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AFLH_ASPPU
ID   AFLH_ASPPU              Reviewed;         278 AA.
AC   P87017; A0A0F0HZ42;
DT   16-OCT-2013, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-2000, sequence version 2.
DT   03-AUG-2022, entry version 97.
DE   RecName: Full=5'-hydroxyaverantin dehydrogenase {ECO:0000303|PubMed:14602595};
DE            Short=HAVN dehydrogenase {ECO:0000303|PubMed:14602595};
DE            EC=1.1.1.352 {ECO:0000269|PubMed:14602595};
DE   AltName: Full=Aflatoxin biosynthesis protein H {ECO:0000303|PubMed:15006741};
GN   Name=aflH {ECO:0000303|PubMed:15006741};
GN   Synonyms=adhA {ECO:0000303|PubMed:11055914}; ORFNames=P875_00052989-1;
OS   Aspergillus parasiticus (strain ATCC 56775 / NRRL 5862 / SRRC 143 / SU-1).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX   NCBI_TaxID=1403190;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND DISRUPTION PHENOTYPE.
RC   STRAIN=ATCC 56775 / NRRL 5862 / SRRC 143 / SU-1;
RX   PubMed=11055914; DOI=10.1128/aem.66.11.4715-4719.2000;
RA   Chang P.K., Yu J., Ehrlich K.C., Boue S.M., Montalbano B.G., Bhatnagar D.,
RA   Cleveland T.E.;
RT   "adhA in Aspergillus parasiticus is involved in conversion of 5'-
RT   hydroxyaverantin to averufin.";
RL   Appl. Environ. Microbiol. 66:4715-4719(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND PATHWAY.
RC   STRAIN=ATCC 56775 / NRRL 5862 / SRRC 143 / SU-1;
RX   PubMed=15094053; DOI=10.1016/s0014-5793(04)00327-8;
RA   Yu J., Bhatnagar D., Cleveland T.E.;
RT   "Completed sequence of aflatoxin pathway gene cluster in Aspergillus
RT   parasiticus.";
RL   FEBS Lett. 564:126-130(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 56775 / NRRL 5862 / SRRC 143 / SU-1;
RA   Yu J., Fedorova N., Yin Y., Losada L., Zafar N., Taujale R., Ehrlich K.C.,
RA   Bhatnagar D., Cleveland T.E., Bennett J.W., Nierman W.C.;
RT   "Draft genome sequence of Aspergillus parasiticus SU-1.";
RL   Submitted (FEB-2015) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   PROTEIN SEQUENCE OF 1-33; 122-132; 168-183; 192-199 AND 207-21, FUNCTION,
RP   CATALYTIC ACTIVITY, SUBUNIT, ACETYLATION AT MET-1, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=14602595; DOI=10.1128/aem.69.11.6418-6426.2003;
RA   Sakuno E., Yabe K., Nakajima H.;
RT   "Involvement of two cytosolic enzymes and a novel intermediate, 5'-
RT   oxoaverantin, in the pathway from 5'-hydroxyaverantin to averufin in
RT   aflatoxin biosynthesis.";
RL   Appl. Environ. Microbiol. 69:6418-6426(2003).
RN   [5]
RP   FUNCTION.
RX   PubMed=1339261; DOI=10.1128/aem.58.11.3527-3537.1992;
RA   Skory C.D., Chang P.K., Cary J., Linz J.E.;
RT   "Isolation and characterization of a gene from Aspergillus parasiticus
RT   associated with the conversion of versicolorin A to sterigmatocystin in
RT   aflatoxin biosynthesis.";
RL   Appl. Environ. Microbiol. 58:3527-3537(1992).
RN   [6]
RP   FUNCTION.
RX   PubMed=8434913; DOI=10.1128/aem.59.2.479-484.1993;
RA   Keller N.P., Dischinger H.C. Jr., Bhatnager D., Cleveland T.E.,
RA   Ullah A.H.J.;
RT   "Purification of a 40-kilodalton methyltransferase active in the aflatoxin
RT   biosynthetic pathway.";
RL   Appl. Environ. Microbiol. 59:479-484(1993).
RN   [7]
RP   FUNCTION.
RX   PubMed=8368836; DOI=10.1128/aem.59.8.2486-2492.1993;
RA   Yabe K., Matsuyama Y., Ando Y., Nakajima H., Hamasaki T.;
RT   "Stereochemistry during aflatoxin biosynthesis: conversion of norsolorinic
RT   acid to averufin.";
RL   Appl. Environ. Microbiol. 59:2486-2492(1993).
RN   [8]
RP   FUNCTION.
RX   PubMed=8368837; DOI=10.1128/aem.59.8.2493-2500.1993;
RA   Yabe K., Hamasaki T.;
RT   "Stereochemistry during aflatoxin biosynthesis: cyclase reaction in the
RT   conversion of versiconal to versicolorin B and racemization of versiconal
RT   hemiacetal acetate.";
RL   Appl. Environ. Microbiol. 59:2493-2500(1993).
RN   [9]
RP   FUNCTION.
RX   PubMed=10543813; DOI=10.1128/aem.65.11.4987-4994.1999;
RA   Motomura M., Chihaya N., Shinozawa T., Hamasaki T., Yabe K.;
RT   "Cloning and characterization of the O-methyltransferase I gene (dmtA) from
RT   Aspergillus parasiticus associated with the conversions of
RT   demethylsterigmatocystin to sterigmatocystin and
RT   dihydrodemethylsterigmatocystin to dihydrosterigmatocystin in aflatoxin
RT   biosynthesis.";
RL   Appl. Environ. Microbiol. 65:4987-4994(1999).
RN   [10]
RP   FUNCTION.
RX   PubMed=10584035; DOI=10.1128/aem.65.12.5639-5641.1999;
RA   Zhou R., Linz J.E.;
RT   "Enzymatic function of the nor-1 protein in aflatoxin biosynthesis in
RT   Aspergillus parasiticus.";
RL   Appl. Environ. Microbiol. 65:5639-5641(1999).
RN   [11]
RP   FUNCTION.
RX   PubMed=16256699; DOI=10.1006/bioo.2001.1216;
RA   Hitchman T.S., Schmidt E.W., Trail F., Rarick M.D., Linz J.E.,
RA   Townsend C.A.;
RT   "Hexanoate synthase, a specialized type I fatty acid synthase in aflatoxin
RT   B1 biosynthesis.";
RL   Bioorg. Chem. 29:293-307(2001).
RN   [12]
RP   FUNCTION.
RX   PubMed=11996570; DOI=10.1021/ja012185v;
RA   Udwary D.W., Casillas L.K., Townsend C.A.;
RT   "Synthesis of 11-hydroxyl O-methylsterigmatocystin and the role of a
RT   cytochrome P-450 in the final step of aflatoxin biosynthesis.";
RL   J. Am. Chem. Soc. 124:5294-5303(2002).
RN   [13]
RP   REVIEW, FUNCTION, PATHWAY, AND NOMENCLATURE.
RX   PubMed=15006741; DOI=10.1128/aem.70.3.1253-1262.2004;
RA   Yu J., Chang P.K., Ehrlich K.C., Cary J.W., Bhatnagar D., Cleveland T.E.,
RA   Payne G.A., Linz J.E., Woloshuk C.P., Bennett J.W.;
RT   "Clustered pathway genes in aflatoxin biosynthesis.";
RL   Appl. Environ. Microbiol. 70:1253-1262(2004).
RN   [14]
RP   FUNCTION.
RX   PubMed=15528514; DOI=10.1128/aem.70.11.6518-6524.2004;
RA   Ehrlich K.C., Chang P.K., Yu J., Cotty P.J.;
RT   "Aflatoxin biosynthesis cluster gene cypA is required for G aflatoxin
RT   formation.";
RL   Appl. Environ. Microbiol. 70:6518-6524(2004).
RN   [15]
RP   FUNCTION.
RX   PubMed=15932995; DOI=10.1128/aem.71.6.2999-3006.2005;
RA   Sakuno E., Wen Y., Hatabayashi H., Arai H., Aoki C., Yabe K., Nakajima H.;
RT   "Aspergillus parasiticus cyclase catalyzes two dehydration steps in
RT   aflatoxin biosynthesis.";
RL   Appl. Environ. Microbiol. 71:2999-3006(2005).
RN   [16]
RP   FUNCTION.
RX   PubMed=16332900; DOI=10.1128/aem.71.12.8963-8965.2005;
RA   Ehrlich K.C., Montalbano B., Boue S.M., Bhatnagar D.;
RT   "An aflatoxin biosynthesis cluster gene encodes a novel oxidase required
RT   for conversion of versicolorin a to sterigmatocystin.";
RL   Appl. Environ. Microbiol. 71:8963-8965(2005).
RN   [17]
RP   FUNCTION.
RX   PubMed=15771506; DOI=10.1021/ja0455188;
RA   Henry K.M., Townsend C.A.;
RT   "Ordering the reductive and cytochrome P450 oxidative steps in
RT   demethylsterigmatocystin formation yields general insights into the
RT   biosynthesis of aflatoxin and related fungal metabolites.";
RL   J. Am. Chem. Soc. 127:3724-3733(2005).
RN   [18]
RP   FUNCTION.
RX   PubMed=16461654; DOI=10.1128/aem.72.2.1096-1101.2006;
RA   Cary J.W., Ehrlich K.C., Bland J.M., Montalbano B.G.;
RT   "The aflatoxin biosynthesis cluster gene, aflX, encodes an oxidoreductase
RT   involved in conversion of versicolorin A to demethylsterigmatocystin.";
RL   Appl. Environ. Microbiol. 72:1096-1101(2006).
RN   [19]
RP   FUNCTION.
RX   PubMed=18486503; DOI=10.1016/j.fgb.2008.03.003;
RA   Cai J., Zeng H., Shima Y., Hatabayashi H., Nakagawa H., Ito Y., Adachi Y.,
RA   Nakajima H., Yabe K.;
RT   "Involvement of the nadA gene in formation of G-group aflatoxins in
RT   Aspergillus parasiticus.";
RL   Fungal Genet. Biol. 45:1081-1093(2008).
RN   [20]
RP   FUNCTION.
RX   PubMed=18403714; DOI=10.1126/science.1154711;
RA   Crawford J.M., Thomas P.M., Scheerer J.R., Vagstad A.L., Kelleher N.L.,
RA   Townsend C.A.;
RT   "Deconstruction of iterative multidomain polyketide synthase function.";
RL   Science 320:243-246(2008).
CC   -!- FUNCTION: 5'-hydroxyaverantin dehydrogenase; part of the gene cluster
CC       that mediates the biosynthesis of aflatoxins, a group of polyketide-
CC       derived furanocoumarins, and part of the most toxic and carcinogenic
CC       compounds among the known mycotoxins (PubMed:15006741). The four major
CC       aflatoxins produced by A.parasiticus are aflatoxin B1 (AFB1), aflatoxin
CC       B2 (AFB2), aflatoxin G1 (AFG1) and aflatoxin G2 (AFG2)
CC       (PubMed:15006741). The first step of the pathway is the conversion of
CC       acetate to norsolorinic acid (NOR) and requires the fatty acid synthase
CC       subunits aflA and aflB, as well as the PKS aflC (PubMed:15006741). AflC
CC       combines a hexanoyl starter unit and 7 malonyl-CoA extender units to
CC       synthesize the precursor NOR (PubMed:18403714). The hexanoyl starter
CC       unit is provided to the acyl-carrier protein (ACP) domain by the fungal
CC       fatty acid synthase aflA/aflB (PubMed:16256699). The second step is the
CC       conversion of NOR to averantin (AVN) and requires the norsolorinic acid
CC       ketoreductase aflD, which catalyzes the dehydration of norsolorinic
CC       acid to form (1'S)-averantin (PubMed:10584035). The norsolorinic acid
CC       reductases aflE and aflF may also play a role in the conversion of NOR
CC       to AVN (PubMed:15006741). The cytochrome P450 monooxygenase aflG then
CC       catalyzes the hydroxylation of AVN to 5'hydroxyaverantin (HAVN)
CC       (PubMed:8368836). The next step is performed by the 5'-hydroxyaverantin
CC       dehydrogenase aflH that transforms HAVN to 5'-oxoaverantin (OAVN) which
CC       is further converted to averufin (AVF) by aflK that plays a dual role
CC       in the pathway, as a 5'-oxoaverantin cyclase that mediates conversion
CC       of 5'-oxoaverantin, as well as a versicolorin B synthase in a later
CC       step in the pathway (PubMed:14602595, PubMed:15006741, PubMed:11055914,
CC       PubMed:15932995). The averufin oxidase aflI catalyzes the conversion of
CC       AVF to versiconal hemiacetal acetate (VHA) (PubMed:15006741). VHA is
CC       then the substrate for the versiconal hemiacetal acetate esterase aflJ
CC       to yield versiconal (VAL) (PubMed:15006741). Versicolorin B synthase
CC       aflK then converts VAL to versicolorin B (VERB) by closing the bisfuran
CC       ring of aflatoxin which is required for DNA-binding, thus giving to
CC       aflatoxin its activity as a mutagen (PubMed:15006741, PubMed:8368837,
CC       PubMed:15932995). Then, the activity of the versicolorin B desaturase
CC       aflL leads to versicolorin A (VERA) (PubMed:15006741, PubMed:8368837).
CC       A branch point starts from VERB since it can also be converted to
CC       dihydrodemethylsterigmatocystin (DMDHST), probably also by aflL, VERA
CC       being a precursor for aflatoxins B1 and G1, and DMDHST for aflatoxins
CC       B2 and G2 (PubMed:15006741). Next, the versicolorin reductase aflM and
CC       the cytochrome P450 monooxygenase aflN are involved in conversion of
CC       VERA to demethylsterigmatocystin (DMST) (PubMed:15006741,
CC       PubMed:1339261, PubMed:15771506). AflX and aflY seem also involved in
CC       this step, through probable aflX-mediated epoxide ring-opening step
CC       following versicolorin A oxidation and aflY-mediated Baeyer-Villiger
CC       oxidation required for the formation of the xanthone ring
CC       (PubMed:16332900, PubMed:16461654). The methyltransferase aflO then
CC       leads to the modification of DMST to sterigmatocystin (ST), and of
CC       DMDHST to dihydrosterigmatocystin (DHST) (PubMed:10543813). Both ST and
CC       DHST are then substrates of the O-methyltransferase aflP to yield O-
CC       methylsterigmatocystin (OMST) and dihydro-O-methylsterigmatocystin
CC       (DHOMST), respectively (PubMed:8434913). Finally OMST is converted to
CC       aflatoxins B1 and G1, and DHOMST to aflatoxins B2 and G2, via the
CC       action of several enzymes including O-methylsterigmatocystin
CC       oxidoreductase aflQ, the cytochrome P450 monooxygenase aflU, but also
CC       the NADH-dependent flavin oxidoreductase nadA which is specifically
CC       required for the synthesis of AFG1 (PubMed:15006741, PubMed:11996570,
CC       PubMed:15528514, PubMed:18486503). {ECO:0000269|PubMed:10543813,
CC       ECO:0000269|PubMed:10584035, ECO:0000269|PubMed:11055914,
CC       ECO:0000269|PubMed:11996570, ECO:0000269|PubMed:1339261,
CC       ECO:0000269|PubMed:14602595, ECO:0000269|PubMed:15528514,
CC       ECO:0000269|PubMed:15771506, ECO:0000269|PubMed:15932995,
CC       ECO:0000269|PubMed:16256699, ECO:0000269|PubMed:16332900,
CC       ECO:0000269|PubMed:16461654, ECO:0000269|PubMed:18403714,
CC       ECO:0000269|PubMed:18486503, ECO:0000269|PubMed:8368836,
CC       ECO:0000269|PubMed:8368837, ECO:0000269|PubMed:8434913,
CC       ECO:0000305|PubMed:15006741}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(1'S,5'S)-5'-hydroxyaverantin + NAD(+) = (S)-5'-oxoaverantin +
CC         H(+) + NADH; Xref=Rhea:RHEA:35475, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:77900,
CC         ChEBI:CHEBI:77933; EC=1.1.1.352;
CC         Evidence={ECO:0000269|PubMed:14602595};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(1'S,5'R)-5'-hydroxyaverantin + NAD(+) = (S)-5'-oxoaverantin +
CC         2 H(+) + NADH; Xref=Rhea:RHEA:35479, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:71536,
CC         ChEBI:CHEBI:77933; EC=1.1.1.352;
CC         Evidence={ECO:0000269|PubMed:14602595};
CC   -!- PATHWAY: Mycotoxin biosynthesis; aflatoxin biosynthesis.
CC       {ECO:0000269|PubMed:15094053}.
CC   -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:14602595}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:14602595}.
CC   -!- DISRUPTION PHENOTYPE: Cells accumulate 5'-hydroxyaverantin.
CC       {ECO:0000269|PubMed:11055914}.
CC   -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC       family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=KJK60750.1; Type=Erroneous gene model prediction; Note=The predicted gene P875_00052989 has been split into 2 genes: P875_00052996-1 (aflH) and P875_00052996-2 (aflJ).; Evidence={ECO:0000305};
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DR   EMBL; U76621; AAB51228.3; -; Genomic_DNA.
DR   EMBL; AY371490; AAS66009.1; -; Genomic_DNA.
DR   EMBL; JZEE01000729; KJK60750.1; ALT_SEQ; Genomic_DNA.
DR   AlphaFoldDB; P87017; -.
DR   SMR; P87017; -.
DR   iPTMnet; P87017; -.
DR   KEGG; ag:AAB51228; -.
DR   BioCyc; MetaCyc:MON-14032; -.
DR   BRENDA; 1.1.1.352; 523.
DR   UniPathway; UPA00287; -.
DR   Proteomes; UP000033540; Unassembled WGS sequence.
DR   GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR   GO; GO:0140396; F:5'-hydroxyaverantin dehydrogenase activity; IEA:UniProtKB-EC.
DR   GO; GO:0016616; F:oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor; IDA:UniProtKB.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0045122; P:aflatoxin biosynthetic process; IDA:UniProtKB.
DR   InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR   InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR   InterPro; IPR002347; SDR_fam.
DR   Pfam; PF00106; adh_short; 1.
DR   PRINTS; PR00081; GDHRDH.
DR   SUPFAM; SSF51735; SSF51735; 1.
DR   PROSITE; PS00061; ADH_SHORT; 1.
PE   1: Evidence at protein level;
KW   Acetylation; Cytoplasm; Direct protein sequencing; NAD; NADP;
KW   Oxidoreductase; Reference proteome.
FT   CHAIN           1..278
FT                   /note="5'-hydroxyaverantin dehydrogenase"
FT                   /id="PRO_0000424162"
FT   ACT_SITE        187
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10001"
FT   BINDING         20..48
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:P16544"
FT   BINDING         191
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:P16544"
FT   MOD_RES         1
FT                   /note="N-acetylmethionine"
FT                   /evidence="ECO:0000269|PubMed:14602595"
SQ   SEQUENCE   278 AA;  29557 MW;  8C60C5437EB9BB71 CRC64;
     MEVLDTTVDL GTLQGKSALI TGGASGIGLA TARAWAAAGM YVTIADIQPL ETGQNILADL
     AGGHVHYVCC DVTSWESQIT AFKEAIQFTP SKALDIVAAF AGVSFAGGNQ VDHVLAAGDP
     RLDVNPSPPD IRNIQVNLIG VYYTSWLGLY YLRLSPTNKA ANPSPDKSLI LMGSIGSYMD
     SPKASTYPAS KFGVRGLFRS TRARTRELGV RCNLLAPWFI DTPLIAPMKK AMAARGIDMA
     QRLTFASVDA CVEAATTCAA NPQLHGTPPI RYAYCLKT
 
 
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