ASCC_ACREG
ID ASCC_ACREG Reviewed; 2115 AA.
AC A0A455R5P9;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 05-JUN-2019, sequence version 1.
DT 03-AUG-2022, entry version 15.
DE RecName: Full=Non-reducing polyketide synthase ascC {ECO:0000303|PubMed:30952781};
DE EC=2.3.1.- {ECO:0000269|PubMed:30952781};
DE AltName: Full=Ascofuranone/ascochlorin biosynthesis clusters protein C {ECO:0000303|PubMed:30952781};
GN Name=ascC {ECO:0000303|PubMed:30952781};
OS Acremonium egyptiacum (Oospora egyptiaca).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Hypocreales incertae sedis; Acremonium.
OX NCBI_TaxID=749675;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY, INDUCTION,
RP AND PATHWAY.
RC STRAIN=F-1392;
RX PubMed=30952781; DOI=10.1073/pnas.1819254116;
RA Araki Y., Awakawa T., Matsuzaki M., Cho R., Matsuda Y., Hoshino S.,
RA Shinohara Y., Yamamoto M., Kido Y., Inaoka D.K., Nagamune K., Ito K.,
RA Abe I., Kita K.;
RT "Complete biosynthetic pathways of ascofuranone and ascochlorin in
RT Acremonium egyptiacum.";
RL Proc. Natl. Acad. Sci. U.S.A. 116:8269-8274(2019).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=12084465; DOI=10.1016/s0925-4439(02)00086-8;
RA Nihei C., Fukai Y., Kita K.;
RT "Trypanosome alternative oxidase as a target of chemotherapy.";
RL Biochim. Biophys. Acta 1587:234-239(2002).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=12798927; DOI=10.1016/s1383-5769(03)00012-6;
RA Yabu Y., Yoshida A., Suzuki T., Nihei C., Kawai K., Minagawa N.,
RA Hosokawa T., Nagai K., Kita K., Ohta N.;
RT "The efficacy of ascofuranone in a consecutive treatment on Trypanosoma
RT brucei brucei in mice.";
RL Parasitol. Int. 52:155-164(2003).
RN [4]
RP BIOTECHNOLOGY.
RX PubMed=20688188; DOI=10.1016/j.parint.2010.07.006;
RA Nakamura K., Fujioka S., Fukumoto S., Inoue N., Sakamoto K., Hirata H.,
RA Kido Y., Yabu Y., Suzuki T., Watanabe Y., Saimoto H., Akiyama H., Kita K.;
RT "Trypanosome alternative oxidase, a potential therapeutic target for
RT sleeping sickness, is conserved among Trypanosoma brucei subspecies.";
RL Parasitol. Int. 59:560-564(2010).
CC -!- FUNCTION: Non-reducing polyketide synthase; part of the asc-1 gene
CC cluster that mediates the biosynthesis of both ascochlorin and
CC ascofuranone, a strong inhibitor of cyanide-insensitive alternative
CC oxidases and a promising drug candidate against African trypanosomiasis
CC (PubMed:30952781). The first step in the pathway is performed by the
CC non-reducing polyketide synthase ascC that produces orsellinic acid by
CC condensing acetyl-CoA with 3 malonyl-CoA units (PubMed:30952781).
CC Orsellinic acid is then prenylated by the prenyltransferase ascA to
CC yield ilicicolinic acid B (PubMed:30952781). Ilicicolinic acid B is
CC further reduced to ilicicolin B by the reductase ascB
CC (PubMed:30952781). The halogenase ascD then chlorinates ilicicolin B to
CC produce ilicicolin A which is converted to ilicicolin A epoxide by the
CC cytochrome P450 monooxygenase ascE that catalyzes stereoselective
CC epoxidation of the terminal double bond of the prenyl group
CC (PubMed:30952781). Ilicicolin A epoxide is the last common precursor
CC for the biosynthesis of ascofuranone and ascochlorin (PubMed:30952781).
CC The terpene cyclase ascF produces a monocyclic terpene, and the
CC cyclization reaction is proposed to be initiated by protonation of the
CC terminal epoxide of ilicicolin A epoxide to generate a monocyclic
CC tertiarycation, which is followed by a series of hydride and methyl
CC shifts with abstraction of proton, leading to the formation of the
CC (14S,15R,19R)-trimethylcyclohexanone ring structure of ilicicolin C,
CC which is finally reduced to ascochlorin by the dehydrogenase ascG
CC (PubMed:30952781). On the other hand, ilicicolin A epoxide is
CC hydroxylated by the cytochrome P450 monooxygenase ascH, and the
CC resultant product is cyclized by the terpene cyclase ascI to
CC ascofuranol via protonation-initiated epoxide ring opening, which
CC facilitates the 6-endo-tet cyclization to form the tetrahy-drofuran
CC ring (PubMed:30952781). Finally, ascofuranol is oxidized into
CC ascofuranone by ascJ (PubMed:30952781). {ECO:0000269|PubMed:30952781}.
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:30952781};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62973;
CC Evidence={ECO:0000269|PubMed:30952781};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:30952781}.
CC -!- INDUCTION: Expression is induced on AF medium.
CC {ECO:0000269|PubMed:30952781}.
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. {ECO:0000305|PubMed:30952781}.
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. {ECO:0000250|UniProtKB:Q5ATJ7}.
CC -!- BIOTECHNOLOGY: Ascofuranone is a specific inhibitor of trypanosome
CC alternative oxidase (TAO), and quickly kills African trypanosomes in
CC vitro and cures infected mice. As an essential factor for trypanosome
CC survival, TAO is a promising drug target due to the absence of
CC alternative oxidases in the mammalian host.
CC {ECO:0000269|PubMed:12084465, ECO:0000269|PubMed:12798927,
CC ECO:0000269|PubMed:20688188}.
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DR EMBL; LC406756; BBF25315.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A455R5P9; -.
DR SMR; A0A455R5P9; -.
DR UniPathway; UPA00213; -.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0016787; F:hydrolase activity; 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 GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 2.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR013094; AB_hydrolase_3.
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; IPR032821; PKS_assoc.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR032088; SAT.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF07859; Abhydrolase_3; 1.
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; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR Pfam; PF16073; SAT; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
DR SUPFAM; SSF53901; SSF53901; 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 Multifunctional enzyme; Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2115
FT /note="Non-reducing polyketide synthase ascC"
FT /id="PRO_0000448992"
FT DOMAIN 1640..1724
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..21
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 14..260
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255"
FT REGION 384..808
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 908..1210
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1285..1580
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1587..1624
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1734..1767
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1777..2107
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT COMPBIAS 1588..1603
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1734..1752
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 553
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 995
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 1897
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT ACT_SITE 2045
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT MOD_RES 1674
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2115 AA; 229487 MW; 226A73E057D25E70 CRC64;
MTLIQTKHSA SAAVFSPQST APKPTHLAHI RARLLEDDLL KPVKEAVVSL PKTWRALVSK
QPELGKNRKA SDLIEAFPSW IEDGKTEVLE TDMSGLITLP LLAVIHIVQY LDYIQRLGIS
HSEFLESVES GGVQGYCIGL LSAIVVSSAE DEEALIQHAA HGIRLSLAIG AFGDIGSSSD
EVVSNTLQVR LRNAGSEEDL VARFPGSYIS TITDAKTMSI IAPPHLIDAL KEHAETEGLR
PRAMHIRSNL HNSRNTELAQ QCSSLFEDCP FASPDTLQVA VRSNKTGCYL EQDATSLVEE
AVSTVLASRC DWSLVMQGLA DDLNQSGSKH HSILLFGMGD SVPGAPFREH SLDISKIDVL
SLVETPLSAT PPASSIDDFP PDSIAIVGSA CRLPGANSLD ELWDLIAAGR SRLEKVRTDR
VNIKESYRAS QDPEWTKKRE FYGNFIDDVD AFDHAFFNIS PREAKYMDPQ QRLLLMAAFE
AMDSSGYLRS HQRNDGDAVG CFLGASYTEY TENTSAYSPS AFTATSTIRA FLSGKISYHF
GWTGPSEVID TACSASIVAV HRAVQAINAG ECPVALAGGV NIITGVNNYF DLGKASFLSQ
TGQCKPFDDS ADGYCRADGV GLVVLKPLSK AVADGDYIQG VIPAIATNQG GIGAPGITVP
DGIAQKALYR GILEKAGLKG EDISYVEAHG TGTQVGDPIE IGSIREVFGG AHRASPLHLG
SLKANIGHSE TAAGVASLLK VLSMVRNRGV PPLQGFKRLN HKIPALELDK MAIPTKLLPW
DSDHRIACIN SYGASGSNSA LICSEWLEEP SKLPDVTGQP LQEYPILLSA ASNESLLRYA
RHLADYITKS SADLTLGNLS YTLSQRRKHH RIRWSTTAKD LIGLIEQLRE CTPADFVQAP
QKSKKIVLTF SGQSRTTIGV SDSARLENPR FEHYIQQCNN ILMSYGCPDL LPYLSQTDPI
SDPTIIQCGT VTVQYACAQC WIDGGLDVAG IVGHSLGELT ALAISGALSL EDTLKVVYTR
AEAIKAKWGP ESGSMLAIHA NQDTVKSIVE IIETMITNPD EALEIACYNS ITSHIVVGKE
SSIEMAEKVI QQDARYHGLR YQRLNTSHGF HSRFTEPLLQ DLIHVERSVE FRKPSIPLET
STQTPVDFAK KRHSKYLSNH AREPVFFVDA ARRLESRLGE CVWLEAGWNT PIVAMTKRAV
ANPSAHTFQA VTSPAAVAME LWREGIATTY WSFFTPKESG LKHIWLPPYS FDRPKYWLEH
VDRAVQERDA AANGSASPPP KKVQQLVTLK KTEGTKSQFR LHTTTERYKR IVSGHAVRSK
PLCPASMYME SAIMGTEQLG ASLVGKTITF ENVSFTKPLG CDENLEVYVN LEQNTAAGEE
AWHYAVQSGG KGSHSEGDFF ATSGEMADIQ LYEMLIADKI EALRNDVDAE RLRTATAYSI
FSRVVEYSDL LRGISSITMG TRQALAQIKV PKSTFEAQES TVSDFYDAIT LDTFIQVLGL
LINSDNDSSA DDEIYVASSI GKMVVSPTEF KKHATWNVYA TYSASDSKAS SGAVFVFSED
RKLVSFATKI QFMRIKAAKL EKVLESANPG SKTKSTNGNA LPSVPRSVPA GPTSAPQQVA
PTTMPSAPAP VPVVAAGASP SKIADLKSLI SVYTGVPVDE MQDNQNFGDM GLDSLASMEL
ADEMESKLGL KVETEDLLLG SVGSLIKLLA PSSGPTAALT EGLVESYDTC SESSDSIRNS
TGFHTTIPAT PAELHSNPPD SLDGSTVWTK PKHSLSARFK LDTMVYKEAE GIDIPADVYV
PQEPPQQPMP VALMIHGGGH LTLSRRAVRP TQTKYLLSQG ILPVSIDYRL CPQVNVIDGP
VADTRDACEW AQRDLPKIMA SRNIEVDASK LIVIGWSTGG TLAMTTAWTL PSAGLPPPVA
ILSFYCPVNY DPEAPIQMGE EHEKRNMSLS EIRRLLGPQP ATSHASHTTD TTKLGWVQAN
DPRSELVLAL IKEPRGMSLL FNGLPPTGEE LPVPDAERAA ALSPLVQVRK GNYDVPTYLI
FGDEDEIAPF GKAVEFAQAL KDAGVKSGFL PIKGGKHIFD LGISPGSKAW DESIGPGYDF
LLGELENAHR RCRDV
