P14550 (AK1A1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Alcohol dehydrogenase [NADP(+)]
EC=1.1.1.2

Alternative name(s):
Aldehyde reductase
Aldo-keto reductase family 1 member A1

Gene names

Name:	AKR1A1
Synonyms:	ALDR1, ALR

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	325 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Catalyzes the NADPH-dependent reduction of a variety of aromatic and aliphatic aldehydes to their corresponding alcohols. Catalyzes the reduction of mevaldate to mevalonic acid and of glyceraldehyde to glycerol. Has broad substrate specificity. In vitro substrates include succinic semialdehyde, 4-nitrobenzaldehyde, 1,2-naphthoquinone, methylglyoxal, and D-glucuronic acid. Plays a role in the activation of procarcinogens, such as polycyclic aromatic hydrocarbon trans-dihydrodiols, and in the metabolism of various xenobiotics and drugs, including the anthracyclines doxorubicin (DOX) and daunorubicin (DAUN). Ref.12 Ref.13 Ref.14
Catalytic activity	An alcohol + NADP+ = an aldehyde + NADPH.
Subunit structure	Monomer By similarity.
Tissue specificity	Widely expressed. Highly expressed in kidney, salivary gland and liver. Detected in trachea, stomach, brain, lung, prostate, placenta, mammary gland, small intestine and lung. Ref.12 Ref.13
Sequence similarities	Belongs to the aldo/keto reductase family.

Ontologies

Keywords
Coding sequence diversity	Polymorphism
Ligand	NADP
Molecular function	Oxidoreductase
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	D-glucuronate catabolic process Inferred from electronic annotation. Source: Compara L-ascorbic acid biosynthetic process Inferred from electronic annotation. Source: Compara aldehyde catabolic process Inferred from electronic annotation. Source: Compara cellular aldehyde metabolic process Traceable author statement Ref.1. Source: ProtInc glucose metabolic process Traceable author statement Ref.1. Source: ProtInc
Cellular_component	apical plasma membrane Inferred from electronic annotation. Source: Compara cytosol Inferred from electronic annotation. Source: Compara
Molecular_function	L-glucuronate reductase activity Inferred from electronic annotation. Source: Compara alditol:NADP+ 1-oxidoreductase activity Traceable author statement Ref.1. Source: ProtInc electron carrier activity Traceable author statement Ref.1. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.10

Chain

2 – 325

324

Alcohol dehydrogenase [NADP(+)]

PRO_0000124617

Regions

Nucleotide binding

211 – 273

63

NADP By similarity

Sites

Active site

50

1

Proton donor

Binding site

113

1

Substrate

Site

80

1

Lowers pKa of active site Tyr

Natural variations

Natural variant

52

1

N → S Reduced activity towards daunorubicin. Ref.14
Corresponds to variant rs2229540 [ dbSNP | Ensembl ].

VAR_048212

Natural variant

55

1

E → D Reduced activity towards daunorubicin. Ref.14
Corresponds to variant rs6690497 [ dbSNP | Ensembl ].

VAR_058909

Experimental info

Mutagenesis

50

1

Y → F: Complete loss of enzymatic activity. Ref.11

Mutagenesis

50

1

Y → H: Complete loss of enzymatic activity. Ref.11

Mutagenesis

80

1

K → M: Complete loss of enzymatic activity. Ref.11

Mutagenesis

113

1

H → Q: Strong decrease in enzymatic activity. Ref.11

Mutagenesis

299

1

I → A: No change in enzymatic activity. Ref.11

Mutagenesis

299

1

I → C: No change in enzymatic activity. Ref.11

Mutagenesis

300

1

V → C: No change in enzymatic activity. Ref.11

Sequence conflict

305

1

V → A in BAF85772. Ref.4

Secondary structure

1

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325

Helix Strand Turn

Details...

Beta strand

5 – 7

3

Beta strand

13 – 17

5

Helix

26 – 39

14

Beta strand

43 – 45

3

Helix

48 – 50

3

Helix

53 – 63

11

Beta strand

68 – 70

3

Helix

72 – 74

3

Beta strand

76 – 81

6

Helix

83 – 85

3

Helix

88 – 102

15

Beta strand

107 – 113

7

Beta strand

115 – 118

4

Beta strand

120 – 122

3

Helix

140 – 153

14

Beta strand

155 – 163

9

Helix

166 – 173

8

Beta strand

182 – 186

5

Helix

194 – 203

10

Beta strand

206 – 210

5

Helix

232 – 241

10

Helix

245 – 255

11

Helix

267 – 274

8

Helix

283 – 290

8

Beta strand

302 – 305

4

Beta strand

308 – 313

6

Beta strand

320 – 323

4

Sequences

	Sequence		Length	Mass (Da)
	P14550 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: F6B27517EB754E37	FASTA	325	36,573
	10 20 30 40 50 60 MAASCVLLHT GQKMPLIGLG TWKSEPGQVK AAVKYALSVG YRHIDCAAIY GNEPEIGEAL 70 80 90 100 110 120 KEDVGPGKAV PREELFVTSK LWNTKHHPED VEPALRKTLA DLQLEYLDLY LMHWPYAFER 130 140 150 160 170 180 GDNPFPKNAD GTICYDSTHY KETWKALEAL VAKGLVQALG LSNFNSRQID DILSVASVRP 190 200 210 220 230 240 AVLQVECHPY LAQNELIAHC QARGLEVTAY SPLGSSDRAW RDPDEPVLLE EPVVLALAEK 250 260 270 280 290 300 YGRSPAQILL RWQVQRKVIC IPKSITPSRI LQNIKVFDFT FSPEEMKQLN ALNKNWRYIV 310 320 PMLTVDGKRV PRDAGHPLYP FNDPY

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The aldo-keto reductase superfamily. cDNAs and deduced amino acid sequences of human aldehyde and aldose reductases." Bohren K.M., Bullock B., Wermuth B., Gabbay K.H. J. Biol. Chem. 264:9547-9551(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE. Tissue: Liver.
[2]	"The structural organization of the human aldehyde reductase gene, AKR1A1, and mapping to chromosome 1p33-->p32." Fujii J., Hamaoka R., Matsumoto A., Fujii T., Yamaguchi Y., Egashira M., Miyoshi O., Niikawa N., Taniguchi N. Cytogenet. Cell Genet. 84:230-232(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Characterization of the human aldehyde reductase gene and promoter." Barski O.A., Gabbay K.H., Bohren K.M. Genomics 60:188-198(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Uterus.
[5]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[6]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Colon and Kidney.
[10]	"Primary structure of aldehyde reductase from human liver." Wermuth B., Omar A., Forster A., di Francesco C., Wolf M., von Wartburg J.-P., Bullock B., Gabbay K.H. Prog. Clin. Biol. Res. 232:297-307(1987) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-325. Tissue: Liver.
[11]	"Mechanism of human aldehyde reductase: characterization of the active site pocket." Barski O.A., Gabbay K.H., Grimshaw C.E., Bohren K.M. Biochemistry 34:11264-11275(1995) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF TYR-50; LYS-80; HIS-113; ILE-299 AND VAL-300.
[12]	"Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family members." O'Connor T., Ireland L.S., Harrison D.J., Hayes J.D. Biochem. J. 343:487-504(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY.
[13]	"Metabolic activation of polycyclic aromatic hydrocarbon trans-dihydrodiols by ubiquitously expressed aldehyde reductase (AKR1A1)." Palackal N.T., Burczynski M.E., Harvey R.G., Penning T.M. Chem. Biol. Interact. 130:815-824(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY.
[14]	"Two allelic variants of aldo-keto reductase 1A1 exhibit reduced in vitro metabolism of daunorubicin." Bains O.S., Takahashi R.H., Pfeifer T.A., Grigliatti T.A., Reid R.E., Riggs K.W. Drug Metab. Dispos. 36:904-910(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, CHARACTERIZATION OF VARIANTS SER-52 AND ASP-55.
[15]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[16]	"Structures of human and porcine aldehyde reductase: an enzyme implicated in diabetic complications." El-Kabbani O., Green N.C., Lin G., Carson M., Narayana S.V.L., Moore K.M., Flynn T.G., DeLucas L.J. Acta Crystallogr. D 50:859-868(1994) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.48 ANGSTROMS).
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

J04794 mRNA. Translation: AAA51711.1.
AF036683 , AF036680, AF036681, AF036682 Genomic DNA. Translation: AAB92369.1.
AF112485, AF112484 Genomic DNA. Translation: AAF01260.1.
AK293083 mRNA. Translation: BAF85772.1.
CR457010 mRNA. Translation: CAG33291.1.
BT007003 mRNA. Translation: AAP35649.1.
AL355480 Genomic DNA. Translation: CAI22459.1.
CH471059 Genomic DNA. Translation: EAX06970.1.
CH471059 Genomic DNA. Translation: EAX06971.1.
CH471059 Genomic DNA. Translation: EAX06972.1.
CH471059 Genomic DNA. Translation: EAX06974.1.
BC000670 mRNA. Translation: AAH00670.1.
BC005394 mRNA. Translation: AAH05394.1.

IPI

IPI00220271.

PIR

A33851.

RefSeq

NP_001189342.1. NM_001202413.1.
NP_001189343.1. NM_001202414.1.
NP_006057.1. NM_006066.3.
NP_697021.1. NM_153326.2.

UniGene

Hs.474584.
Hs.721160.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2ALR	X-ray	2.48	A	2-325	[»]

ProteinModelPortal

P14550.

ModBase

Search...

Protein-protein interaction databases

IntAct

P14550. 2 interactions.

MINT

MINT-5001699.

STRING

9606.ENSP00000312606.

PTM databases

PhosphoSite

P14550.

Polymorphism databases

DMDM

113600.

2D gel databases

REPRODUCTION-2DPAGE

IPI00220271.
P14550.

SWISS-2DPAGE

P14550.

UCD-2DPAGE

P14550.

Proteomic databases

PaxDb

P14550.

PeptideAtlas

P14550.

PRIDE

P14550.

Protocols and materials databases

DNASU

10327.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000351829; ENSP00000312606; ENSG00000117448.
ENST00000372070; ENSP00000361140; ENSG00000117448.

GeneID

10327.

KEGG

hsa:10327.

UCSC

uc001cod.3. human.

Organism-specific databases

CTD

10327.

GeneCards

GC01P046017.

HGNC

HGNC:380. AKR1A1.

HPA

CAB006246.
HPA017919.
HPA019649.
HPA027734.

MIM

103830. gene.

neXtProt

NX_P14550.

PharmGKB

PA24674.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0656.

HOGENOM

HOG000250272.

HOVERGEN

HBG000020.

InParanoid

P14550.

KO

K00002.

OMA

ICYDSTH.

OrthoDB

EOG4J118N.

PhylomeDB

P14550.

Enzyme and pathway databases

SABIO-RK

P14550.

Gene expression databases

ArrayExpress

P14550.

Bgee

P14550.

CleanEx

HS_AKR1A1.

Genevestigator

P14550.

GermOnline

ENSG00000117448. Homo sapiens.

Family and domain databases

Gene3D

3.20.20.100. 1 hit.

InterPro

IPR001395. Aldo/ket_red.
IPR018170. Aldo/ket_reductase_CS.
IPR020471. Aldo/keto_reductase_subgr.
IPR023210. NADP_OxRdtase_dom.
[Graphical view]

PANTHER

PTHR11732. PTHR11732. 1 hit.

Pfam

PF00248. Aldo_ket_red. 1 hit.
[Graphical view]

PIRSF

PIRSF000097. AKR. 1 hit.

PRINTS

PR00069. ALDKETRDTASE.

SUPFAM

SSF51430. Aldo/ket_red. 1 hit.

PROSITE

PS00798. ALDOKETO_REDUCTASE_1. 1 hit.
PS00062. ALDOKETO_REDUCTASE_2. 1 hit.
PS00063. ALDOKETO_REDUCTASE_3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P14550.

ChEMBL

CHEMBL2246.

ChiTaRS

AKR1A1. human.

EvolutionaryTrace

P14550.

GenomeRNAi

10327.

NextBio

39151.

SOURCE

Search...

Entry information

Entry name

AK1A1_HUMAN

Accession

Primary (citable) accession number: P14550
Secondary accession number(s): A8KAL8, D3DQ04, Q6IAZ4

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 1, 1990
Last sequence update:	January 23, 2007
Last modified:	May 29, 2013
This is version 145 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.