PRX4_PENRO
ID PRX4_PENRO Reviewed; 329 AA.
AC A0A023I4C8;
DT 07-OCT-2020, integrated into UniProtKB/Swiss-Prot.
DT 09-JUL-2014, sequence version 1.
DT 03-AUG-2022, entry version 18.
DE RecName: Full=Short-chain dehydrogenase/reductase prx4 {ECO:0000303|PubMed:24239699};
DE EC=1.1.99.- {ECO:0000305|PubMed:24239699};
DE AltName: Full=PR-toxin biosynthesis cluster protein 4 {ECO:0000303|PubMed:24239699};
GN Name=prx4 {ECO:0000303|PubMed:24239699};
GN Synonyms=ORF4 {ECO:0000303|PubMed:27921136};
OS Penicillium roqueforti.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=5082;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DISRUPTION PHENOTYPE, AND
RP PATHWAY.
RC STRAIN=CECT 2905;
RX PubMed=24239699; DOI=10.1016/j.fgb.2013.10.009;
RA Hidalgo P.I., Ullan R.V., Albillos S.M., Montero O., Fernandez-Bodega M.A.,
RA Garcia-Estrada C., Fernandez-Aguado M., Martin J.F.;
RT "Molecular characterization of the PR-toxin gene cluster in Penicillium
RT roqueforti and Penicillium chrysogenum: cross talk of secondary metabolite
RT pathways.";
RL Fungal Genet. Biol. 62:11-24(2014).
RN [2]
RP FUNCTION.
RX PubMed=16345540; DOI=10.1128/aem.39.4.770-776.1980;
RA Moreau S., Lablache-Combier A., Biguet J.;
RT "Production of eremofortins A, B, and C relative to formation of PR toxin
RT by Penicillium roqueforti.";
RL Appl. Environ. Microbiol. 39:770-776(1980).
RN [3]
RP FUNCTION.
RX PubMed=8440737; DOI=10.1016/S0021-9258(18)53644-9;
RA Proctor R.H., Hohn T.M.;
RT "Aristolochene synthase. Isolation, characterization, and bacterial
RT expression of a sesquiterpenoid biosynthetic gene (Ari1) from Penicillium
RT roqueforti.";
RL J. Biol. Chem. 268:4543-4548(1993).
RN [4]
RP FUNCTION.
RX PubMed=15186158; DOI=10.1021/ja0499593;
RA Felicetti B., Cane D.E.;
RT "Aristolochene synthase: mechanistic analysis of active site residues by
RT site-directed mutagenesis.";
RL J. Am. Chem. Soc. 126:7212-7221(2004).
RN [5]
RP FUNCTION.
RX PubMed=26274339; DOI=10.1002/anie.201506128;
RA Riclea R., Dickschat J.S.;
RT "Identification of intermediates in the biosynthesis of PR toxin by
RT Penicillium roqueforti.";
RL Angew. Chem. Int. Ed. 54:12167-12170(2015).
RN [6]
RP FUNCTION, AND PATHWAY.
RX PubMed=27921136; DOI=10.1007/s00253-016-7995-5;
RA Hidalgo P.I., Poirier E., Ullan R.V., Piqueras J., Meslet-Cladiere L.,
RA Coton E., Coton M.;
RT "Penicillium roqueforti PR toxin gene cluster characterization.";
RL Appl. Microbiol. Biotechnol. 101:2043-2056(2017).
CC -!- FUNCTION: Short-chain dehydrogenase/reductase; part of the gene cluster
CC that mediates the biosynthesis of PR-toxin, a bicyclic sesquiterpene
CC belonging to the eremophilane class and acting as a mycotoxin
CC (PubMed:24239699, PubMed:27921136). The first step of the pathway is
CC catalyzed by the aristolochene synthase which performs the cyclization
CC of trans,trans-farnesyl diphosphate (FPP) to the bicyclic sesquiterpene
CC aristolochene (PubMed:8440737, PubMed:15186158, PubMed:24239699).
CC Following the formation of aristolochene, the non-oxygenated
CC aristolochene is converted to the trioxygenated intermediate
CC eremofortin B, via 7-epi-neopetasone (PubMed:24239699,
CC PubMed:26274339). This conversion appears to involve three enzymes, a
CC hydroxysterol oxidase-like enzyme, the quinone-oxidase prx3 that forms
CC the quinone-type-structure in the bicyclic nucleus of aristolochene
CC with the C8-oxo group and the C-3 hydroxyl group, and the P450
CC monooxygenase ORF6 that introduces the epoxide at the double bond
CC between carbons 1 and 2 (PubMed:24239699, PubMed:27921136). No monoxy
CC or dioxy-intermediates have been reported to be released to the broth,
CC so these three early oxidative reactions may be coupled together
CC (PubMed:24239699). Eremofortin B is further oxidized by another P450
CC monooxygenase, that introduces a second epoxide between carbons 7 and
CC 11 prior to acetylation to eremofortin A by the acetyltransferase ORF8
CC (PubMed:16345540, PubMed:24239699, PubMed:27921136). The second
CC epoxidation may be performed by a second P450 monooxygenase
CC (PubMed:24239699). After the acetylation step, eremofortin A is
CC converted to eremofortin C and then to PR-toxin (PubMed:24239699).
CC First the conversion of eremofortin A to eremofortin C proceeds by
CC oxidation of the side chain of the molecule at C-12 and is catalyzed by
CC the short-chain oxidoreductase prx1 (PubMed:16345540, PubMed:24239699).
CC The cytochrome P450 monooxygenase ORF6 is probably also involved in
CC this step (PubMed:27921136). The primary alcohol formed at C-12 is
CC finally oxidized by the short-chain alcohol dehydrogenase prx4 that
CC forms PR-toxin (PubMed:16345540, PubMed:24239699).
CC {ECO:0000269|PubMed:15186158, ECO:0000269|PubMed:16345540,
CC ECO:0000269|PubMed:24239699, ECO:0000269|PubMed:26274339,
CC ECO:0000269|PubMed:27921136, ECO:0000269|PubMed:8440737}.
CC -!- PATHWAY: Sesquiterpene biosynthesis. {ECO:0000269|PubMed:24239699,
CC ECO:0000305|PubMed:27921136}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- DISRUPTION PHENOTYPE: Reduces the production of PR-toxin and leads to a
CC large increase in mycophenolic acid production.
CC {ECO:0000269|PubMed:24239699}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
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DR EMBL; KC013363; AGS83385.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A023I4C8; -.
DR SMR; A0A023I4C8; -.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR002347; SDR_fam.
DR Pfam; PF00106; adh_short; 1.
DR PRINTS; PR00081; GDHRDH.
DR PRINTS; PR00080; SDRFAMILY.
DR SUPFAM; SSF51735; SSF51735; 1.
PE 3: Inferred from homology;
KW Glycoprotein; Membrane; NAD; Oxidoreductase; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..329
FT /note="Short-chain dehydrogenase/reductase prx4"
FT /id="PRO_0000451216"
FT TRANSMEM 238..258
FT /note="Helical"
FT /evidence="ECO:0000255"
FT ACT_SITE 194
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10001"
FT BINDING 52..60
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 79..80
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 107..109
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 194..198
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 232..234
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT CARBOHYD 91
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 329 AA; 35536 MW; 65E1A7108F30F6CA CRC64;
MIPRWQPASI PLLLHLDTLR CHHVSVQPPR ATMTSLNIKE EDIPRLDGKV VVISGGASGI
GLAAANIFAR AGAKIFLFDC NPPDSGEAPE NSTFIKADIT SWAELKAAFA QAGHVDIAVA
NAGVSEEQPY FEDTFDEQGE LKEPGFAVVD VNFKGTVMFT KLAVSYMRKQ GKGGSVVITA
SATGYAPEQN LPVYSAIKSG LVGLVRSLRS TLPRFDISIN AVAPAATITK LLPMDIAGPL
MAAGLPVSSA HMVGLAVVYS AVARQPRMVE TYGKENVLDL ESKWNGRTIL TLGEHYTELE
EKLADLRPVW FGWRNTDLTK KQQATADFR
