ASCB_ACREG
ID ASCB_ACREG Reviewed; 1093 AA.
AC A0A455R7E6;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 05-JUN-2019, sequence version 1.
DT 25-MAY-2022, entry version 14.
DE RecName: Full=Non-canonical non-ribosomal peptide synthetase ascB {ECO:0000303|PubMed:30952781};
DE EC=2.3.1.- {ECO:0000269|PubMed:30952781};
DE AltName: Full=Ascofuranone/ascochlorin biosynthesis clusters protein B {ECO:0000303|PubMed:30952781};
GN Name=ascB {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-canonical non-ribosomal peptide synthetase; part of the
CC asc-1 gene cluster that mediates the biosynthesis of both ascochlorin
CC and 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=AH2 + ATP + ilicicolinate B = A + AMP + diphosphate +
CC ilicicolin B; Xref=Rhea:RHEA:63080, ChEBI:CHEBI:13193,
CC ChEBI:CHEBI:17499, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:146152, ChEBI:CHEBI:146153, ChEBI:CHEBI:456215;
CC Evidence={ECO:0000269|PubMed:30952781};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63081;
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: Contains three distinct domains: an adenylation (A) domain that
CC activates the substrate amino acid which is subsequently covalently
CC linked as a thioester (aminoacyl-S-PCP) to the 4'-phosphopantetheine
CC prosthetic group of the second domain, the peptidyl carrier protein
CC (PCP) domain, as well as a thioester reductase (TR) release domain.
CC {ECO:0000250|UniProtKB:S0DXJ2}.
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}.
CC -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR EMBL; LC406756; BBF25314.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A455R7E6; -.
DR SMR; A0A455R7E6; -.
DR UniPathway; UPA00213; -.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0016740; F:transferase activity; IEA:UniProtKB-KW.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.40.50.12780; -; 1.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR042099; ANL_N_sf.
DR InterPro; IPR013120; Far_NAD-bd.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR Pfam; PF00501; AMP-binding; 1.
DR Pfam; PF07993; NAD_binding_4; 1.
DR Pfam; PF00550; PP-binding; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
DR PROSITE; PS00455; AMP_BINDING; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Multifunctional enzyme; NADP; Oxidoreductase; Phosphopantetheine;
KW Phosphoprotein; Transferase.
FT CHAIN 1..1093
FT /note="Non-canonical non-ribosomal peptide synthetase ascB"
FT /id="PRO_0000448980"
FT DOMAIN 591..678
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..27
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 35..392
FT /note="Adenylation (A) domain"
FT /evidence="ECO:0000255"
FT REGION 721..971
FT /note="Thioester reductase (TR) domain"
FT /evidence="ECO:0000255"
FT MOD_RES 627
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 1093 AA; 117895 MW; 46E88B0055BE43FA CRC64;
MTVNGHHTNG VNGANGTNGH ANGSNGINDT KAVKEIVPFV KPQVNFASAQ RLEGCIHSLP
ELVDFNSLNN QHHTFCVQAK SSEPFDTITH GEFKVAVSKC AAWLKENLPI RPSSDDKALT
KMAPVALFME SDIGLVIHEF ALMSIGVPPL VLSPRLSPVA INALLEATGA ASFIVSPRMS
EPLKGALAAL AAKGVSTHIG NPYKAYYQPG ADPKSVAPFE VPQNPEDVIL LLHSSGTTGL
PKPIPTTHRQ LLFAVNCHKF DTEEQAQSLN LSTLPLFHGF GLVAPGLSMS AGKPTLYPAS
DGIPNAKSIV DLINKTNAKS MMTVPFLLDD ITNLPNEEGI KALVHMDFVG TGGAALGAGI
GDRLAKGGVK LLNFYGTTET GPLSLTFAPT DNYDWKYFRL RTDCEYKIDE LEPRDGERRF
RLTVYPYGSE GFEISDQLIR NEQYPETDFA AVGRDDDVIV LATGEKANPL ILETKLTEAP
MVKAAIAFGE NQFNLGVIVE PAEPLTPDTE SAFRESIWPI ITAACDQMDA FSRIPSPDAV
VLVPAGVVIP RTDKGSIARK ETYALFDKQI KGVYEQLLKA AADAVEPLDL DNLEQNLKSL
IQEHLHIQAP ASDWGVEDSL FDIGVDSLQV LQLRRILVTA ASKTEAFKDT DCEKMIPPEF
VYMNPSIREI AAALTKGSDG GDVSLEDAAK EVVELAETYS LKGVSAQEKA PSSSEGAFVM
LTGATGSLGS HVAADLARRD NVAKVVCLVR KDKGTNQPPM PGGNPFDKKI LKARGIQLTD
EQFGKLATLE VDPTADKLGL IPMAYGMMQA KVTHVIHAAW PMNYLIRLRN FQYQFKFLRN
LLEFASQGPA PTKKRFVFIS SIATVARIGL AQPGSISEAP VSPSDSACGI GYADGKLVCE
KIMEKAAQDY GGQLDVTSVR CGQMTGSKKT GVWNSNEQIP MLLKSAQGLG SLPQLSGELS
WIPVDDAAST VSEIAFSDGS MPIVQHLENP IRQSWDAMLQ SFGRELGLPA GKVPFGEWLD
QVAAADGDDE TFPVKKLTFF FKSFFQSVAC GQVVLDTTVS RGQSKTLNAM TAVGDETVKA
YADYWKSTGY LSK
