ASCF_ACREG
ID ASCF_ACREG Reviewed; 273 AA.
AC A0A455RAK9;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 05-JUN-2019, sequence version 1.
DT 25-MAY-2022, entry version 11.
DE RecName: Full=Terpene cyclase ascF {ECO:0000303|PubMed:30952781};
DE EC=5.4.99.- {ECO:0000269|PubMed:30952781};
DE AltName: Full=Ascofuranone/ascochlorin biosynthesis clusters protein F {ECO:0000303|PubMed:30952781};
GN Name=ascF {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 DISRUPTION PHENOTYPE, 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: Terpene cyclase; part of the asc-1 gene cluster that mediates
CC the biosynthesis of both ascochlorin and ascofuranone, a strong
CC inhibitor of cyanide-insensitive alternative oxidases and a promising
CC drug candidate against African trypanosomiasis (PubMed:30952781). The
CC first step in the pathway is performed by the non-reducing polyketide
CC synthase ascC that produces orsellinic acid by condensing acetyl-CoA
CC with 3 malonyl-CoA units (PubMed:30952781). Orsellinic acid is then
CC prenylated by the prenyltransferase ascA to yield ilicicolinic acid B
CC (PubMed:30952781). Ilicicolinic acid B is further reduced to ilicicolin
CC B by the reductase ascB (PubMed:30952781). The halogenase ascD then
CC chlorinates ilicicolin B to produce ilicicolin A which is converted to
CC ilicicolin A epoxide by the cytochrome P450 monooxygenase ascE that
CC catalyzes stereoselective epoxidation of the terminal double bond of
CC the prenyl group (PubMed:30952781). Ilicicolin A epoxide is the last
CC common precursor for the biosynthesis of ascofuranone and ascochlorin
CC (PubMed:30952781). The terpene cyclase ascF produces a monocyclic
CC terpene, and the cyclization reaction is proposed to be initiated by
CC protonation of the terminal epoxide of ilicicolin A epoxide to generate
CC a monocyclic tertiarycation, which is followed by a series of hydride
CC and methyl shifts with abstraction of proton, leading to the formation
CC of the (14S,15R,19R)-trimethylcyclohexanone ring structure of
CC ilicicolin C, which is finally reduced to ascochlorin by the
CC dehydrogenase ascG (PubMed:30952781). On the other hand, ilicicolin A
CC epoxide is hydroxylated by the cytochrome P450 monooxygenase ascH, and
CC the 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=ilicicolin A epoxide = ilicicolin C; Xref=Rhea:RHEA:63096,
CC ChEBI:CHEBI:146155, ChEBI:CHEBI:146156;
CC Evidence={ECO:0000269|PubMed:30952781};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63097;
CC Evidence={ECO:0000269|PubMed:30952781};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:30952781}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-pass membrane
CC protein {ECO:0000255}.
CC -!- INDUCTION: Expression is induced on AF medium.
CC {ECO:0000269|PubMed:30952781}.
CC -!- DISRUPTION PHENOTYPE: Still produces ascofuranone but impairs the
CC production of ascochlorin and leads to the accumulation of ilicicolin A
CC epoxide. {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 paxB family. {ECO:0000305}.
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DR EMBL; LC406756; BBF25318.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A455RAK9; -.
DR UniPathway; UPA00213; -.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016853; F:isomerase activity; IEA:UniProtKB-KW.
DR GO; GO:0016829; F:lyase activity; IEA:InterPro.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR InterPro; IPR039020; PaxB-like.
DR PANTHER; PTHR42038; PTHR42038; 1.
PE 1: Evidence at protein level;
KW Isomerase; Membrane; Transmembrane; Transmembrane helix.
FT CHAIN 1..273
FT /note="Terpene cyclase ascF"
FT /id="PRO_0000449004"
FT TRANSMEM 18..38
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 49..69
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 78..98
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 113..133
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 153..173
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 178..198
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 217..237
FT /note="Helical"
FT /evidence="ECO:0000255"
SQ SEQUENCE 273 AA; 31078 MW; C73AA40003AAC969 CRC64;
MAFGVEPPEH VTPWFKPVYE ATFQFGGVAW TLCYILIARE GMRTKSYGMP LFALANNFAW
EMVYALWVVD NAFEKTAMTI WMLIDTPIIY SILKHGVLEW QHAPMVSRNL KSILVGLIAL
CAAAHWSWQS WWIGNEMGKR DDLEGADLTQ MAYWAVSMCQ FLVSTMSLAM LCVRGHSGGV
SWMIWLSRFL GTLIGLNMNY AWAYYTWPEA HEYFMSAPAV FVWGVTTVCD IIYGFVLYHV
KSNERELSDG RKVAAEADDE QVGGWSKMKT GKN
