AK1A1_PIG
ID AK1A1_PIG Reviewed; 325 AA.
AC P50578; I3L929;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 13-FEB-2019, sequence version 3.
DT 03-AUG-2022, entry version 133.
DE RecName: Full=Aldo-keto reductase family 1 member A1;
DE EC=1.1.1.2 {ECO:0000269|PubMed:12732097};
DE EC=1.1.1.33 {ECO:0000250|UniProtKB:P51635};
DE EC=1.1.1.372 {ECO:0000269|PubMed:12732097};
DE EC=1.1.1.54 {ECO:0000250|UniProtKB:P51635};
DE AltName: Full=Alcohol dehydrogenase [NADP(+)];
DE AltName: Full=Aldehyde reductase;
DE AltName: Full=Glucuronate reductase {ECO:0000250|UniProtKB:P51635};
DE EC=1.1.1.19 {ECO:0000250|UniProtKB:P51635};
DE AltName: Full=Glucuronolactone reductase {ECO:0000250|UniProtKB:P51635};
DE EC=1.1.1.20 {ECO:0000250|UniProtKB:P51635};
GN Name=AKR1A1; Synonyms=ALR {ECO:0000303|PubMed:12732097}, ALR1;
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=7484379; DOI=10.1007/978-1-4615-1965-2_25;
RA Flynn T.G., Green N.C., Bhatia M.B., El-Kabbani O.;
RT "Structure and mechanism of aldehyde reductase.";
RL Adv. Exp. Med. Biol. 372:193-201(1995).
RN [2]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
RX PubMed=7552731; DOI=10.1038/nsb0895-687;
RA el-Kabbani O., Judge K., Ginell S.L., Myles D.A., DeLucas L.J., Flynn T.G.;
RT "Structure of porcine aldehyde reductase holoenzyme.";
RL Nat. Struct. Biol. 2:687-692(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Duroc;
RG Porcine genome sequencing project;
RL Submitted (NOV-2009) to the EMBL/GenBank/DDBJ databases.
RN [4] {ECO:0007744|PDB:1AE4}
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
RX PubMed=9329083;
RX DOI=10.1002/(sici)1097-0134(199710)29:2<186::aid-prot6>3.0.co;2-b;
RA El-Kabbani O., Carper D.A., McGowan M.H., Devedjiev Y., Rees-Milton K.J.,
RA Flynn T.G.;
RT "Studies on the inhibitor-binding site of porcine aldehyde reductase:
RT crystal structure of the holoenzyme-inhibitor ternary complex.";
RL Proteins 29:186-192(1997).
RN [5]
RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND CATALYTIC ACTIVITY.
RX PubMed=12732097; DOI=10.1042/bj20021818;
RA Crosas B., Hyndman D.J., Gallego O., Martras S., Pares X., Flynn T.G.,
RA Farres J.;
RT "Human aldose reductase and human small intestine aldose reductase are
RT efficient retinal reductases: consequences for retinoid metabolism.";
RL Biochem. J. 373:973-979(2003).
CC -!- FUNCTION: Catalyzes the NADPH-dependent reduction of a wide variety of
CC carbonyl-containing compounds to their corresponding alcohols. Displays
CC enzymatic activity towards endogenous metabolites such as aromatic and
CC aliphatic aldehydes, ketones, monosaccharides and bile acids, with a
CC preference for negatively charged substrates, such as glucuronate and
CC succinic semialdehyde (By similarity). Plays an important role in
CC ascorbic acid biosynthesis by catalyzing the reduction of D-glucuronic
CC acid and D-glucurono-gamma-lactone (By similarity). Functions as a
CC detoxifiying enzyme by reducing a range of toxic aldehydes. Reduces
CC methylglyoxal and 3-deoxyglucosone, which are present at elevated
CC levels under hyperglycemic conditions and are cytotoxic. Involved also
CC in the detoxification of lipid-derived aldehydes like acrolein (By
CC similarity). Plays a role in the activation of procarcinogens, such as
CC polycyclic aromatic hydrocarbon trans-dihydrodiols, and in the
CC metabolism of various xenobiotics and drugs (By similarity). Displays
CC no reductase activity towards retinoids (PubMed:12732097).
CC {ECO:0000250|UniProtKB:P14550, ECO:0000250|UniProtKB:P51635,
CC ECO:0000269|PubMed:12732097}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a primary alcohol + NADP(+) = an aldehyde + H(+) + NADPH;
CC Xref=Rhea:RHEA:15937, ChEBI:CHEBI:15378, ChEBI:CHEBI:15734,
CC ChEBI:CHEBI:17478, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.2;
CC Evidence={ECO:0000269|PubMed:12732097};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=glycerol + NADP(+) = D-glyceraldehyde + H(+) + NADPH;
CC Xref=Rhea:RHEA:23592, ChEBI:CHEBI:15378, ChEBI:CHEBI:17378,
CC ChEBI:CHEBI:17754, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC EC=1.1.1.372; Evidence={ECO:0000269|PubMed:12732097};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=glycerol + NADP(+) = H(+) + L-glyceraldehyde + NADPH;
CC Xref=Rhea:RHEA:38111, ChEBI:CHEBI:15378, ChEBI:CHEBI:17754,
CC ChEBI:CHEBI:27975, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC EC=1.1.1.372; Evidence={ECO:0000269|PubMed:12732097};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-gulonate + NADP(+) = aldehydo-D-glucuronate + H(+) + NADPH;
CC Xref=Rhea:RHEA:14909, ChEBI:CHEBI:13115, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:142686;
CC EC=1.1.1.19; Evidence={ECO:0000250|UniProtKB:P51635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-gulono-1,4-lactone + NADP(+) = D-glucurono-3,6-lactone +
CC H(+) + NADPH; Xref=Rhea:RHEA:18925, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17587, ChEBI:CHEBI:18268, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; EC=1.1.1.20;
CC Evidence={ECO:0000250|UniProtKB:P51635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=allyl alcohol + NADP(+) = acrolein + H(+) + NADPH;
CC Xref=Rhea:RHEA:12168, ChEBI:CHEBI:15368, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16605, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.54;
CC Evidence={ECO:0000250|UniProtKB:P51635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=hydroxyacetone + NADP(+) = H(+) + methylglyoxal + NADPH;
CC Xref=Rhea:RHEA:27986, ChEBI:CHEBI:15378, ChEBI:CHEBI:17158,
CC ChEBI:CHEBI:27957, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC Evidence={ECO:0000250|UniProtKB:P51635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3-deoxyfructose + NADP(+) = 3-deoxyglucosone + H(+) + NADPH;
CC Xref=Rhea:RHEA:58668, ChEBI:CHEBI:15378, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:60777, ChEBI:CHEBI:142685;
CC Evidence={ECO:0000250|UniProtKB:P51635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-mevalonate + NADP(+) = H(+) + mevaldate + NADPH;
CC Xref=Rhea:RHEA:20193, ChEBI:CHEBI:15378, ChEBI:CHEBI:36464,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58219, ChEBI:CHEBI:58349; EC=1.1.1.33;
CC Evidence={ECO:0000250|UniProtKB:P51635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=NADP(+) + pyridine 3-methanol = H(+) + NADPH + pyridine-3-
CC carbaldehyde; Xref=Rhea:RHEA:58776, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:28345, ChEBI:CHEBI:45213, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; Evidence={ECO:0000269|PubMed:12732097};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=700 uM for pyridine-3-carbaldehyde {ECO:0000269|PubMed:12732097};
CC KM=4600 uM for D,L-glyceraldehyde {ECO:0000269|PubMed:12732097};
CC Note=kcat is 11000 min(-1) for pyridine-3-carbaldehyde as substrate.
CC kcat is 2500 min(-1) for D,L-glyceraldehyde as substrate.
CC {ECO:0000269|PubMed:12732097};
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q9JII6}. Apical cell membrane
CC {ECO:0000250|UniProtKB:Q9JII6}.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family. {ECO:0000305}.
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DR EMBL; U46064; AAB60266.1; -; mRNA.
DR EMBL; AEMK02000049; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; NP_999055.1; NM_213890.1.
DR PDB; 1AE4; X-ray; 2.40 A; A=1-325.
DR PDB; 1CWN; X-ray; 2.00 A; A=2-325.
DR PDB; 1HQT; X-ray; 2.20 A; A=1-325.
DR PDB; 3CV7; X-ray; 2.41 A; A=1-325.
DR PDB; 3FX4; X-ray; 1.99 A; A=1-325.
DR PDB; 3H4G; X-ray; 1.85 A; A=1-325.
DR PDBsum; 1AE4; -.
DR PDBsum; 1CWN; -.
DR PDBsum; 1HQT; -.
DR PDBsum; 3CV7; -.
DR PDBsum; 3FX4; -.
DR PDBsum; 3H4G; -.
DR AlphaFoldDB; P50578; -.
DR SMR; P50578; -.
DR STRING; 9823.ENSSSCP00000020540; -.
DR ChEMBL; CHEMBL4049; -.
DR DrugCentral; P50578; -.
DR PeptideAtlas; P50578; -.
DR PRIDE; P50578; -.
DR GeneID; 396924; -.
DR KEGG; ssc:396924; -.
DR CTD; 10327; -.
DR eggNOG; KOG1577; Eukaryota.
DR HOGENOM; CLU_023205_0_0_1; -.
DR InParanoid; P50578; -.
DR TreeFam; TF106492; -.
DR BioCyc; MetaCyc:MON-14995; -.
DR BRENDA; 1.1.1.2; 6170.
DR SABIO-RK; P50578; -.
DR EvolutionaryTrace; P50578; -.
DR PRO; PR:P50578; -.
DR Proteomes; UP000008227; Unplaced.
DR Proteomes; UP000314985; Unplaced.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0004032; F:alditol:NADP+ 1-oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0047655; F:allyl-alcohol dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0047941; F:glucuronolactone reductase activity; ISS:UniProtKB.
DR GO; GO:0047956; F:glycerol dehydrogenase [NADP+] activity; IEA:RHEA.
DR GO; GO:0047939; F:L-glucuronate reductase activity; ISS:UniProtKB.
DR GO; GO:1990002; F:methylglyoxal reductase (NADPH-dependent, acetol producing); IEA:RHEA.
DR GO; GO:0019726; F:mevaldate reductase (NADPH) activity; IEA:UniProtKB-EC.
DR GO; GO:0046185; P:aldehyde catabolic process; IEA:InterPro.
DR GO; GO:0110095; P:cellular detoxification of aldehyde; ISS:UniProtKB.
DR GO; GO:0042840; P:D-glucuronate catabolic process; ISS:UniProtKB.
DR GO; GO:0019853; P:L-ascorbic acid biosynthetic process; ISS:UniProtKB.
DR GO; GO:0006629; P:lipid metabolic process; IEA:UniProtKB-KW.
DR CDD; cd19106; AKR_AKR1A1-4; 1.
DR Gene3D; 3.20.20.100; -; 1.
DR InterPro; IPR020471; AKR.
DR InterPro; IPR044481; AKR1A.
DR InterPro; IPR018170; Aldo/ket_reductase_CS.
DR InterPro; IPR023210; NADP_OxRdtase_dom.
DR InterPro; IPR036812; NADP_OxRdtase_dom_sf.
DR Pfam; PF00248; Aldo_ket_red; 1.
DR PIRSF; PIRSF000097; AKR; 1.
DR PRINTS; PR00069; ALDKETRDTASE.
DR SUPFAM; SSF51430; SSF51430; 1.
DR PROSITE; PS00798; ALDOKETO_REDUCTASE_1; 1.
DR PROSITE; PS00062; ALDOKETO_REDUCTASE_2; 1.
DR PROSITE; PS00063; ALDOKETO_REDUCTASE_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell membrane; Cytoplasm; Lipid metabolism;
KW Membrane; NADP; Oxidoreductase; Phosphoprotein; Reference proteome.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P14550"
FT CHAIN 2..325
FT /note="Aldo-keto reductase family 1 member A1"
FT /id="PRO_0000124619"
FT ACT_SITE 50
FT /note="Proton donor"
FT /evidence="ECO:0000269|PubMed:7552731"
FT BINDING 11..20
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000255"
FT BINDING 21..23
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 45
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 113
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:7552731"
FT BINDING 162..163
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 184
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 211..273
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:7552731"
FT SITE 80
FT /note="Lowers pKa of active site Tyr"
FT /evidence="ECO:0000250|UniProtKB:P14550"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:P14550"
FT MOD_RES 4
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P51635"
FT MOD_RES 127
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9JII6"
FT MOD_RES 127
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9JII6"
FT MOD_RES 145
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9JII6"
FT MOD_RES 211
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P14550"
FT CONFLICT 61
FT /note="Q -> T (in Ref. 1; AAB60266)"
FT CONFLICT 271
FT /note="L -> P (in Ref. 1; AAB60266)"
FT STRAND 5..7
FT /evidence="ECO:0007829|PDB:3H4G"
FT STRAND 13..17
FT /evidence="ECO:0007829|PDB:3H4G"
FT TURN 26..28
FT /evidence="ECO:0007829|PDB:3H4G"
FT HELIX 29..38
FT /evidence="ECO:0007829|PDB:3H4G"
FT STRAND 43..45
FT /evidence="ECO:0007829|PDB:3H4G"
FT HELIX 48..50
FT /evidence="ECO:0007829|PDB:3H4G"
FT HELIX 53..63
FT /evidence="ECO:0007829|PDB:3H4G"
FT STRAND 68..70
FT /evidence="ECO:0007829|PDB:3H4G"
FT HELIX 72..74
FT /evidence="ECO:0007829|PDB:3H4G"
FT STRAND 76..81
FT /evidence="ECO:0007829|PDB:3H4G"
FT HELIX 83..85
FT /evidence="ECO:0007829|PDB:3H4G"
FT HELIX 88..102
FT /evidence="ECO:0007829|PDB:3H4G"
FT STRAND 107..113
FT /evidence="ECO:0007829|PDB:3H4G"
FT STRAND 115..118
FT /evidence="ECO:0007829|PDB:3H4G"
FT STRAND 120..122
FT /evidence="ECO:0007829|PDB:3H4G"
FT STRAND 131..133
FT /evidence="ECO:0007829|PDB:3FX4"
FT HELIX 140..152
FT /evidence="ECO:0007829|PDB:3H4G"
FT STRAND 155..163
FT /evidence="ECO:0007829|PDB:3H4G"
FT HELIX 166..173
FT /evidence="ECO:0007829|PDB:3H4G"
FT STRAND 182..186
FT /evidence="ECO:0007829|PDB:3H4G"
FT HELIX 194..203
FT /evidence="ECO:0007829|PDB:3H4G"
FT STRAND 206..211
FT /evidence="ECO:0007829|PDB:3H4G"
FT TURN 212..217
FT /evidence="ECO:0007829|PDB:3CV7"
FT HELIX 228..230
FT /evidence="ECO:0007829|PDB:3H4G"
FT HELIX 232..241
FT /evidence="ECO:0007829|PDB:3H4G"
FT HELIX 245..255
FT /evidence="ECO:0007829|PDB:3H4G"
FT HELIX 267..274
FT /evidence="ECO:0007829|PDB:3H4G"
FT HELIX 283..290
FT /evidence="ECO:0007829|PDB:3H4G"
FT STRAND 302..305
FT /evidence="ECO:0007829|PDB:3FX4"
FT STRAND 311..313
FT /evidence="ECO:0007829|PDB:3H4G"
FT HELIX 320..322
FT /evidence="ECO:0007829|PDB:3FX4"
SQ SEQUENCE 325 AA; 36582 MW; 1572641AEA57043F CRC64;
MAASCVLLHT GQKMPLIGLG TWKSEPGQVK AAIKYALTVG YRHIDCAAIY GNELEIGEAL
QETVGPGKAV PREELFVTSK LWNTKHHPED VEPALRKTLA DLQLEYLDLY LMHWPYAFER
GDNPFPKNAD GTIRYDATHY KDTWKALEAL VAKGLVRALG LSNFSSRQID DVLSVASVRP
AVLQVECHPY LAQNELIAHC QARGLEVTAY SPLGSSDRAW RDPNEPVLLE EPVVQALAEK
YNRSPAQILL RWQVQRKVIC IPKSVTPSRI LQNIQVFDFT FSPEEMKQLD ALNKNLRFIV
PMLTVDGKRV PRDAGHPLYP FNDPY
