CTVA_ASPTN
ID CTVA_ASPTN Reviewed; 2438 AA.
AC Q0C9L7;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 93.
DE RecName: Full=Highly reducing polyketide synthase ctvA {ECO:0000303|PubMed:26954888};
DE Short=HR-PKS ctvA {ECO:0000303|PubMed:26954888};
DE EC=2.3.1.- {ECO:0000269|PubMed:26954888};
DE AltName: Full=Citreoviridin biosynthesis protein A {ECO:0000303|PubMed:26954888};
GN Name=ctvA {ECO:0000303|PubMed:26954888}; ORFNames=ATEG_09617;
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 BIOTECHNOLOGY.
RX PubMed=2523213; DOI=10.1016/0003-9861(89)90554-7;
RA Sayood S.F., Suh H., Wilcox C.S., Schuster S.M.;
RT "Effect of citreoviridin and isocitreoviridin on beef heart mitochondrial
RT ATPase.";
RL Arch. Biochem. Biophys. 270:714-721(1989).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=22753871; DOI=10.1182/blood-2011-12-399063;
RA Yavlovich A., Viard M., Zhou M., Veenstra T.D., Wang J.M., Gong W.,
RA Heldman E., Blumenthal R., Raviv Y.;
RT "Ectopic ATP synthase facilitates transfer of HIV-1 from antigen-presenting
RT cells to CD4(+) target cells.";
RL Blood 120:1246-1253(2012).
RN [4]
RP BIOTECHNOLOGY.
RX PubMed=22822083; DOI=10.1158/0008-5472.can-12-0567;
RA Chang H.Y., Huang H.C., Huang T.C., Yang P.C., Wang Y.C., Juan H.F.;
RT "Ectopic ATP synthase blockade suppresses lung adenocarcinoma growth by
RT activating the unfolded protein response.";
RL Cancer Res. 72:4696-4706(2012).
RN [5]
RP FUNCTION, AND PATHWAY.
RX PubMed=26954888; DOI=10.1021/acs.orglett.6b00299;
RA Lin T.S., Chiang Y.M., Wang C.C.;
RT "Biosynthetic pathway of the reduced polyketide product citreoviridin in
RT Aspergillus terreus var. aureus revealed by heterologous expression in
RT Aspergillus nidulans.";
RL Org. Lett. 18:1366-1369(2016).
CC -!- FUNCTION: Highly reducing polyketide synthase (HR-PKS); part of the
CC gene cluster that mediates the biosynthesis of citreoviridin, an
CC inhibitor of the of F1-ATPase beta-subunit (PubMed:26954888). The HR-
CC PKS ctvA accepts acetyl-CoA as the starter unit and catalyzes eight
CC iterations of malonyl-CoA extension and four iterations of SAM-
CC dependent methylation at C4, C12, C14, and C16 (PubMed:26954888). The
CC KR and DH domains selectively act on the first six iterations to
CC generate the hexaene chain (PubMed:26954888). In the last three
CC iterations, the KR and DH domains terminate their functions to yield a
CC beta,delta-diketo ester moiety, which then undergoes intramolecular
CC cyclization to yield an alpha-pyrone intermediate (PubMed:26954888).
CC Subsequently, ctvB methylates the alpha-pyrone hydroxyl group to
CC generate citreomontanin (PubMed:26954888). In order to form the
CC tetrahydrofuran ring with the correct stereochemistry, the terminal
CC alkenes of citreomontanin need to undergo isomerization to yield a
CC (17Z)-hexaene, a step that could be catalyzed by ctvC
CC (PubMed:26954888). The (17Z)-hexaene then undergoes bisepoxidation by
CC ctvC to form a (17R,16R,15S,14R)-bisepoxide moiety (PubMed:26954888).
CC Lastly, ctvD acts as a regioselective hydrolase to form the
CC tetrahydrofuran ring with the substituents in the correct absolute
CC configuration, completing the biosynthesis of citreoviridin
CC (PubMed:26954888). {ECO:0000269|PubMed:26954888}.
CC -!- COFACTOR:
CC Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942;
CC Evidence={ECO:0000250|UniProtKB:Q9Y8A5};
CC Note=Binds 1 phosphopantetheine covalently.
CC {ECO:0000250|UniProtKB:Q9Y8A5};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000305|PubMed:26954888}.
CC -!- BIOTECHNOLOGY: Citreoviridin inhibits mitochondrial oxidative
CC phosphorylation by binding to the beta-subunit of F1-ATPase
CC (PubMed:2523213). Ectopic mitochondrial ATP synthase is a factor that
CC mediates HIV-1 transfer between antigen-presenting cells (APCs) and
CC CD4+ target cells, and citreoviridin can completely block antigen-
CC presenting cell (APC)-mediated transfer of HIV-1 at the APC-target
CC cells (PubMed:22753871). Inhibition of Ectopic mitochondrial ATP
CC synthase by citreoviridin can also lead to suppression of cancer growth
CC by activating the unfolded protein response (PubMed:22822083).
CC {ECO:0000269|PubMed:22753871, ECO:0000269|PubMed:22822083,
CC ECO:0000269|PubMed:2523213}.
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DR EMBL; CH476608; EAU29808.1; -; Genomic_DNA.
DR RefSeq; XP_001218239.1; XM_001218238.1.
DR AlphaFoldDB; Q0C9L7; -.
DR SMR; Q0C9L7; -.
DR STRING; 33178.CADATEAP00005395; -.
DR EnsemblFungi; EAU29808; EAU29808; ATEG_09617.
DR GeneID; 4354473; -.
DR VEuPathDB; FungiDB:ATEG_09617; -.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_000022_31_0_1; -.
DR OMA; GGFEGWW; -.
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:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
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:0032259; P:methylation; IEA:UniProtKB-KW.
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; -; 2.
DR Gene3D; 3.40.50.150; -; 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; IPR013217; Methyltransf_12.
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; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 1.
DR Pfam; PF00109; ketoacyl-synt; 2.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF08242; Methyltransf_12; 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; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme; NADP;
KW Oxidoreductase; Phosphopantetheine; Phosphoprotein; Reference proteome;
KW S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..2438
FT /note="Highly reducing polyketide synthase ctvA"
FT /id="PRO_0000437743"
FT DOMAIN 2318..2396
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 7..367
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 475..777
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 866..1153
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255"
FT REGION 1297..1492
FT /note="Methyltransferase (CMet) domain"
FT /evidence="ECO:0000255"
FT REGION 2022..2193
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255"
FT REGION 2402..2438
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2421..2438
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 105
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 569
FT /note="For malonyltransferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 898
FT /note="For beta-hydroxyacyl dehydratase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2356
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2438 AA; 264092 MW; D9C9277C4CC84F42 CRC64;
MAHMEPIAIV GTACRFAGSS SSPSKLWELL QNPRDVASEP PADRFNIDAF YDPEGSNPMA
TNARQGVSCA APQYGSVGVA RNNLANRISY FFDWQGPSMS IDTACSASMV ALYEAVSALT
RHDCNLAAAL GANLMLSPQM FIAASNLQML SPTSRSRMWD AQADGYARGE GVASVLLKRL
SDAVADGDPI ECVIRAVGVN HDGRSMGFTM PSSDAQVQLI RSTYAKAGLD PRSAEDRPQY
VEAHGTGTLA GDPQEASALH QAFFSSSDED TVLHVGSIKT VVGHAEGTAG LAGLIKASQC
IQHGIIPPNL LFNRLNPALE PYARQLRVPV DVVPWPPLSP GVPRRVSVNS FGFGGTNAHV
ILESYEPAEG LIKVDCNQNA VLPFVFSAES DFSLGSVLEQ YSRYLSRNPD VEVHDLAWTL
LERRSALMHR VGFWAPDIAH LKRSIQDELA VRKGGAPSTL ICRPHGKTRK HILGVFTGQG
AQWAQMGLEL ITTSNTARGW LDELQQSLDA LPEPYRPGFS LFQELAADSA TSRLSEALLS
QTLCTAMQVI WVKMLWALNI HFDAVVGHSS GEIAAGFAAG FLTAEDAIRI AYLRGVFCSA
PGSSGEGAML AAGLSMDEAT ALCEDVSSSE GRINVAASNS PESVTVSGDR DAILRAEQLL
KDRGIFVRLL RVSTAYHSHH MQACSQPYQD ALRGCNIQIQ TPMSTTTWYS SVYAGRPMEE
GSVTETLGTG EYWAENLVSP VLFSQALSAA MSATNPSLIV EVGPHPALKG PALQTLSGIT
PAEIPYIGVS VRNNSAIESM ATAIGAFWAH LGPQAINPRG YLALFQPNTK PSVVRGLPLY
PFDHRQEHGY QTRKANGWLY RRNTPHPLLG SLSEDLGEGE LRWNHYLSPR RIRWLDGHRV
QGQIVVPATA YIVMALEAAL ALAVVKEKSL HLIRIDDLII GQAISFQDER DEVETLFHLP
PMLENRDDNT AVGRFRCQMA ASGGHIKTCA EGILTVTWGS PQDDVLPCPV FPSPAGLADV
TDMEEYYASL RTLGYEYTGV FQGIHSLSRK MGIATGQVYN PALTGFLIHP AVLDTGLQGL
LAAAGEGQLT TLHVPTRIDT VSVNPAVCSI DSLSFEAAVT RTGADGIVGD VELYTAANGP
GAVFFEGVHV SSLVPPSAAD DPSVFWVQHW TPLVLDVNRS ESRLSPEWMT VLEGYERRAF
LALKDILQEV TPELRATFDW HRESVVSWIE HIMEETRMGQ RASCKPEWLG QNLENLGHIW
GRPDASIEDR MMYRVYQNLL PFLRGEAKML DALRQDELLT QFYRDEHELR DVNRRLGQLV
GDLAVRFPRM KLLEVGAGTG SATREVLKHV SRAYHSYTFT DISVGFFEDM LETLPEHADR
LIFQKLDVGQ DPLEQGFTEN AYDVIIAANV LHATPALHET LRNVRRLLKP GGYLIALEIT
NIDAIRIGYL MCAFDGWWLG REDGRPWGPV VSASQWDSLL RETGFGGIDS ITDRAADELT
MYSVFAAQAV DDQITRIREP LTPLPPQPPF CRGVIIGGSP NLVTGVRAII HPFFSDVEHV
SAIENLTEGA PAVVLMVADL SDTPCFQSLT ESRLAGLKAL VKMAEKTLWV TMGSEAENPF
LCLSKGFLTS MNYEHPNVFQ YLNIIDPADV QPVVLSEHLL RLAHTTQNND FTLTSCVHST
ELELRLYPGG ILKFPRINAS NVLNRRYAAA RRPVTSPVTD MQESVVVLGQ GPDGKLQLLL
GEERLLGDRT GVTINVRYST NRAVRINGAG YLVLVLGQDK VTKTRLVALA GQSASVISTS
CYWEIPADIS EEQEAAYLYA TATALLAASL IQSNGTTILV HGADAILRHA IAIEAASRVV
QPIFTTTSPS AASSTGFGKS ILVHQNESRR QLAHLLPRYF TAAVNFDSND HRLFDRMMAI
GHQSGVTQEH LLTTLTAVLP RPSASSLPAH PQAVIDALRK AALTAYQLTV QSTAPGHIAT
SIADIQSCSQ ELAVADWTPP CGSVPVHLQP ASQLVRLSAQ KTYLLVGMTG ALGQSITQWL
IARGARNIVL TSRNPSVDPA WILEMQSTTG ARVLVTSMDV TSRASILAVA HALKAGWPPL
GGVVNGAMVL WDQLFVDAPL SVLTGQLAPK VQGSLLLDEI FGQEPGLDFF ILFGSAIATI
GNLGQSAYTA ASNFMVALAA RRRARGLVAS VLQPAQVAGT MGYLRDKDDS FWARMFDMIG
RHLVSEPDLH ELFAHAILSG RGPPSDVGFG PGEGECVIGG LSVQDPAVYP NILWFRTPKV
WPFIHYHHEG TGPSSAATGS VPLVEQLKCA TSLAQVGEVV EAGVAAKLHH RLHLPGEVGS
GNVTGDTRLT ELGVDSLIAV DLRRWFAQEL EVDIPVLQML SGCSVKELAA AATALLQPKF
YPGVVGDSDV GSEKDGSSDS RGDTSSSSYQ VITPEESD
