O43488 (ARK72_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Aflatoxin B1 aldehyde reductase member 2
EC=1.1.1.n11

Alternative name(s):
AFB1 aldehyde reductase 1
Short name=AFB1-AR 1
Aldoketoreductase 7
Succinic semialdehyde reductase
Short name=SSA reductase

Gene names

Name:	AKR7A2
Synonyms:	AFAR, AFAR1, AKR7

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	359 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Catalyzes the NADPH-dependent reduction of succinic semialdehyde to gamma-hydroxybutyrate. May have an important role in producing the neuromodulator gamma-hydroxybutyrate (GHB). Has broad substrate specificity. Has NADPH-dependent aldehyde reductase activity towards 2-carboxybenzaldehyde, 2-nitrobenzaldehyde and pyridine-2-aldehyde (in vitro). Can reduce 1,2-naphthoquinone and 9,10-phenanthrenequinone (in vitro). Can reduce the dialdehyde protein-binding form of aflatoxin B1 (AFB1) to the non-binding AFB1 dialcohol. May be involved in protection of liver against the toxic and carcinogenic effects of AFB1, a potent hepatocarcinogen. Ref.3 Ref.9
Catalytic activity	4-hydroxybutanoate + NADP+ = succinate semialdehyde + NADPH. Ref.7
Subunit structure	Homodimer. Ref.3
Subcellular location	Golgi apparatus By similarity. Cytoplasm Ref.3.
Tissue specificity	Detected in brain, liver, small intestine and testis, and at lower levels in heart, prostate, skeletal muscle and spleen. Detected in kidney proximal and distal tubules, endothelial cells lining the Bowman's capsules and some cysts. Detected at low levels in lung and pancreas (at protein level). Widely expressed. Ref.3 Ref.7
Sequence similarities	Belongs to the aldo/keto reductase family. Aldo/keto reductase 2 subfamily.
Caution	It is uncertain whether Met-1 or Met-30 is the initiator.
Biophysicochemical properties	Kinetic parameters: KM=20 µM for succinic semialdehyde Ref.7 KM=17 µM for 2-carboxybenzaldehyde KM=8 µM for 9,10-phenanthrenequinone KM=102 µM for 1,2-naphthoquinone
Sequence caution	The sequence AAC52104.1 differs from that shown. Reason: Erroneous initiation. The sequence AAH04111.3 differs from that shown. Reason: Erroneous initiation. The sequence AAH10852.1 differs from that shown. Reason: Erroneous initiation. The sequence AAH11586.1 differs from that shown. Reason: Erroneous initiation. The sequence AAH12171.1 differs from that shown. Reason: Erroneous initiation. The sequence AAH13996.1 differs from that shown. Reason: Erroneous initiation. The sequence AAP36011.1 differs from that shown. Reason: Erroneous initiation. The sequence CAA76347.1 differs from that shown. Reason: Erroneous initiation. The sequence CAB72321.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Cellular component	Cytoplasm Golgi apparatus
Coding sequence diversity	Polymorphism
Ligand	NADP
Molecular function	Oxidoreductase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	carbohydrate metabolic process Traceable author statement Ref.3. Source: ProtInc cellular aldehyde metabolic process Traceable author statement Ref.3. Source: ProtInc daunorubicin metabolic process Inferred from mutant phenotype PubMed 20837989. Source: UniProtKB doxorubicin metabolic process Inferred from mutant phenotype PubMed 20837989. Source: UniProtKB
Cellular_component	Golgi apparatus Inferred from electronic annotation. Source: UniProtKB-SubCell mitochondrion Inferred from electronic annotation. Source: Compara
Molecular_function	alditol:NADP+ 1-oxidoreductase activity Traceable author statement Ref.3. Source: ProtInc electron carrier activity Traceable author statement Ref.3. Source: UniProtKB phenanthrene-9,10-epoxide hydrolase activity Inferred from direct assay PubMed 20837989. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 359

359

Aflatoxin B1 aldehyde reductase member 2

PRO_0000070375

Regions

Nucleotide binding

171 – 172

2

NADP

Nucleotide binding

226 – 236

11

NADP

Nucleotide binding

318 – 326

9

NADP

Sites

Active site

77

1

Proton donor By similarity

Binding site

72

1

NADP

Binding site

141

1

Substrate By similarity

Binding site

197

1

NADP

Binding site

250

1

NADP

Binding site

260

1

Substrate By similarity

Binding site

263

1

Substrate By similarity

Binding site

359

1

Substrate By similarity

Site

105

1

Lowers pKa of active site Tyr By similarity

Amino acid modifications

Modified residue

40

1

Phosphoserine By similarity

Natural variations

Natural variant

135

1

V → M.
Corresponds to variant rs6670759 [ dbSNP | Ensembl ].

VAR_048209

Natural variant

142

1

A → T. Ref.3 Ref.12
Corresponds to variant rs1043657 [ dbSNP | Ensembl ].

VAR_017413

Natural variant

157

1

Q → H. Ref.12
Corresponds to variant rs859208 [ dbSNP | Ensembl ].

VAR_017414

Natural variant

180

1

E → K.
Corresponds to variant rs859210 [ dbSNP | Ensembl ].

VAR_060222

Natural variant

198

1

G → S.
Corresponds to variant rs2231200 [ dbSNP | Ensembl ].

VAR_048210

Natural variant

214

1

C → Y.
Corresponds to variant rs2235794 [ dbSNP | Ensembl ].

VAR_017415

Natural variant

255

1

S → N.
Corresponds to variant rs2231203 [ dbSNP | Ensembl ].

VAR_048211

Secondary structure

1

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359

Helix Strand Turn

Details...

Beta strand

39 – 43

5

Turn

48 – 50

3

Helix

53 – 65

13

Beta strand

70 – 72

3

Helix

77 – 80

4

Helix

81 – 87

7

Beta strand

101 – 106

6

Helix

116 – 130

15

Beta strand

135 – 140

6

Helix

149 – 161

13

Beta strand

164 – 172

9

Helix

175 – 188

14

Beta strand

193 – 199

7

Helix

206 – 208

3

Helix

211 – 218

8

Beta strand

221 – 225

5

Helix

229 – 234

6

Helix

239 – 242

4

Turn

243 – 245

3

Beta strand

252 – 254

3

Helix

257 – 264

8

Helix

267 – 284

18

Helix

285 – 287

3

Helix

291 – 302

12

Helix

307 – 309

3

Beta strand

312 – 315

4

Helix

320 – 330

11

Helix

337 – 350

14

Helix

351 – 353

3

Sequences

	Sequence		Length	Mass (Da)
	O43488 [UniParc]. Last modified November 14, 2003. Version 3. Checksum: 2C9775FE4B977D2A	FASTA	359	39,589
	10 20 30 40 50 60 MLSAASRVVS RAAVHCALRS PPPEARALAM SRPPPPRVAS VLGTMEMGRR MDAPASAAAV 70 80 90 100 110 120 RAFLERGHTE LDTAFMYSDG QSETILGGLG LGLGGGDCRV KIATKANPWD GKSLKPDSVR 130 140 150 160 170 180 SQLETSLKRL QCPQVDLFYL HAPDHGTPVE ETLHACQRLH QEGKFVELGL SNYASWEVAE 190 200 210 220 230 240 ICTLCKSNGW ILPTVYQGMY NATTRQVETE LFPCLRHFGL RFYAYNPLAG GLLTGKYKYE 250 260 270 280 290 300 DKDGKQPVGR FFGNSWAETY RNRFWKEHHF EAIALVEKAL QAAYGASAPS VTSAALRWMY 310 320 330 340 350 HHSQLQGAHG DAVILGMSSL EQLEQNLAAT EEGPLEPAVV DAFNQAWHLV AHECPNYFR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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].
[2]	"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] OF 2-359. Tissue: Pancreas, Skin and Uterus.
[3]	"Molecular cloning, expression and catalytic activity of a human AKR7 member of the aldo-keto reductase superfamily: evidence that the major 2-carboxybenzaldehyde reductase from human liver is a homologue of rat aflatoxin B1-aldehyde reductase." Ireland L.S., Harrison D.J., Neal G.E., Hayes J.D. Biochem. J. 332:21-34(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 5-359, PARTIAL PROTEIN SEQUENCE, FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, VARIANT THR-142. Tissue: Liver.
[4]	"Cloning of the human aflatoxin B1-aldehyde reductase gene at 1p35-1p36.1 in a region frequently altered in human tumor cells." Praml C., Savelyeva L., Perri P., Schwab M. Cancer Res. 58:5014-5018(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 7-359. Tissue: Brain.
[5]	"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 (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 30-359.
[6]	Lubec G., Vishwanath V. Submitted (MAR-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 222-236; 251-261 AND 279-297, MASS SPECTROMETRY. Tissue: Brain and Cajal-Retzius cell.
[7]	"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: CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, TISSUE SPECIFICITY.
[8]	"Novel homodimeric and heterodimeric rat gamma-hydroxybutyrate synthases that associate with the Golgi apparatus define a distinct subclass of aldo-keto reductase 7 family proteins." Kelly V.P., Sherratt P.J., Crouch D.H., Hayes J.D. Biochem. J. 366:847-861(2002) [PubMed] [Europe PMC] [Abstract] Cited for: GENE STRUCTURE.
[9]	"Synthesis and catabolism of gamma-hydroxybutyrate in SH-SY5Y human neuroblastoma cells: role of the aldo-keto reductase AKR7A2." Lyon R.C., Johnston S.M., Watson D.G., McGarvie G., Ellis E.M. J. Biol. Chem. 282:25986-25992(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[10]	"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].
[11]	"Structure of the aflatoxin aldehyde reductase in complex with NADPH." Structural genomics consortium (SGC) Submitted (FEB-2009) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEX WITH NADP.
[12]	"Genetic variation of aflatoxin B1 aldehyde reductase genes (AFAR) in human tumour cells." Praml C., Schulz W., Claas A., Mollenhauer J., Poustka A., Ackermann R., Schwab M., Henrich K.-O. Cancer Lett. 272:160-166(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS THR-142 AND HIS-157.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AL035413 Genomic DNA. Translation: CAB72321.1. Different initiation.
BC004111 mRNA. Translation: AAH04111.3. Different initiation.
BC007352 mRNA. Translation: AAH07352.2.
BC010852 mRNA. Translation: AAH10852.1. Different initiation.
BC011586 mRNA. Translation: AAH11586.1. Different initiation.
BC012171 mRNA. Translation: AAH12171.1. Different initiation.
BC013996 mRNA. Translation: AAH13996.1. Different initiation.
AF026947 mRNA. Translation: AAC52104.1. Different initiation.
Y16675 mRNA. Translation: CAA76347.1. Different initiation.
BT007347 mRNA. Translation: AAP36011.1. Different initiation.
BK000395 mRNA. Translation: DAA00088.1.

IPI

IPI00305978.

RefSeq

NP_003680.2. NM_003689.3.

UniGene

Hs.571886.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2BP1	X-ray	2.40	A/B/C/D	1-359	[»]

ProteinModelPortal

O43488.

ModBase

Search...

Protein-protein interaction databases

IntAct

O43488. 2 interactions.

MINT

MINT-5002225.

STRING

9606.ENSP00000235835.

PTM databases

PhosphoSite

O43488.

2D gel databases

REPRODUCTION-2DPAGE

IPI00305978.
O43488.

UCD-2DPAGE

O43488.

Proteomic databases

PaxDb

O43488.

PRIDE

O43488.

Protocols and materials databases

DNASU

8574.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000235835; ENSP00000235835; ENSG00000053371.

GeneID

8574.

KEGG

hsa:8574.

UCSC

uc001bbw.3. human.

Organism-specific databases

CTD

8574.

GeneCards

GC01M019630.

H-InvDB

HIX0000198.

HGNC

HGNC:389. AKR7A2.

HPA

CAB032841.

MIM

603418. gene.

neXtProt

NX_O43488.

PharmGKB

PA24682.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0667.

HOGENOM

HOG000250286.

HOVERGEN

HBG050576.

InParanoid

O43488.

KO

K15303.

OMA

HHFEAIA.

OrthoDB

EOG4V4385.

PhylomeDB

O43488.

Enzyme and pathway databases

SABIO-RK

O43488.

Gene expression databases

ArrayExpress

O43488.

Bgee

O43488.

CleanEx

HS_AKR7A2.

Genevestigator

O43488.

GermOnline

ENSG00000053371. Homo sapiens.

Family and domain databases

Gene3D

3.20.20.100. 1 hit.

InterPro

IPR001395. Aldo/ket_red.
IPR023210. NADP_OxRdtase_dom.
[Graphical view]

PANTHER

PTHR11732. PTHR11732. 1 hit.

Pfam

PF00248. Aldo_ket_red. 1 hit.
[Graphical view]

SUPFAM

SSF51430. Aldo/ket_red. 1 hit.

ProtoNet

Search...

Other

EvolutionaryTrace

O43488.

GenomeRNAi

8574.

NextBio

32161.

PMAP-CutDB

O43488.

SOURCE

Search...

Entry information

Entry name

ARK72_HUMAN

Accession

Primary (citable) accession number: O43488
Secondary accession number(s): O75749, Q5TG63

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	November 14, 2003
Last modified:	May 1, 2013
This is version 129 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.