ASCJ_ACREG
ID ASCJ_ACREG Reviewed; 296 AA.
AC A0A455R5K2;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 05-JUN-2019, sequence version 1.
DT 03-AUG-2022, entry version 9.
DE RecName: Full=Short-chain dehydrogenase/reductase ascJ {ECO:0000303|PubMed:30952781};
DE EC=1.1.99.- {ECO:0000269|PubMed:30952781};
DE AltName: Full=Ascofuranone/ascochlorin biosynthesis clusters protein J {ECO:0000303|PubMed:30952781};
GN Name=ascJ {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: Short-chain dehydrogenase/reductase; part of the asc-2 gene
CC cluster that mediates the biosynthesis of 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=A + ascofuranol = AH2 + ascofuranone; Xref=Rhea:RHEA:63112,
CC ChEBI:CHEBI:13193, ChEBI:CHEBI:17499, ChEBI:CHEBI:146159,
CC ChEBI:CHEBI:146160; Evidence={ECO:0000269|PubMed:30952781};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63113;
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 -!- 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 short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
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DR EMBL; LC406757; BBF25320.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A455R5K2; -.
DR SMR; A0A455R5K2; -.
DR UniPathway; UPA00213; -.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR002347; SDR_fam.
DR Pfam; PF00106; adh_short; 1.
DR PRINTS; PR00081; GDHRDH.
DR SUPFAM; SSF51735; SSF51735; 1.
PE 1: Evidence at protein level;
KW NAD; Oxidoreductase.
FT CHAIN 1..296
FT /note="Short-chain dehydrogenase/reductase ascJ"
FT /id="PRO_0000449005"
FT ACT_SITE 168
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10001"
FT BINDING 20..28
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 47..48
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 75..77
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 155
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 168..172
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 208..210
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
SQ SEQUENCE 296 AA; 31856 MW; 49F3A7D691D5C977 CRC64;
MTDIHIQDGD LSSLKDKVVV ITGGSSGIGL ATTNLLLDLG AKVVIGDLQP PTTRVDSERC
SFHKVDVTVW SDQLTLFKEA RELHGRIDHV FANAGVGPKA DYLSTALDQN GDLVEPTFLT
LDVNLKAVIY TATIACYYMR EEQQSPAGGS IVIVSSVAGV SRFRAVDYAT AKHGNLGFAR
GLHQRLTAEN SPTRVNLIAP SWTNTGFMPP QIMAAVGVEP QEPASVGRAA AYLMADDSRK
GQMIHIAKGR YREVEESIML PAAEKVVDVE NGGVMEDDTL AKIIETMGIF KAKATQ
