
TitleThe catalytic mechanism of Drosophila alcohol dehydrogenase: evidence for a proton relay modulated by the coupled ionization of the active site Lysine/Tyrosine pair and a NAD+ ribose OH switch.
[26]
PubMed ID15170253
JournalJ Mol Evol
Year2004
Volume58
Pages493-505
AuthorsEliopoulos E, Goulielmos GN, Loukas M
TitleFunctional constraints of alcohol dehydrogenase (ADH) of tephritidae and relationships with other Dipteran species.
[27]
PubMed ID15581900
JournalJ Mol Biol
Year2005
Volume345
Pages579-98
AuthorsBenach J, Winberg JO, Svendsen JS, Atrian S, Gonzalez-Duarte R, Ladenstein R
TitleDrosophila alcohol dehydrogenase: acetate-enzyme interactions and novel insights into the effects of electrostatics on catalysis.
Related PDB1mg5
[28]
PubMed ID19011748
JournalCell Mol Life Sci
Year2008
Volume65
Pages3918-35
AuthorsLadenstein R, Winberg JO, Benach J
TitleMedium- and short-chain dehydrogenase/reductase gene and protein families : Structure-function relationships in short-chain alcohol dehydrogenases.

comments
Whilst this enzyme does not utilize a zinc ion for catalysis, its counterparts (homologous enzymes) from vertebrates (such as D00018 in EzCatDB) requires zinc ion for catalysis (see [5]).
The catalytic mechanism of this enzyme must be similar to those of the homologous enzymes with the catalytic triad, Ser-Tyr-Lys (S00320, S00324, S00325, S00326, S00328, S00329, S00331, S00336 in EzCatDB).
According to the literature [20] and [28], the reaction proceeds as follows:
(A) Hydride transfer from substrate to NAD (Dehydrogenation):
(A0) Lys156 (of 1mg5) modulates the activity (or pKa) of Tyr152 via 2'-hydroxyl group of NAD, along with the N1 atom of the nicotinamide group in NAD, whereas Ser139 modulates the pKa of hydroxyl oxygen of the substrate.
(A1) Tyr152 acts as a general base to deprotonate the hydroxyl oxygen of the substrate. Meanwhile, the hydride transfer (a pro-S hydride transfer) occurs from the carbon atom with the hydroxyl group of the substrate to the C4 atom of the nicotinamide.
(B) Hydride transfer from NADH to substrate (Reduction):
(B0) Lys156 modulates the activity (or pKa) of Tyr152 via 2'-hydroxyl group of NAD(P)H, along with the N1 atom of the nicotinamide group in NADH, whereas Ser139 modulates the pKa of carbonyl oxygen of the substrate.
(B1) Tyr152 acts as a general acid to protonate the carbonyl oxygen of the substrate. Meanwhile, the hydride transfer occurs from the C4 atom of the nicotinamide to the carbonyl carbon of the substrate.

createdupdated
2005-01-062011-06-22


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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