ASCH_ACREG
ID ASCH_ACREG Reviewed; 512 AA.
AC A0A455R624;
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 ascH {ECO:0000303|PubMed:30952781};
DE EC=1.14.14.- {ECO:0000269|PubMed:30952781};
DE AltName: Full=Ascofuranone/ascochlorin biosynthesis clusters protein H {ECO:0000303|PubMed:30952781};
GN Name=ascH {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, DISRUPTION
RP PHENOTYPE, INDUCTION, 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-2 gene cluster
CC that mediates the biosynthesis of ascofuranone, a strong inhibitor of
CC cyanide-insensitive alternative oxidases and a promising drug candidate
CC against African trypanosomiasis (PubMed:30952781). The first step in
CC the pathway is performed by the non-reducing polyketide synthase ascC
CC that produces orsellinic acid by condensing acetyl-CoA with 3 malonyl-
CC CoA units (PubMed:30952781). Orsellinic acid is then prenylated by the
CC prenyltransferase ascA to yield ilicicolinic acid B (PubMed:30952781).
CC Ilicicolinic acid B is further reduced to ilicicolin B by the reductase
CC ascB (PubMed:30952781). The halogenase ascD then chlorinates ilicicolin
CC B to produce ilicicolin A which is converted to ilicicolin A epoxide by
CC the 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 A epoxide + NADPH + O2 = 16-hydroxy-
CC ilicicolin A epoxide + H2O + NADP(+); Xref=Rhea:RHEA:63104,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:146155,
CC ChEBI:CHEBI:146158; Evidence={ECO:0000269|PubMed:30952781};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63105;
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 -!- DISRUPTION PHENOTYPE: Impairs the production of ascofuranone and leads
CC to the accumulation of ilicicolin A epoxide.
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; LC406757; BBF25322.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A455R624; -.
DR SMR; A0A455R624; -.
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; IPR002401; Cyt_P450_E_grp-I.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR00385; P450.
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..512
FT /note="Cytochrome P450 monooxygenase ascH"
FT /id="PRO_0000449001"
FT TRANSMEM 12..32
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 458
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 272
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 277
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 512 AA; 57116 MW; C0961FA00B32AA01 CRC64;
MGLSLGYSPD RGSIGSWICA APLILALFVI SYRLFQSVID YRLSHRNGCK PPPTYPHKDW
YLGLHHVFGL LKAKKENRLP TAFSELFDAS GPDVHTLGHY VLGKKSYWTR DPENIKAVLS
SKFNDWGLPS ARKATFRTCL GGGIFGVDGK EWEHSRAMLK PSFTRTQIGD TATLSKHADN
LIARIPEGET VDLAELFPLL TMDVGTEMLF GESVGSLDPA EIKQATRFTT SFDYIVQTMS
KHMALPILTK LRDKTLQGCV EFVDDFAADV VNRTIANESK TEKPSSLGKY IFPTELAKMG
LPEKQIRIEV INIMVAGRDT TAALLSLIWW YLAKRPDAVM KLHQELEPLG GRPPTGEEVK
KMKYLRNFVN EILRLHPINP LNSRTAAKDT TLPRGGGPDG KSPVFIRKGT QLMFSSAALQ
RRKDLYGEDA LDLRPERWER IRPSAFEYIP FGGGPRICPG QQLALTEASY FTARLLQEFQ
GVTSESSGPF QEAFAILVTS GDGVKVKFHK KH
