TERA_ASPTN
ID TERA_ASPTN Reviewed; 2081 AA.
AC Q0D1N9;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 25-MAY-2022, entry version 84.
DE RecName: Full=Non-reducing polyketide synthase terA {ECO:0000303|PubMed:24816227};
DE EC=2.3.1.- {ECO:0000269|PubMed:24816227};
DE AltName: Full=Terrein biosynthesis cluster protein terA {ECO:0000303|PubMed:24816227};
GN Name=terA {ECO:0000303|PubMed:24816227}; ORFNames=ATEG_00145;
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=15558216; DOI=10.1007/s00018-004-4341-3;
RA Park S.H., Kim D.S., Kim W.G., Ryoo I.J., Lee D.H., Huh C.H., Youn S.W.,
RA Yoo I.D., Park K.C.;
RT "Terrein: a new melanogenesis inhibitor and its mechanism.";
RL Cell. Mol. Life Sci. 61:2878-2885(2004).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=15603975; DOI=10.1016/j.bmcl.2004.10.057;
RA Lee S., Kim W.G., Kim E., Ryoo I.J., Lee H.K., Kim J.N., Jung S.H.,
RA Yoo I.D.;
RT "Synthesis and melanin biosynthesis inhibitory activity of (+/-)-terrein
RT produced by Penicillium sp. 20135.";
RL Bioorg. Med. Chem. Lett. 15:471-473(2005).
RN [4]
RP BIOTECHNOLOGY.
RX PubMed=18776656; DOI=10.1038/ja.2008.60;
RA Arakawa M., Someno T., Kawada M., Ikeda D.;
RT "A new terrein glucoside, a novel inhibitor of angiogenin secretion in
RT tumor angiogenesis.";
RL J. Antibiot. 61:442-448(2008).
RN [5]
RP BIOTECHNOLOGY.
RX PubMed=18358890; DOI=10.1016/j.joen.2008.01.015;
RA Lee J.C., Yu M.K., Lee R., Lee Y.H., Jeon J.G., Lee M.H., Jhee E.C.,
RA Yoo I.D., Yi H.K.;
RT "Terrein reduces pulpal inflammation in human dental pulp cells.";
RL J. Endod. 34:433-437(2008).
RN [6]
RP BIOTECHNOLOGY.
RX PubMed=19493001; DOI=10.1111/j.1600-0625.2009.00847.x;
RA Park S.H., Kim D.S., Lee H.K., Kwon S.B., Lee S., Ryoo I.J., Kim W.G.,
RA Yoo I.D., Park K.C.;
RT "Long-term suppression of tyrosinase by terrein via tyrosinase degradation
RT and its decreased expression.";
RL Exp. Dermatol. 18:562-566(2009).
RN [7]
RP BIOTECHNOLOGY.
RX PubMed=21104936; DOI=10.1002/cbf.1708;
RA Lee Y.H., Lee N.H., Bhattarai G., Oh Y.T., Yu M.K., Yoo I.D., Jhee E.C.,
RA Yi H.K.;
RT "Enhancement of osteoblast biocompatibility on titanium surface with
RT Terrein treatment.";
RL Cell Biochem. Funct. 28:678-685(2010).
RN [8]
RP BIOTECHNOLOGY.
RX PubMed=23417151; DOI=10.3892/or.2013.2288;
RA Porameesanaporn Y., Uthaisang-Tanechpongtamb W., Jarintanan F.,
RA Jongrungruangchok S., Thanomsub Wongsatayanon B.;
RT "Terrein induces apoptosis in HeLa human cervical carcinoma cells through
RT p53 and ERK regulation.";
RL Oncol. Rep. 29:1600-1608(2013).
RN [9]
RP FUNCTION, DISRUPTION PHENOTYPE, AND DOMAIN.
RX PubMed=24816227; DOI=10.1016/j.chembiol.2014.03.010;
RA Zaehle C., Gressler M., Shelest E., Geib E., Hertweck C., Brock M.;
RT "Terrein biosynthesis in Aspergillus terreus and its impact on
RT phytotoxicity.";
RL Chem. Biol. 21:719-731(2014).
RN [10]
RP BIOTECHNOLOGY.
RX PubMed=25318762; DOI=10.3892/ijmm.2014.1964;
RA Chen Y.F., Wang S.Y., Shen H., Yao X.F., Zhang F.L., Lai D.;
RT "The marine-derived fungal metabolite, terrein, inhibits cell proliferation
RT and induces cell cycle arrest in human ovarian cancer cells.";
RL Int. J. Mol. Med. 34:1591-1598(2014).
RN [11]
RP BIOTECHNOLOGY.
RX PubMed=26416516; DOI=10.1002/cbf.3145;
RA Lee Y.H., Lee S.J., Jung J.E., Kim J.S., Lee N.H., Yi H.K.;
RT "Terrein reduces age-related inflammation induced by oxidative stress
RT through Nrf2/ERK1/2/HO-1 signalling in aged HDF cells.";
RL Cell Biochem. Funct. 33:479-486(2015).
RN [12]
RP FUNCTION, AND INDUCTION.
RX PubMed=26173180; DOI=10.7554/elife.07861;
RA Gressler M., Meyer F., Heine D., Hortschansky P., Hertweck C., Brock M.;
RT "Phytotoxin production in Aspergillus terreus is regulated by independent
RT environmental signals.";
RL Elife 4:0-0(2015).
RN [13]
RP INDUCTION.
RX PubMed=25852654; DOI=10.3389/fmicb.2015.00184;
RA Gressler M., Hortschansky P., Geib E., Brock M.;
RT "A new high-performance heterologous fungal expression system based on
RT regulatory elements from the Aspergillus terreus terrein gene cluster.";
RL Front. Microbiol. 6:184-184(2015).
RN [14]
RP BIOTECHNOLOGY.
RX PubMed=25592371; DOI=10.3892/or.2015.3719;
RA Zhang F., Mijiti M., Ding W., Song J., Yin Y., Sun W., Li Z.;
RT "(+)-Terrein inhibits human hepatoma Bel-7402 proliferation through cell
RT cycle arrest.";
RL Oncol. Rep. 33:1191-1200(2015).
RN [15]
RP BIOTECHNOLOGY.
RX PubMed=27127118;
RA Shibata A., Ibaragi S., Mandai H., Tsumura T., Kishimoto K., Okui T.,
RA Hassan N.M., Shimo T., Omori K., Hu G.F., Takashiba S., Suga S., Sasaki A.;
RT "Synthetic terrein inhibits progression of head and neck cancer by
RT suppressing angiogenin production.";
RL Anticancer Res. 36:2161-2168(2016).
CC -!- FUNCTION: Non-reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of terrein, a fungal metabolite with
CC ecological, antimicrobial, antiproliferative, and antioxidative
CC activities (PubMed:24816227, PubMed:26173180). The first step in the
CC pathway is performed by the polyketide synthase terA that produces 4-
CC hydroxy-6-methylpyranon (4-HMP), orsellinic acid (OA), and 2,3-dehydro-
CC 6-hydroxymellein (2,3-dehydro-6-HM) by condensing acetyl-CoA with two,
CC three, or four malonyl-CoA units, respectively (PubMed:24816227). 4-HMP
CC and OA are not pathway intermediates, but are rather shunt or side
CC products (PubMed:24816227). 2,3-dehydro-6-HM is further converted to 6-
CC hydroxymellein (6-HM) by the 6-hydroxymellein synthase terB
CC (PubMed:24816227). The monooxygenases terC and terD, the multicopper
CC oxidase terE and the Kelch-like protein terF are then involved in the
CC transformation of 6-HM to terrein (PubMed:24816227). Even if they are
CC co-regulated with the other terrein cluster genes, terH and terI seem
CC to be dispensable for terrein production; whereas one or both of the 2
CC transporters terG and terJ are probably required for efficient
CC secretion of metabolites (PubMed:24816227).
CC {ECO:0000269|PubMed:24816227, ECO:0000269|PubMed:26173180}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + 2 H(+) + 3 malonyl-CoA = 3 CO2 + 4 CoA +
CC orsellinate; Xref=Rhea:RHEA:62972, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16162, ChEBI:CHEBI:16526, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57288, ChEBI:CHEBI:57384;
CC Evidence={ECO:0000269|PubMed:24816227};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62973;
CC Evidence={ECO:0000269|PubMed:24816227};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:24816227, ECO:0000269|PubMed:26173180}.
CC -!- INDUCTION: Expression is induced by methionine (PubMed:26173180).
CC Nitrogen starvation induces expression of terA and promotes terrein
CC production during fruit infection, via regulation by areA and atfA
CC (PubMed:26173180). Iron limitation acts as a third independent signal
CC for terrein cluster induction via the iron response regulator hapX
CC (PubMed:26173180). Finally, expression is under the control of the
CC terrein cluster-specific transcription factor terR (PubMed:25852654).
CC {ECO:0000269|PubMed:25852654, ECO:0000269|PubMed:26173180}.
CC -!- DOMAIN: Multidomain protein; including a starter unit:ACP transacylase
CC (SAT) that selects the starter unit; a ketosynthase (KS) that catalyzes
CC repeated decarboxylative condensation to elongate the polyketide
CC backbone; a malonyl-CoA:ACP transacylase (MAT) that selects and
CC transfers the extender unit malonyl-CoA; a product template (PT) domain
CC that controls the immediate cyclization regioselectivity of the
CC reactive polyketide backbone; and an acyl-carrier protein (ACP) that
CC serves as the tether of the growing and completed polyketide via its
CC phosphopantetheinyl arm (By similarity).
CC {ECO:0000250|UniProtKB:Q5B0D0}.
CC -!- DOMAIN: The release of the polyketide chain from the non-reducing
CC polyketide synthase is mediated by the thioesterase (TE) domain
CC localized at the C-ter of the protein (By similarity).
CC {ECO:0000250|UniProtKB:Q5ATJ7}.
CC -!- DISRUPTION PHENOTYPE: Impairs the production of terrein
CC (PubMed:24816227). {ECO:0000269|PubMed:24816227}.
CC -!- BIOTECHNOLOGY: Terrein shows anticancer activity on various tumors
CC including cervical carcinoma, ovarian cancer, and head and neck cancer
CC (PubMed:23417151, PubMed:25318762, PubMed:27127118, PubMed:25592371).
CC The secondary metabolite acts as angiogenesis inhibitors through the
CC inhibition of angiogenin secretion (PubMed:18776656, PubMed:27127118).
CC Terrein has also anti-inflammatory activity (PubMed:18358890). It shows
CC an alleviative function of age-related inflammation characterized as an
CC anti-oxidant and might therefore be a useful nutraceutical compound for
CC anti-aging (PubMed:26416516). Terrein may enhance osseointegration by
CC decreasing the level of ROS and has a potentially synergistic effect on
CC osteoblast differentiation (PubMed:21104936). Terrein has also been
CC shown to act as a melanogenesis inhibitor (PubMed:15558216,
CC PubMed:15603975, PubMed:19493001). {ECO:0000269|PubMed:15558216,
CC ECO:0000269|PubMed:15603975, ECO:0000269|PubMed:18358890,
CC ECO:0000269|PubMed:18776656, ECO:0000269|PubMed:19493001,
CC ECO:0000269|PubMed:21104936, ECO:0000269|PubMed:23417151,
CC ECO:0000269|PubMed:25318762, ECO:0000269|PubMed:25592371,
CC ECO:0000269|PubMed:26416516, ECO:0000269|PubMed:27127118}.
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DR EMBL; CH476594; EAU38791.1; -; Genomic_DNA.
DR RefSeq; XP_001210231.1; XM_001210231.1.
DR AlphaFoldDB; Q0D1N9; -.
DR SMR; Q0D1N9; -.
DR STRING; 341663.Q0D1N9; -.
DR EnsemblFungi; EAU38791; EAU38791; ATEG_00145.
DR GeneID; 4354902; -.
DR VEuPathDB; FungiDB:ATEG_00145; -.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_000022_6_0_1; -.
DR OMA; YWLDYHN; -.
DR OrthoDB; 68112at2759; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR Gene3D; 1.10.1200.10; -; 2.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
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; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR030918; PT_fungal_PKS.
DR InterPro; IPR032088; SAT.
DR InterPro; IPR001031; Thioesterase.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF00550; PP-binding; 2.
DR Pfam; PF14765; PS-DH; 1.
DR Pfam; PF16073; SAT; 1.
DR Pfam; PF00975; Thioesterase; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 2.
DR SUPFAM; SSF47336; SSF47336; 2.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR TIGRFAMs; TIGR04532; PT_fungal_PKS; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 2.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Multifunctional enzyme; Phosphopantetheine; Phosphoprotein;
KW Reference proteome; Repeat; Transferase.
FT CHAIN 1..2081
FT /note="Non-reducing polyketide synthase terA"
FT /id="PRO_0000437590"
FT DOMAIN 1580..1658
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 1699..1776
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 85..190
FT /note="N-terminal acylcarrier protein transacylase (SAT)
FT domain (SAT)"
FT /evidence="ECO:0000255"
FT REGION 319..752
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 849..1147
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1259..1536
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1549..1578
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1659..1700
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1783..1809
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1840..2070
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000255"
FT COMPBIAS 1558..1576
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1666..1680
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1783..1806
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 488
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 1617
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1736
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2081 AA; 227018 MW; AF925B791918A6D7 CRC64;
MAGSLKLYVF GDEAGDFAGP LQKLCEQRKE VLFLHFLDEL NKVLRDEVRR QPRDVRVQIP
EFTDVLDLVR HYRDSGSRNQ ILETTLTLAF RIGVKVHGAA QRLSKHGDAA VAQSWTTLII
GAQKEASIAA LAEFNESKGI PHANQAYISA NSKDVVSISG PPETVTSLLQ HSEYLQKFRT
ISLDIFAPFH APHLYNDDDV AEVLQPFSGK NEKRKLFIPV ISGLGTLYSP DMDVETLMAD
VVRDILIRPL LFENVMKTVT ETTTASSHQN CQIFSVGPSQ AINSLASTLR ADTSLNVTTE
GPIHTGSPDY EPLNGAQKIA IVGMAGRFPN SDDLESFWST LQQGLDLHRR VPPDRFDIDA
HYDPTGKKLN STHTPYGCFI EKPGLFDPRF FNMSQREAYQ TDPMGRLALV TAYEALEMSG
FVPNRTPSSM LDRIGTFYGQ TSDDWRTLNA AEKIDMYYIP GTIRAFATGR INYHFKFKGP
SYNVDTACSS SFAAIQLACT SLLAKECDTA LAGGLNVMTT PDLFAGLSRA HFLSKTGSCK
TFDDGADGFC RGDGVGTVVL KRLEDAEADN DPILAVVLGT ATNHSSEAVS ITRPHGPAQE
ALYRKILKHT GVDPVDVSYV EMHGTGTQAG DGTEMKSITN VFAPRDKGRR QPDQLIHLGA
LKANIGHGEA SAGVASLIKT VIMMQKNAIP PHVGIKTTMN KTFPHDLNER GVRIAFKETP
WVRPDGGKRR AYLNNFGASG GNTGLLLEDR PAPVSTRASD PRTSFVVSLS AKSAYSLDQN
INRLATYLEG NPDTSLPALS YTTTARRVHY PHRVSYAVRS IPETIKSLRS AQSKAIKPDP
ASSGKIAFLF TGQGSHYTAL GKQLFEDCQT FRNDLVEFNR IGQKQGFPTF LPLIDGSEDV
ASLSPVALQL GQSCIQIALA RLWKSWGITP SSVLGHSLGE YAALNVAGVL SASDTIYLVG
RRAQLLEELC TPGSHKMLAI AASVSSVKEI LGDKDIEVAC INGPNETVIS GLAEQMESYS
KTLKATDVKC SLLSTAYAFH SAQIQVIVEQ YRKVASSVHF GPPNVPVISP LLGDVVTDGN
VFGPDYLCRQ AREAVNFMGA LKAAESKGVV DNNVIWLEIG PAPVCSAFVK SSLGSKALTL
PSLRKQEDVW KTLSGTLSNL YSKGLTIEWE EVHREYEASH TVLALPSYCF EEKNYWLDYH
NNWCLTKGQK LVESAAPKRR GRHLLTPSVQ KVIKEDFGQT KITVVAESDL SDPDLNHAVT
GHLVNGSALC PAGVYAESAL TLAGYIYHRV KKTEDIGMDV RALEIVKPLI AKGRDQKEKQ
VFRITATADQ PLKLVKISYN SVSADGSLGV LHATCHVEYG DIKTWRAEWS RLAYLVRSRI
DVMNDGVKGR QYQKLDRKAA YEGFSGFVEY DKQYHGMKEV IMDQKNLEAT SILEFQPSND
YGEFEIDPRF IDNISHLSGF ILNGSGATDT RKQVFVSHGW DHLQIAEPLS SSKSYSNYVK
MHEIEKATMA GDVYIFDGEE MVALVGGVKF KAIPRAVINQ LLPPVKGSKA LEKSAPRQNP
KATATKTTQK PQAPVPVPQK QNKAIIDDFL ALLCEELGVE LSELQDDTAF ADIGLDSLMS
LSITGRMREE LDLEAIPSSV FTDYPTVGQV KELILKLAGS SSDENTTDTP DEEEDPATAD
ADNTEMIREN PLESVSPNVS SSEAMDGFLA IVCEEVGVDL EELLEVQNFA GAGVDSLMSL
TITGRAREDL DMDIPSSFFV DYPTVDQARL AIASLMGGGD QTGATTPYSG SDDAKSSTSS
LTAGSVLTPD DDMDAQDISQ LTRPATSIVL QGSLKTASKT LFLLPDGSGS ATSYAALPRV
SPDTCVVALN CPFMKTPSEY TTGIEGVAAL YLSEIRRRQP EGPYVLGGWS AGGILAYAVA
CQLIEMGEEI EDLFLIDSPC PINLQPLPSE LLHFIDSLGL LGAQGSAPKW LIPHFEASIK
NLTAFVPHAM DPDEAPRTHI IWARDGLVSE SDEKQFPRSD AEAKSVKFLL DGRQNLGTYG
WEKLIGSENI SVDFIEGNHF TMMREPKVNQ LPSILDRLIG A
