CTVC_ASPTN
ID CTVC_ASPTN Reviewed; 473 AA.
AC Q0C9L4;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 71.
DE RecName: Full=FAD-dependent monooxygenase ctvC {ECO:0000303|PubMed:26954888};
DE EC=1.-.-.- {ECO:0000269|PubMed:26954888};
DE AltName: Full=Citreoviridin biosynthesis protein C {ECO:0000305};
GN Name=ctvC {ECO:0000303|PubMed:26954888}; ORFNames=ATEG_09620;
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: FAD-dependent monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of citreoviridin, an inhibitor of the of F1-
CC ATPase beta-subunit (PubMed:26954888). The HR-PKS ctvA accepts acetyl-
CC CoA as the starter unit and catalyzes eight iterations of malonyl-CoA
CC extension and four iterations of SAM-dependent methylation at C4, C12,
CC C14, and C16 (PubMed:26954888). The KR and DH domains selectively act
CC on the first six iterations to generate the hexaene chain
CC (PubMed:26954888). In the last three iterations, the KR and DH domains
CC terminate their functions to yield a beta,delta-diketo ester moiety,
CC which then undergoes intramolecular cyclization to yield an alpha-
CC pyrone intermediate (PubMed:26954888). Subsequently, ctvB methylates
CC the alpha-pyrone hydroxyl group to generate citreomontanin
CC (PubMed:26954888). In order to form the tetrahydrofuran ring with the
CC correct stereochemistry, the terminal alkenes of citreomontanin need to
CC undergo isomerization to yield a (17Z)-hexaene, a step that could be
CC catalyzed by ctvC (PubMed:26954888). The (17Z)-hexaene then undergoes
CC bisepoxidation by ctvC to form a (17R,16R,15S,14R)-bisepoxide moiety
CC (PubMed:26954888). Lastly, ctvD acts as a regioselective hydrolase to
CC form the tetrahydrofuran ring with the substituents in the correct
CC absolute configuration, completing the biosynthesis of citreoviridin
CC (PubMed:26954888). {ECO:0000269|PubMed:26954888}.
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000305};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000305|PubMed:26954888}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-pass membrane
CC protein {ECO:0000255}.
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}.
CC -!- SIMILARITY: Belongs to the paxM FAD-dependent monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; CH476608; EAU29811.1; -; Genomic_DNA.
DR RefSeq; XP_001218242.1; XM_001218241.1.
DR AlphaFoldDB; Q0C9L4; -.
DR SMR; Q0C9L4; -.
DR STRING; 33178.CADATEAP00005399; -.
DR EnsemblFungi; EAU29811; EAU29811; ATEG_09620.
DR GeneID; 4354538; -.
DR VEuPathDB; FungiDB:ATEG_09620; -.
DR eggNOG; KOG2614; Eukaryota.
DR HOGENOM; CLU_009665_12_2_1; -.
DR OMA; ERSGKHW; -.
DR OrthoDB; 462247at2759; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR Gene3D; 3.50.50.60; -; 1.
DR InterPro; IPR002938; FAD-bd.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR Pfam; PF01494; FAD_binding_3; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW FAD; Flavoprotein; Glycoprotein; Membrane; Oxidoreductase;
KW Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..473
FT /note="FAD-dependent monooxygenase ctvC"
FT /id="PRO_0000437741"
FT TRANSMEM 218..238
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 451..471
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 38..39
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 133
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 310
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 320..324
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT CARBOHYD 358
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 473 AA; 53717 MW; AEBF90C4C73B7162 CRC64;
MEGKGPSFKV IIVGASVTGL TLAHCLHRAG IDYVVLEKHH EVHPPIGAAV AILPNGGRIM
EQLGIFRHIE DRCQPFQRVH LCFQDGFYYD SLSPSVVLKR FGLKFAALER TQLLEILYTH
LPDKSRVLTS KGVVRITPHG NKMSVTTADG DEFQGDLVVG ADGVHSVTRR EMWRIANIEQ
PGLIPFKEQA SMSVEFSCIF GMSNPIPGRK HWQHIIRIGP GFTFLIFPAA GDSLFWVLIE
KLPHKYIYPD VPRFSQEDAV TRCEAAASQP VWQEVRFRDI WAQRRGFRMV ALEENLFRTW
HHGRIICIGD SISKMTPNIG QGANTAIEAA AGLANVIYAI TQNHHQPSDD TIHRALANFS
ERHRKRLDAI HLESRWITRL EACQGWVVTA FTRYVAPHCG DLFALGVVRN SYNGEVLQFL
PLTERSGKHW PKLEWWNTWG LSKWQEFGER LVYCFGVVIL LWISWAVFNV NQL
