NADA_ASPPU
ID NADA_ASPPU Reviewed; 444 AA.
AC Q6UEF0; A0A0F0HZ66;
DT 30-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 42.
DE RecName: Full=NADH-dependent flavin oxidoreductase nadA {ECO:0000305};
DE EC=1.-.-.- {ECO:0000305|PubMed:18486503};
DE AltName: Full=Aflatoxin biosynthesis protein nadA {ECO:0000303|PubMed:15006741};
GN Name=nadA {ECO:0000303|PubMed:10978525}; ORFNames=P875_00053008;
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].
RC STRAIN=ATCC 56775 / NRRL 5862 / SRRC 143 / SU-1;
RX PubMed=10855719; DOI=10.1007/s002530051660;
RA Yu J., Chang P.-K., Bhatnagar D., Cleveland T.E.;
RT "Genes encoding cytochrome P450 and monooxygenase enzymes define one end of
RT the aflatoxin pathway gene cluster in Aspergillus parasiticus.";
RL Appl. Microbiol. Biotechnol. 53:583-590(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=ATCC 56775 / NRRL 5862 / SRRC 143 / SU-1;
RX PubMed=10978525; DOI=10.1016/s0167-4781(00)00148-2;
RA Yu J., Chang P., Bhatnagar D., Cleveland T.E.;
RT "Cloning of a sugar utilization gene cluster in Aspergillus parasiticus.";
RL Biochim. Biophys. Acta 1493:211-214(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=ATCC 56775 / NRRL 5862 / SRRC 143 / SU-1;
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 [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
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 [5]
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 [6]
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 [7]
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 [8]
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 [9]
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 [10]
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 [11]
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 [12]
RP FUNCTION.
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 [13]
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 [14]
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 [15]
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 [16]
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 [17]
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 [18]
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 [19]
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 [20]
RP FUNCTION, INDUCTION, DISRUPTION PHENOTYPE, AND SUBCELLULAR LOCATION.
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 [21]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=19325828; DOI=10.3390/ijms9091717;
RA Ehrlich K.C., Scharfenstein L.L. Jr., Montalbano B.G., Chang P.K.;
RT "Are the genes nadA and norB involved in formation of aflatoxin G(1)?";
RL Int. J. Mol. Sci. 9:1717-1729(2008).
RN [22]
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: NADH-dependent flavin oxidoreductase; part of the gene
CC cluster that mediates the biosynthesis of aflatoxins, a group of
CC polyketide-derived furanocoumarins, and part of the most toxic and
CC carcinogenic compounds among the known mycotoxins (PubMed:15006741).
CC The four major aflatoxins produced by A.parasiticus are aflatoxin B1
CC (AFB1), aflatoxin B2 (AFB2), aflatoxin G1 (AFG1) and aflatoxin G2
CC (AFG2) (PubMed:15006741). The first step of the pathway is the
CC conversion of acetate to norsolorinic acid (NOR) and requires the fatty
CC acid synthase subunits aflA and aflB, as well as the PKS aflC
CC (PubMed:15006741). AflC combines a hexanoyl starter unit and 7 malonyl-
CC CoA extender units to synthesize the precursor NOR (PubMed:18403714).
CC The hexanoyl starter unit is provided to the acyl-carrier protein (ACP)
CC domain by the fungal fatty acid synthase aflA/aflB (PubMed:16256699).
CC The second step is the conversion of NOR to averantin (AVN) and
CC requires the norsolorinic acid ketoreductase aflD, which catalyzes the
CC dehydration of norsolorinic acid to form (1'S)-averantin
CC (PubMed:10584035). The norsolorinic acid reductases aflE and aflF may
CC also play a role in the conversion of NOR to AVN (PubMed:15006741). The
CC cytochrome P450 monooxygenase aflG then catalyzes the hydroxylation of
CC AVN to 5'hydroxyaverantin (HAVN) (PubMed:8368836). The next step is
CC performed by the 5'-hydroxyaverantin dehydrogenase aflH that transforms
CC HAVN to 5'-oxoaverantin (OAVN) which is further converted to averufin
CC (AVF) by aflK that plays a dual role in the pathway, as a 5'-
CC oxoaverantin cyclase that mediates conversion of 5'-oxoaverantin, as
CC well as a versicolorin B synthase in a later step in the pathway
CC (PubMed:15006741, PubMed:11055914, PubMed:15932995). The averufin
CC oxidase aflI catalyzes the conversion of AVF to versiconal hemiacetal
CC acetate (VHA) (PubMed:15006741). VHA is then the substrate for the
CC versiconal hemiacetal acetate esterase aflJ to yield versiconal (VAL)
CC (PubMed:15006741). Versicolorin B synthase aflK then converts VAL to
CC versicolorin B (VERB) by closing the bisfuran ring of aflatoxin which
CC is required for DNA-binding, thus giving to aflatoxin its activity as a
CC mutagen (PubMed:15006741, PubMed:8368837, PubMed:15932995). Then, the
CC activity of the versicolorin B desaturase aflL leads to versicolorin A
CC (VERA) (PubMed:15006741, PubMed:8368837). A branch point starts from
CC VERB since it can also be converted to dihydrodemethylsterigmatocystin
CC (DMDHST), probably also by aflL, VERA being a precursor for aflatoxins
CC B1 and G1, and DMDHST for aflatoxins B2 and G2 (PubMed:15006741). Next,
CC the versicolorin reductase aflM and the cytochrome P450 monooxygenase
CC aflN are involved in conversion of VERA to demethylsterigmatocystin
CC (DMST) (PubMed:15006741, PubMed:1339261, PubMed:15771506). AflX and
CC aflY seem also involved in this step, through probable aflX-mediated
CC epoxide ring-opening step following versicolorin A oxidation and aflY-
CC mediated Baeyer-Villiger oxidation required for the formation of the
CC xanthone ring (PubMed:16332900, PubMed:16461654). The methyltransferase
CC aflO then leads to the modification of DMST to sterigmatocystin (ST),
CC and of DMDHST to dihydrosterigmatocystin (DHST) (PubMed:10543813). Both
CC ST and DHST are then substrates of the O-methyltransferase aflP to
CC yield O-methylsterigmatocystin (OMST) and dihydro-O-
CC methylsterigmatocystin (DHOMST), respectively (PubMed:8434913). Finally
CC OMST is converted to aflatoxins B1 and G1, and DHOMST to aflatoxins B2
CC and G2, via the action of several enzymes including O-
CC methylsterigmatocystin oxidoreductase aflQ, the cytochrome P450
CC monooxygenase aflU, but also the NADH-dependent flavin oxidoreductase
CC nadA which is specifically required for the synthesis of AFG1
CC (PubMed:15006741, PubMed:11996570, PubMed:15528514, PubMed:18486503,
CC PubMed:19325828). {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:15528514, ECO:0000269|PubMed:15771506,
CC ECO:0000269|PubMed:15932995, ECO:0000269|PubMed:16256699,
CC ECO:0000269|PubMed:16332900, ECO:0000269|PubMed:16461654,
CC ECO:0000269|PubMed:18403714, ECO:0000269|PubMed:18486503,
CC ECO:0000269|PubMed:19325828, ECO:0000269|PubMed:8368836,
CC ECO:0000269|PubMed:8368837, ECO:0000269|PubMed:8434913,
CC ECO:0000305|PubMed:15006741}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:18486503}.
CC -!- INDUCTION: Expression is regulated by the aflatoxin cluster-specific
CC transcription factor aflR (PubMed:18486503).
CC {ECO:0000269|PubMed:18486503}.
CC -!- DISRUPTION PHENOTYPE: Does not show any remarkable difference in
CC production of B-group aflatoxin (AFB1 and AFB2) compared to the wild-
CC type but leads to significant decrease in production of G-group
CC aflatoxins (AFG1 and AFG2) (PubMed:18486503). Leads to the accumulation
CC of a yellow AFG1 precursor called NADA (PubMed:18486503,
CC PubMed:19325828). {ECO:0000269|PubMed:18486503,
CC ECO:0000269|PubMed:19325828}.
CC -!- SIMILARITY: Belongs to the NADH:flavin oxidoreductase/NADH oxidase
CC family. {ECO:0000305}.
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DR EMBL; AY371490; AAS66029.1; -; Genomic_DNA.
DR EMBL; JZEE01000729; KJK60775.1; -; Genomic_DNA.
DR AlphaFoldDB; Q6UEF0; -.
DR SMR; Q6UEF0; -.
DR EnsemblFungi; KJK60775; KJK60775; P875_00053008.
DR Proteomes; UP000033540; Unassembled WGS sequence.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0010181; F:FMN binding; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0045122; P:aflatoxin biosynthetic process; IMP:GO_Central.
DR Gene3D; 3.20.20.70; -; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR001155; OxRdtase_FMN_N.
DR Pfam; PF00724; Oxidored_FMN; 1.
PE 2: Evidence at transcript level;
KW Cytoplasm; FAD; Flavoprotein; FMN; NAD; Oxidoreductase; Reference proteome.
FT CHAIN 1..444
FT /note="NADH-dependent flavin oxidoreductase nadA"
FT /id="PRO_0000438344"
FT REGION 127..149
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 37..40
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250|UniProtKB:P54550"
FT BINDING 123
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250|UniProtKB:P54550"
FT BINDING 192..195
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P54550"
FT BINDING 345..346
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250|UniProtKB:P54550"
FT CONFLICT 34
FT /note="G -> A (in Ref. 5; KJK60775)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 444 AA; 48459 MW; 3F69B6D9BD320632 CRC64;
MARAGQAVDP SPLGQPLEFH FARRSAPNRF LKAGMSERMC SWTEENPSAR GIPSRELIET
YRTWGRGNIG AIVTGNVMID PNHIEAEGNP TIPPNALFSG ERFDQFANLA AAARANGSLI
LAQISHPGRQ TPSHRQPEPI SASDVPLDTE NMGNTFAVPR AATENEIKNI ITGFAHAAEF
LDRAGYDGVE LHAAHGYLLN QFLSRATNLR TDKYGGTLTN RMRLILEIRA AITEKVRPGF
IVGIKINSVE FQPNGIVPDE ACELCCALEE HRFDFVELSG GKYKNLEEDD NAKHIISKRH
EAFFLDVAQK VVSSLTKMKS YLTGGFRSTA GMVDGLQTVD GIGLARPFCQ EPYLCHDILR
GKIPGAIIPV MDQLNYQLTV AAACIQMRQI GNKVQPVDLS SQDAVDAITA AAEGWLKRKA
IDRSEEAFKP PLLSGDAAPL SVEA
