ID   ATX_ASPTN               Reviewed;        1803 AA.
AC   Q0CJ59;
DT   02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT   17-OCT-2006, sequence version 1.
DT   03-AUG-2022, entry version 88.
DE   RecName: Full=6-methylsalicylic acid synthase {ECO:0000303|PubMed:9003280};
DE            Short=6-MSAS {ECO:0000303|PubMed:9003280};
DE            EC=2.3.1.165 {ECO:0000269|PubMed:9003280};
DE   AltName: Full=Polyketide synthase atX {ECO:0000305};
DE   AltName: Full=Terreic acid biosynthesis protein X {ECO:0000303|PubMed:9003280};
GN   Name=atX {ECO:0000303|PubMed:9003280};
GN   Synonyms=pksM {ECO:0000303|PubMed:9438344}; ORFNames=ATEG_06275;
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, AND CATALYTIC ACTIVITY.
RX   PubMed=9003280; DOI=10.1007/s004380050289;
RA   Fujii I., Ono Y., Tada H., Gomi K., Ebizuka Y., Sankawa U.;
RT   "Cloning of the polyketide synthase gene atX from Aspergillus terreus and
RT   its identification as the 6-methylsalicylic acid synthase gene by
RT   heterologous expression.";
RL   Mol. Gen. Genet. 253:1-10(1996).
RN   [3]
RP   FUNCTION, AND INDUCTION.
RX   PubMed=9438344; DOI=10.1007/bf02826548;
RA   Pazoutova S., Linka M., Storkova S., Schwab H.;
RT   "Polyketide synthase gene pksM from Aspergillus terreus expressed during
RT   growth phase.";
RL   Folia Microbiol. (Praha) 42:419-430(1997).
RN   [4]
RP   BIOTECHNOLOGY.
RX   PubMed=10051623; DOI=10.1073/pnas.96.5.2227;
RA   Kawakami Y., Hartman S.E., Kinoshita E., Suzuki H., Kitaura J., Yao L.,
RA   Inagaki N., Franco A., Hata D., Maeda-Yamamoto M., Fukamachi H., Nagai H.,
RA   Kawakami T.;
RT   "Terreic acid, a quinone epoxide inhibitor of Bruton's tyrosine kinase.";
RL   Proc. Natl. Acad. Sci. U.S.A. 96:2227-2232(1999).
RN   [5]
RP   BIOTECHNOLOGY.
RX   PubMed=23686727; DOI=10.1002/jobm.201200617;
RA   Olesen S.H., Ingles D.J., Yang Y., Schoenbrunn E.;
RT   "Differential antibacterial properties of the MurA inhibitors terreic acid
RT   and fosfomycin.";
RL   J. Basic Microbiol. 54:322-326(2014).
RN   [6]
RP   FUNCTION.
RX   PubMed=24534845; DOI=10.1016/j.jbiotec.2014.01.038;
RA   Boruta T., Bizukojc M.;
RT   "Culture-based and sequence-based insights into biosynthesis of secondary
RT   metabolites by Aspergillus terreus ATCC 20542.";
RL   J. Biotechnol. 175:53-62(2014).
RN   [7]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=25265334; DOI=10.1021/ol502242a;
RA   Guo C.J., Sun W.W., Bruno K.S., Wang C.C.;
RT   "Molecular genetic characterization of terreic acid pathway in Aspergillus
RT   terreus.";
RL   Org. Lett. 16:5250-5253(2014).
CC   -!- FUNCTION: 6-methylsalicylic acid synthase; part of the gene cluster
CC       that mediates the biosynthesis of terreic acid, a quinone epoxide
CC       inhibitor of Bruton's tyrosine kinase (PubMed:24534845,
CC       PubMed:25265334). The first step of the pathway is the synthesis of 6-
CC       methylsalicylic acid (6-MSA) by the 6-methylsalicylic acid synthase atX
CC       (PubMed:9003280, PubMed:9438344, PubMed:25265334). In the biosynthesis
CC       of 6-MSA, atX utilizes one acetyl-CoA and three malonyl-CoAs as its
CC       substrates and catalyzes a series of programmed reactions including
CC       Claisen condensation, dehydration, reduction, and cyclization to yield
CC       6-MSA (PubMed:9003280, PubMed:9438344, PubMed:25265334). The 6-
CC       methylsalicylic acid decarboxylase atA then catalyzes the
CC       decarboxylative hydroxylation of 6-MSA to 3-methylcatechol
CC       (PubMed:25265334). The next step is the conversion of 3-methylcatechol
CC       to terremutin via several oxidation steps involving the cytochrome P450
CC       monooxygenase atE and probably also the cytochrome P450 monooxygenase
CC       atG (PubMed:25265334). Lastly, atC is required for the oxidation of
CC       terremutin to terreic acid (PubMed:25265334). No function could be
CC       assigned to atD yet, although it is involved in the biosynthesis of
CC       terreic acid (PubMed:25265334). {ECO:0000269|PubMed:25265334,
CC       ECO:0000269|PubMed:9003280, ECO:0000269|PubMed:9438344,
CC       ECO:0000305|PubMed:24534845}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=acetyl-CoA + 3 H(+) + 3 malonyl-CoA + NADPH = 6-
CC         methylsalicylate + 3 CO2 + 4 CoA + H2O + NADP(+);
CC         Xref=Rhea:RHEA:12240, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:16526, ChEBI:CHEBI:36658, ChEBI:CHEBI:57287,
CC         ChEBI:CHEBI:57288, ChEBI:CHEBI:57384, ChEBI:CHEBI:57783,
CC         ChEBI:CHEBI:58349; EC=2.3.1.165;
CC         Evidence={ECO:0000269|PubMed:9003280};
CC   -!- PATHWAY: Secondary metabolite biosynthesis.
CC       {ECO:0000269|PubMed:25265334}.
CC   -!- INDUCTION: Expression is observed in the middle of the vegetative
CC       growth phase (PubMed:9438344). {ECO:0000269|PubMed:9438344}.
CC   -!- DISRUPTION PHENOTYPE: Abolishes the production of terreic acid
CC       (PubMed:25265334). {ECO:0000269|PubMed:25265334}.
CC   -!- BIOTECHNOLOGY: Terreic acid is a metabolite with antibiotic properties
CC       (PubMed:23686727). Terric acid acts also as a selective inhibitor of
CC       human Bruton's tyrosine kinase in mast cells and other immune cells
CC       (PubMed:10051623). {ECO:0000269|PubMed:10051623,
CC       ECO:0000269|PubMed:23686727}.
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DR   EMBL; CH476602; EAU32819.1; -; Genomic_DNA.
DR   RefSeq; XP_001215453.1; XM_001215453.1.
DR   AlphaFoldDB; Q0CJ59; -.
DR   SMR; Q0CJ59; -.
DR   STRING; 341663.Q0CJ59; -.
DR   PRIDE; Q0CJ59; -.
DR   EnsemblFungi; EAU32819; EAU32819; ATEG_06275.
DR   GeneID; 4322099; -.
DR   VEuPathDB; FungiDB:ATEG_06275; -.
DR   eggNOG; KOG1202; Eukaryota.
DR   HOGENOM; CLU_000022_35_3_1; -.
DR   OMA; HRRFWRT; -.
DR   OrthoDB; 19161at2759; -.
DR   Proteomes; UP000007963; Unassembled WGS sequence.
DR   GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR   GO; GO:0050641; F:6-methylsalicylic acid synthase activity; IEA:UniProtKB-EC.
DR   GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR   GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR   GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR   GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR   Gene3D; 1.10.1200.10; -; 1.
DR   Gene3D; 3.10.129.110; -; 1.
DR   Gene3D; 3.40.366.10; -; 1.
DR   Gene3D; 3.40.47.10; -; 1.
DR   InterPro; IPR001227; Ac_transferase_dom_sf.
DR   InterPro; IPR036736; ACP-like_sf.
DR   InterPro; IPR014043; Acyl_transferase.
DR   InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR   InterPro; IPR018201; Ketoacyl_synth_AS.
DR   InterPro; IPR014031; Ketoacyl_synth_C.
DR   InterPro; IPR014030; Ketoacyl_synth_N.
DR   InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR   InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR   InterPro; IPR032821; PKS_assoc.
DR   InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR   InterPro; IPR020807; PKS_dehydratase.
DR   InterPro; IPR042104; PKS_dehydratase_sf.
DR   InterPro; IPR013968; PKS_KR.
DR   InterPro; IPR020806; PKS_PP-bd.
DR   InterPro; IPR009081; PP-bd_ACP.
DR   InterPro; IPR016039; Thiolase-like.
DR   Pfam; PF00698; Acyl_transf_1; 1.
DR   Pfam; PF16197; KAsynt_C_assoc; 1.
DR   Pfam; PF00109; ketoacyl-synt; 1.
DR   Pfam; PF02801; Ketoacyl-synt_C; 1.
DR   Pfam; PF08659; KR; 1.
DR   Pfam; PF00550; PP-binding; 1.
DR   Pfam; PF14765; PS-DH; 1.
DR   SMART; SM00827; PKS_AT; 1.
DR   SMART; SM00826; PKS_DH; 1.
DR   SMART; SM00825; PKS_KS; 1.
DR   SMART; SM00823; PKS_PP; 1.
DR   SUPFAM; SSF47336; SSF47336; 1.
DR   SUPFAM; SSF51735; SSF51735; 2.
DR   SUPFAM; SSF52151; SSF52151; 1.
DR   SUPFAM; SSF53901; SSF53901; 1.
DR   SUPFAM; SSF55048; SSF55048; 1.
DR   PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR   PROSITE; PS50075; CARRIER; 1.
PE   1: Evidence at protein level;
KW   Acyltransferase; Multifunctional enzyme; NADP; Oxidoreductase;
KW   Phosphopantetheine; Phosphoprotein; Reference proteome; Transferase.
FT   CHAIN           1..1803
FT                   /note="6-methylsalicylic acid synthase"
FT                   /id="PRO_0000437633"
FT   DOMAIN          1726..1801
FT                   /note="Carrier"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   REGION          1..40
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          47..473
FT                   /note="Ketosynthase (KS) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          581..894
FT                   /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          940..1214
FT                   /note="Dehydrogenase (DH) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          1434..1628
FT                   /note="Ketoreductase (KR) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          1701..1721
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        216
FT                   /note="For beta-ketoacyl synthase activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT   ACT_SITE        667
FT                   /note="For malonyltransferase activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT   MOD_RES         1761
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ   SEQUENCE   1803 AA;  193794 MW;  302EF6DDA3A0E3C6 CRC64;
     MEVHGDEVLS VDSGVSTPPS TGSGFRRPLE TPGTEIGNLN LNPQNEVAVV GMACRLAGGN
     NSPEELWQSI LNRKDASGEI PSMRWEPYYR RDIRNPKILD QTTKRGYFLD HVENFDAAFF
     GVSPKEAEQM DPQQRLSLEV TWEALEDAGI PPQSLSGSET AVFMGVNSDD YSKLLLEDIP
     NVEAWMGIGT AYCGVPNRIS YHLNLMGPST AVDAACASSL VAIHHGRQAI LQGESEVAIV
     GGVNALCGPG LTRVLDKAGA TSTEGRCLSF DEDAKGYGRG EGAAVVILKR LSTAIRDGDH
     IRAIIKGSAV AQDGKTNGIM APNAKAQELV AWNALRTAGV DPLTVGYVEA HATSTPLGDP
     TEVSAVSAVY GKGRPEGNPC FIGSVKPNVG HLEAGAGAVG FIKAVMAVEK AIFPPQTNLK
     RLNSRIDWGQ AGVKVVQETL EWPGNEDDVR RAGVCSYGYG GTVSHAIIEE FAQQLQRPTT
     NTTDEDPLPR ILLLSAPQER RLALQARTQA SWIAAEGRNR TLESIATTLS TRRGHHDYRA
     AIIAENHDDA VQKLSDIVNG KAAEWTTSSR VLDASCSKDV VWVFSGHGAQ WTAMATDLLK
     DIVFYQTISR LDPIVEREMG FSALHSLASG DFESSIKVQV LTYLVQVGLA AILRSKGLEP
     QAVIGHSVGE IAASVAAGCL TAEEGALIVT RRANLYRRVM GAGAMVLVNI PFVDMEKELQ
     GRTDLVAAID SSPSSCVVSG ATEAVLALVE DLKSRGVNAF RVKTDIPFHH PMLDQLSEPL
     REAMAGSLSP RKPRVRLYST SAEDPRSMVA RDIYYWTSNM VNPVRLTAAV QAAVDDGLRL
     FLEVSSHPIV SHSVRETMLD LGVEDFTVTN TMARNKPADK TILSSIAQLH CRGAVVNWKK
     QLPGPWALDV PLTTWDHKPY WRHIHTGPIS ASTLHDVDKH TLLGQRVPVA GETTMVFTTQ
     MDDQTKPFPG SHPLHGSEIV PAAALVNTFL HATGATTLSN ITLRVPVAIS QPRDIQVVVS
     QNQIKICSRL TQKAGSGADE GSWLTHTTGQ WEAGGSKNAP AQLDIAAIKA RLANNKLADN
     FSIDYLDKVG VSAMGFPWAV TEHYGTLQEM IARVDVAPDV PATSPLPWDA ASWAPILDAA
     TSVGSTLFFD QPRLRMPAHI HGVQVYTTQP PLKVGYLYVE KAGDRDLAVH VSVCDELGTV
     LARFESMRFS EIEGTPGSNG SEESLVHQLA WPPAIYSEKP LTINNVVLVS RDKNVADLYC
     GSLKDRVSSI TVLDAAADLL SLSQDSSSVL QAKDTAVVYV PGPLHSADSI PTAAHSFLME
     LLLLVKIIVN GSLPTKVFVL TDRVCESESA TALAQSPIHG VSRIIAAEHP DQWGGLIDVE
     TPGQFPLETM KYVQEADNIR ISDGIPRIAR LRPLPRDKLL PPSKQTSLLP RPESTYLITG
     GLGALGLEVA QFLVEKGARR LILVSRRALP PRREWADILA DASSSLAPAL ETIQALEAQG
     ATVHTLAVDI SSPDAAPQLA VAIDSLSLPP VRGVVHAAGV LDSQLVLSAT SDSVERVLAP
     KITGALVLGT VFPPKALDFF MLFSSCGQLL GFPGQASYAS GNAFLDAFAT SRRHQGDNAV
     AVQWTSWRSL GMAASTDFIN AELASKGITD ITRDEGFRAW MHISKYDIDQ AAVLRSLAFE
     ADEPLPTPIL TDIAVRKAGS ASSADAPSAA PKETNEMPES IPERRTWLDE RIRDCVARVL
     QLGSSDEVDS KAALSDLGVD SVMTVSLRGQ LQKTLGVKVP PTLTWSCPTV SHLVGWFLEK
     MGN