ASCG_ACREG
ID ASCG_ACREG Reviewed; 534 AA.
AC A0A455R4X0;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 05-JUN-2019, sequence version 1.
DT 03-AUG-2022, entry version 11.
DE RecName: Full=Cytochrome P450 monooxygenase ascG {ECO:0000303|PubMed:30952781};
DE EC=1.14.14.- {ECO:0000269|PubMed:30952781};
DE AltName: Full=Ascofuranone/ascochlorin biosynthesis clusters protein G {ECO:0000303|PubMed:30952781};
GN Name=ascG {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: Cytochrome P450 monooxygenase; part of the asc-1 gene cluster
CC that mediates the biosynthesis of both ascochlorin and ascofuranone, a
CC strong inhibitor of cyanide-insensitive alternative oxidases and a
CC 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=H(+) + ilicicolin C + NADPH + O2 = ascochlorin + 2 H2O +
CC NADP(+); Xref=Rhea:RHEA:63100, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:146156, ChEBI:CHEBI:146157;
CC Evidence={ECO:0000269|PubMed:30952781};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63101;
CC Evidence={ECO:0000269|PubMed:30952781};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:30952781}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- INDUCTION: Expression is induced on AF medium.
CC {ECO:0000269|PubMed:30952781}.
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 cytochrome P450 family. {ECO:0000305}.
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DR EMBL; LC406756; BBF25319.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A455R4X0; -.
DR SMR; A0A455R4X0; -.
DR UniPathway; UPA00213; -.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002403; Cyt_P450_E_grp-IV.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00465; EP450IV.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Transmembrane; Transmembrane helix.
FT CHAIN 1..534
FT /note="Cytochrome P450 monooxygenase ascG"
FT /id="PRO_0000449000"
FT TRANSMEM 13..33
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 469
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P04798"
FT CARBOHYD 466
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 534 AA; 60915 MW; 45641E5E804C46B4 CRC64;
MGSLLFDSPV GRFVASFPAL SAAAGLIVAI SFIYIRFIKT PKLDLPVVGN PGDKWDAQKH
IVAGARKYPD TPYILPMDPP IVVLPIKIQD EVRNLPENVV SFTKEHQRNF FAQYTGIGDH
RPEMITAIRQ DLTRHIVSTI PGLQEEVRYG FDKEFGDCKD WTPFPLYMKV LRIVALTSGR
VFVGRPLSRE EEWLQRTISY TMDCVKARNA IREYPWWKRR WVTSSLPEIA KLTEHRTRGG
VLLKPIMDAQ LAKDSKREKI INEETGDEEG NFIEWLLKHT PGDLKMDPEN LALNQMVLAF
ASVHTSSMSV THAILELVTR PEYFAPLREE LEEVRRADGH TVDDDGYIRL KKESINKLRK
LDSFMKESQR FNPPISTSGT RICTADLKLS TGHTLPKGTR ICFPSYDVHH NPKTTTYSPE
YNPPGYTPPD QFDGLRFFKL REMPGKESRH QFATANHESL VFGFGNHTCP GRFFAANQIK
IILAELLMNW DVRLKGDVEQ KGGPEKRPQN MVVDLVITPN PMAMVEMKRR SRAV
