AZPB5_ASPTN
ID AZPB5_ASPTN Reviewed; 255 AA.
AC Q0CF71;
DT 17-JUN-2020, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 25-MAY-2022, entry version 55.
DE RecName: Full=Probable esterase ATEG_07663 {ECO:0000303|PubMed:31908094};
DE EC=3.1.2.- {ECO:0000305|PubMed:31908094};
DE AltName: Full=Azasperpyranone A biosynthesis cluster B protein ATEG_07663 {ECO:0000303|PubMed:31908094};
GN ORFNames=ATEG_07663;
OS Aspergillus terreus (strain NIH 2624 / FGSC A1156).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=341663;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=NIH 2624 / FGSC A1156;
RA Birren B.W., Lander E.S., Galagan J.E., Nusbaum C., Devon K., Henn M.,
RA Ma L.-J., Jaffe D.B., Butler J., Alvarez P., Gnerre S., Grabherr M.,
RA Kleber M., Mauceli E.W., Brockman W., Rounsley S., Young S.K., LaButti K.,
RA Pushparaj V., DeCaprio D., Crawford M., Koehrsen M., Engels R.,
RA Montgomery P., Pearson M., Howarth C., Larson L., Luoma S., White J.,
RA Alvarado L., Kodira C.D., Zeng Q., Oleary S., Yandava C., Denning D.W.,
RA Nierman W.C., Milne T., Madden K.;
RT "Annotation of the Aspergillus terreus NIH2624 genome.";
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP FUNCTION.
RX PubMed=24412543; DOI=10.1016/j.chembiol.2013.12.005;
RA Wang M., Beissner M., Zhao H.;
RT "Aryl-aldehyde formation in fungal polyketides: discovery and
RT characterization of a distinct biosynthetic mechanism.";
RL Chem. Biol. 21:257-263(2014).
RN [3]
RP FUNCTION.
RX PubMed=23621425; DOI=10.1021/ja401945a;
RA Chiang Y.M., Oakley C.E., Ahuja M., Entwistle R., Schultz A., Chang S.L.,
RA Sung C.T., Wang C.C., Oakley B.R.;
RT "An efficient system for heterologous expression of secondary metabolite
RT genes in Aspergillus nidulans.";
RL J. Am. Chem. Soc. 135:7720-7731(2013).
RN [4]
RP FUNCTION, INDUCTION, DISRUPTION PHENOTYPE, AND BIOTECHNOLOGY.
RX PubMed=31908094; DOI=10.1002/anie.201915514;
RA Huang X., Zhang W., Tang S., Wei S., Lu X.;
RT "Collaborative biosynthesis of a class of bioactive azaphilones by two
RT separate gene clusters containing four PKS/NRPSs with transcriptional
RT cosstalk in fungi.";
RL Angew. Chem. Int. Ed. 59:4349-4353(2020).
CC -!- FUNCTION: Probable esterase; part of the cluster B that mediates the
CC biosynthesis of azasperpyranones, members of the azaphilone family that
CC exhibit anti-cancer activities (PubMed:31908094). Azasperpyranones are
CC synthesized by 2 clusters, A and B (PubMed:31908094). Cluster A is
CC responsible for the production of the polyhydric phenol moiety while
CC the azaphilonoid scaffold is produced by the cluster B
CC (PubMed:31908094). The non-reducing polyketide synthase ATEG_03629
CC produces 5-methyl orsellinic acid, which is then reduced to 5-methyl
CC orsellinic aldehyde by the NRPS-like protein ATEG_03630
CC (PubMed:24412543). 5-methyl orsellinic aldehyde is then first
CC hydroxylated by the FAD-dependent monooxygenase ATEG_03635 and
CC subsequently hydroxylated by the cytochrome P450 monooxygenase
CC ATEG_03631 to produce the unstable polyhydric phenol precursor of
CC azasperpyranones (PubMed:31908094). On the other hand, the polyketide
CC synthase ATEG_07659 is responsible for producing the 3,5-
CC dimethyloctadienone moiety from acetyl-CoA, three malonyl-CoA, and two
CC S-adenosyl methionines (SAM) (Probable). The 3,5-dimethyloctadienone
CC moiety is then loaded onto the SAT domain of ATEG_07661 and extended
CC with four malonyl-CoA and one SAM, which leads to the formation of 2,4-
CC dihydroxy-6-(5,7-dimethyl-2-oxo-trans-3-trans-5-nonadienyl)-3-
CC methylbenzaldehyde (compound 8) after reductive release and aldol
CC condensation (Probable). The FAD-dependent monooxygenase ATEG_07662 is
CC the next enzyme in the biosynthesis sequence and hydroxylates the side
CC chain at the benzylic position of compound 8 (Probable). In Aspergillus
CC nidulans, afoF, the ortholog of the FAD-dependent oxygenase ATEG_07660,
CC is the key enzyme for the biosynthesis of asperfuranone by catalyzing
CC the hydroxylation at C-8 of to prevent the formation of a six-membered
CC ring hemiacetal intermediate and thus facilitatings the formation of a
CC five-membered ring to produce asperfuranone (Probable). In Aspergillus
CC terreus, ATEG_07660 is probably not functional, which leads to the
CC formation of the six-membered ring hemiacetal intermediate
CC presperpyranone instead of asperfuranone (Probable). Finally,
CC ATEG_03636 is involved in the condensation of the polyhydric phenol
CC moiety produced by cluster A and the perasperpyranone precursor
CC produced by cluster B, to yield azasperpyranone A (Probable). Further
CC modifications of azasperpyranone A result in the production of
CC derivatives, including azasperpyranone B to F (PubMed:31908094).
CC {ECO:0000269|PubMed:24412543, ECO:0000269|PubMed:31908094,
CC ECO:0000305|PubMed:31908094}.
CC -!- INDUCTION: Expression is induced by the azasperpyranone cluster A-
CC specific transcription factor ATEG_07666 which is itself regulated by
CC the azasperpyranone transcriptional regulator ATEG_07667.
CC {ECO:0000269|PubMed:31908094}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of azasperpyranone A.
CC {ECO:0000269|PubMed:31908094}.
CC -!- BIOTECHNOLOGY: Azasperpyranones display potential anti-cancer
CC activities (PubMed:31908094). Azasperpyranones A, C, D, and F exhibit
CC potent growth-inhibitory activity against the A549, HepG2, HCT-116, and
CC HL-60 cell lines, with IC(50) values of 2.39-14.42 mm, respectively
CC (PubMed:31908094). Moreover, azasperpyranone D significantly inhibits
CC HCT-116 xenograft tumor growth in BALB/c-nu mice (PubMed:31908094). In
CC addition, azasperpyranones A and C can bind with four kinds of
CC therapeutic targets for cancer, eEF2K, FGFR, survivin, and TNF-a
CC (PubMed:31908094). {ECO:0000269|PubMed:31908094}.
CC -!- SIMILARITY: Belongs to the LovG family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; CH476604; EAU31925.1; -; Genomic_DNA.
DR RefSeq; XP_001216284.1; XM_001216284.1.
DR AlphaFoldDB; Q0CF71; -.
DR SMR; Q0CF71; -.
DR EnsemblFungi; EAU31925; EAU31925; ATEG_07663.
DR GeneID; 4322608; -.
DR VEuPathDB; FungiDB:ATEG_07663; -.
DR eggNOG; KOG2551; Eukaryota.
DR HOGENOM; CLU_051938_0_0_1; -.
DR OMA; YHIEAIR; -.
DR OrthoDB; 1190789at2759; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0016787; F:hydrolase activity; IEA:UniProtKB-KW.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR005645; FSH_dom.
DR Pfam; PF03959; FSH1; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
PE 1: Evidence at protein level;
KW Hydrolase; Reference proteome.
FT CHAIN 1..255
FT /note="Probable esterase ATEG_07663"
FT /id="PRO_0000450091"
FT ACT_SITE 122
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P38777"
FT ACT_SITE 200
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P38777"
FT ACT_SITE 227
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P38777"
SQ SEQUENCE 255 AA; 27521 MW; 6BC348029803E5D2 CRC64;
MSPPRFSGRQ DGRTDPTTAL PRVLCLHGGG TNARIFRTQC RVIRAHLADS FRLVFADGPF
PSGPGPDVTA VYGDWGPFRA WLPHPAVKDP DVDKIDECIA AAMAADDRAG ATGAWVGLLG
FSQGARVAAS LLLRQQRHQQ RQKASLGFAY GATNAISEYR FAVLFAGRGP LLDMGAGDDN
TRPEAELLEL PTIHVHGLQD PGLEMHRDLL RCCLGSSARL VQWDGDHRVP IRRKDVSAVA
AEIRDLASRG ILGDG
