AZAG_ASPNA
ID AZAG_ASPNA Reviewed; 468 AA.
AC G3XMC1;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 14-DEC-2011, sequence version 1.
DT 25-MAY-2022, entry version 37.
DE RecName: Full=FAD-linked oxidoreductase azaG {ECO:0000303|PubMed:22921072};
DE EC=1.-.-.- {ECO:0000305|PubMed:22921072};
DE AltName: Full=Azaphilone biosynthesis cluster protein azaG {ECO:0000303|PubMed:22921072};
DE Flags: Precursor;
GN Name=azaG {ECO:0000303|PubMed:22921072}; ORFNames=ASPNIDRAFT_189194;
OS Aspergillus niger (strain ATCC 1015 / CBS 113.46 / FGSC A1144 / LSHB Ac4 /
OS NCTC 3858a / NRRL 328 / USDA 3528.7).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=380704;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 1015 / CBS 113.46 / FGSC A1144 / LSHB Ac4 / NCTC 3858a / NRRL
RC 328 / USDA 3528.7;
RX PubMed=21543515; DOI=10.1101/gr.112169.110;
RA Andersen M.R., Salazar M.P., Schaap P.J., van de Vondervoort P.J.I.,
RA Culley D., Thykaer J., Frisvad J.C., Nielsen K.F., Albang R., Albermann K.,
RA Berka R.M., Braus G.H., Braus-Stromeyer S.A., Corrochano L.M., Dai Z.,
RA van Dijck P.W.M., Hofmann G., Lasure L.L., Magnuson J.K., Menke H.,
RA Meijer M., Meijer S.L., Nielsen J.B., Nielsen M.L., van Ooyen A.J.J.,
RA Pel H.J., Poulsen L., Samson R.A., Stam H., Tsang A., van den Brink J.M.,
RA Atkins A., Aerts A., Shapiro H., Pangilinan J., Salamov A., Lou Y.,
RA Lindquist E., Lucas S., Grimwood J., Grigoriev I.V., Kubicek C.P.,
RA Martinez D., van Peij N.N.M.E., Roubos J.A., Nielsen J., Baker S.E.;
RT "Comparative genomics of citric-acid-producing Aspergillus niger ATCC 1015
RT versus enzyme-producing CBS 513.88.";
RL Genome Res. 21:885-897(2011).
RN [2]
RP FUNCTION, AND INDUCTION.
RX PubMed=22921072; DOI=10.1016/j.chembiol.2012.07.004;
RA Zabala A.O., Xu W., Chooi Y.H., Tang Y.;
RT "Characterization of a silent azaphilone gene cluster from Aspergillus
RT niger ATCC 1015 reveals a hydroxylation-mediated pyran-ring formation.";
RL Chem. Biol. 19:1049-1059(2012).
CC -!- FUNCTION: FAD-linked oxidoreductase; part of the gene cluster that
CC mediates the biosynthesis of azaphilones, a class of fungal metabolites
CC characterized by a highly oxygenated pyrano-quinone bicyclic core and
CC exhibiting a broad range of bioactivities (PubMed:22921072). In the
CC first step, the non-reducing polyketide synthase azaA forms the
CC hexaketide precursor from successive condensations of five malonyl-CoA
CC units, presumably with a simple acetyl-CoA starter unit
CC (PubMed:22921072). The reactive polyketide chain then undergoes a PT-
CC mediated C2-C7 cyclization to afford the aromatic ring and is
CC eventually released as an aldehyde through the R-domain
CC (PubMed:22921072). The putative ketoreductase azaE is proposed to
CC catalyze the reduction of the terminal ketone resulting in the early
CC culture product FK17-P2a (PubMed:22921072). The monooxygenase azaH was
CC demonstrated to be the only enzyme required to convert FK17-P2a to
CC azanigerone E (PubMed:22921072). AzaH first hydroxylates the
CC benzaldehyde intermediate FK17-P2a at C4, which triggers the formation
CC of the pyran-ring to afford azanigerone E (PubMed:22921072). In
CC parallel, the 2,4-dimethylhexanoyl chain is synthesized by the HR-PKS
CC azaB and is proposed to be transferred to the C4-hydroxyl of
CC azanigerone E by the acyltransferase azaD directly from the ACP domain
CC of azaB (PubMed:22921072). Alternatively, the 2,4-dimethyl-hexanoyl
CC chain may be offloaded from the HR-PKS as a carboxylic acid and
CC converted to an acyl-CoA by azaF (PubMed:22921072). The resulting acyl-
CC CoA molecule could then be taken up as a substrate by AzaD to form
CC azanigerone B (PubMed:22921072). To yield the carboxylic acid
CC substituent in azanigerone A, the hydroxypropyl side chain of
CC azanigerone B would need to undergo a C-C oxidative cleavage catalyzed
CC by cytochrome P450 AzaI (PubMed:22921072). AzaI is proposed to act on a
CC vicinal diol that leads to a C-C bond scission either through an
CC alkoxyradical intermediate or a peroxy complex (PubMed:22921072). In
CC the biosynthesis of azanigerone A, azanigerone B first undergoes
CC hydroxylation at C10, possibly catalyzed by one of the two FAD-
CC dependent monooxygenases encoded in the cluster, azaG or azaL,
CC resulting in the vicinal diol azanigerone C (PubMed:22921072).
CC Oxidative cleavage of azanigerone C by azaI would yield the
CC corresponding aldehyde derivative of azanigerone A (PubMed:22921072).
CC Finally, the dehydrogenase azaJ is proposed to convert the aldehyde
CC functional group into the carboxylic acid, completing the conversion
CC from azanigerone B to azanigerone A (PubMed:22921072). Alternatively,
CC the oxidation of aldehyde to carboxylic acid may be catalyzed by the
CC same P450 enzyme azaI via consecutive oxidation or by endogenous
CC alcohol dehydrogenase (PubMed:22921072). {ECO:0000269|PubMed:22921072}.
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:Q5BEJ5};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:22921072}.
CC -!- INDUCTION: Expression is under the control of the azaphilone cluster-
CC specific transcription factor azaR (PubMed:22921072).
CC {ECO:0000269|PubMed:22921072}.
CC -!- SIMILARITY: Belongs to the oxygen-dependent FAD-linked oxidoreductase
CC family. {ECO:0000305}.
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DR EMBL; ACJE01000001; EHA28234.1; -; Genomic_DNA.
DR AlphaFoldDB; G3XMC1; -.
DR SMR; G3XMC1; -.
DR STRING; 380704.G3XMC1; -.
DR EnsemblFungi; EHA28234; EHA28234; ASPNIDRAFT_189194.
DR HOGENOM; CLU_018354_0_0_1; -.
DR Proteomes; UP000009038; Unassembled WGS sequence.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR Gene3D; 3.30.465.10; -; 1.
DR InterPro; IPR016166; FAD-bd_PCMH.
DR InterPro; IPR036318; FAD-bd_PCMH-like_sf.
DR InterPro; IPR016169; FAD-bd_PCMH_sub2.
DR InterPro; IPR006094; Oxid_FAD_bind_N.
DR Pfam; PF01565; FAD_binding_4; 1.
DR SUPFAM; SSF56176; SSF56176; 1.
DR PROSITE; PS51387; FAD_PCMH; 1.
PE 2: Evidence at transcript level;
KW FAD; Flavoprotein; Glycoprotein; Oxidoreductase; Reference proteome;
KW Signal.
FT SIGNAL 1..16
FT /evidence="ECO:0000255"
FT CHAIN 17..468
FT /note="FAD-linked oxidoreductase azaG"
FT /evidence="ECO:0000255"
FT /id="PRO_5005680459"
FT DOMAIN 54..228
FT /note="FAD-binding PCMH-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00718"
FT CARBOHYD 44
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 272
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 348
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 464
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 468 AA; 51637 MW; FDB2CB1195B35C27 CRC64;
MQLSGILSWL LSWLWASQTT LDLQGLYGPS LSPNAEIVLA SDANYTHVTT QRWTVHGAPH
YLGAIIPVTE HDIQHIIKIS REHAINFLVV GAGHGATVTF ERFRHGIAID LQQFKDVHLD
VDAERLTVAG ATVFSDIIDP LYSAQREIVT PSAPCVGVVG MTLGGGIGSL QGLHGLLLDS
LESVRLVTPI GDLIEVSETQ YPELFWGLRG AGSNFGVVTS ATYRTHQATH GGLVTNVDIF
AATEHASIWQ ALSAFDDTLP PELALTLAVA YNRTIDQPLV LVNAIYYGPE EQALELLSPF
TSLTPIMSRS VTVPWNALLD TTFFGLAAQE GGACAKNQAV NIYSIGLNHT DVPAWESYME
QLLQFYRQNP TYDGRFLVQR YPTQGALSTL DSNTAYPHRQ IKMHINLEGW YTDPYLEDPV
NAFLKQSRRH FQQSSGFDNL AVYVNYAHGD EGPDVWYTAE KLENLTRL
