ID PRX6_PENRW Reviewed; 298 AA. AC B6H060; DT 07-OCT-2020, integrated into UniProtKB/Swiss-Prot. DT 16-DEC-2008, sequence version 1. DT 29-MAY-2024, entry version 69. DE RecName: Full=Short-chain dehydrogenase/reductase prx6 {ECO:0000303|PubMed:24239699}; DE EC=1.1.99.- {ECO:0000305|PubMed:24239699}; DE AltName: Full=PR-toxin biosynthesis cluster protein 6 {ECO:0000303|PubMed:24239699}; GN Name=prx6 {ECO:0000303|PubMed:24239699}; GN ORFNames=Pc12g06270, PCH_Pc12g06270; OS Penicillium rubens (strain ATCC 28089 / DSM 1075 / NRRL 1951 / Wisconsin OS 54-1255) (Penicillium chrysogenum). OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes; OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium; OC Penicillium chrysogenum species complex. OX NCBI_TaxID=500485; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=ATCC 28089 / DSM 1075 / NRRL 1951 / Wisconsin 54-1255; RX PubMed=18820685; DOI=10.1038/nbt.1498; RA van den Berg M.A., Albang R., Albermann K., Badger J.H., Daran J.-M., RA Driessen A.J.M., Garcia-Estrada C., Fedorova N.D., Harris D.M., RA Heijne W.H.M., Joardar V.S., Kiel J.A.K.W., Kovalchuk A., Martin J.F., RA Nierman W.C., Nijland J.G., Pronk J.T., Roubos J.A., van der Klei I.J., RA van Peij N.N.M.E., Veenhuis M., von Doehren H., Wagner C., Wortman J.R., RA Bovenberg R.A.L.; RT "Genome sequencing and analysis of the filamentous fungus Penicillium RT chrysogenum."; RL Nat. Biotechnol. 26:1161-1168(2008). RN [2] RP FUNCTION, INDUCTION, AND PATHWAY. 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). 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). The first step of the pathway is catalyzed by the CC aristolochene synthase which performs the cyclization of trans,trans- CC farnesyl diphosphate (FPP) to the bicyclic sesquiterpene aristolochene CC (PubMed:24239699). Following the formation of aristolochene, the non- CC oxygenated aristolochene is converted to the trioxygenated intermediate CC eremofortin B, via 7-epi-neopetasone (PubMed:24239699). This conversion CC appears to involve three enzymes, a hydroxysterol oxidase-like enzyme, CC the quinone-oxidase prx3 that forms the quinone-type-structure in the CC bicyclic nucleus of aristolochene with the C8-oxo group and the C-3 CC hydroxyl group, and the P450 monooxygenase prx9 that introduces the CC epoxide at the double bond between carbons 1 and 2 (By similarity) CC (PubMed:24239699). No monoxy or dioxy-intermediates have been reported CC to be released to the broth, so these three early oxidative reactions CC may be coupled together (PubMed:24239699). Eremofortin B is further CC oxidized by another P450 monooxygenase, that introduces a second CC epoxide between carbons 7 and 11 prior to acetylation to eremofortin A CC by the acetyltransferase prx11 (By similarity). The second epoxidation CC may be performed by a second P450 monooxygenase (PubMed:24239699). CC After the acetylation step, eremofortin A is converted to eremofortin C CC and then to PR-toxin (PubMed:24239699). First the conversion of CC eremofortin A to eremofortin C proceeds by oxidation of the side chain CC of the molecule at C-12 and is catalyzed by the short-chain CC oxidoreductase prx1 (PubMed:24239699). The cytochrome P450 CC monooxygenase prx8 also plays a role in this step (By similarity). The CC primary alcohol formed at C-12 is finally oxidized by the short-chain CC alcohol dehydrogenase prx4 that forms PR-toxin (PubMed:24239699). CC {ECO:0000250|UniProtKB:W6Q3Z9, ECO:0000250|UniProtKB:W6QB15, CC ECO:0000250|UniProtKB:W6QP10, ECO:0000269|PubMed:24239699}. CC -!- PATHWAY: Sesquiterpene biosynthesis. {ECO:0000305|PubMed:24239699}. CC -!- INDUCTION: Expression and the subsequent production of PR-toxin take CC place under static culture conditions (oxygen limited), whereas no CC expression of the PR-toxin genes occurs under the strongly aerated CC conditions required for optimal penicillin production CC (PubMed:24239699). There is a negative control of the transcription of CC the PR-toxin genes by the penicillin biosynthesis gene product(s), or CC by a regulatory peptide encoded by a small ORF inside the penicillin CC gene cluster (PubMed:24239699). {ECO:0000269|PubMed:24239699}. CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR) CC family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AM920427; CAP80254.1; -; Genomic_DNA. DR RefSeq; XP_002557470.1; XM_002557424.1. DR AlphaFoldDB; B6H060; -. DR SMR; B6H060; -. DR KEGG; pcs:Pc12g06270; -. DR VEuPathDB; FungiDB:PCH_Pc12g06270; -. DR eggNOG; KOG4169; Eukaryota. DR HOGENOM; CLU_010194_13_0_1; -. DR OMA; AIHFMRH; -. DR OrthoDB; 2099897at2759; -. DR BioCyc; PCHR:PC12G06270-MONOMER; -. DR Proteomes; UP000000724; Contig Pc00c12. DR GO; GO:0005737; C:cytoplasm; IEA:TreeGrafter. DR GO; GO:0016404; F:15-hydroxyprostaglandin dehydrogenase (NAD+) activity; IEA:TreeGrafter. DR GO; GO:0044249; P:cellular biosynthetic process; IEA:UniProt. DR GO; GO:1901576; P:organic substance biosynthetic process; IEA:UniProt. DR GO; GO:0006693; P:prostaglandin metabolic process; IEA:TreeGrafter. DR CDD; cd05323; ADH_SDR_c_like; 1. DR Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1. DR InterPro; IPR036291; NAD(P)-bd_dom_sf. DR InterPro; IPR020904; Sc_DH/Rdtase_CS. DR InterPro; IPR002347; SDR_fam. DR PANTHER; PTHR44229; 15-HYDROXYPROSTAGLANDIN DEHYDROGENASE [NAD(+)]; 1. DR PANTHER; PTHR44229:SF4; 15-HYDROXYPROSTAGLANDIN DEHYDROGENASE [NAD(+)]; 1. DR Pfam; PF00106; adh_short; 1. DR PRINTS; PR00081; GDHRDH. DR SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1. DR PROSITE; PS00061; ADH_SHORT; 1. PE 2: Evidence at transcript level; KW NADP; Oxidoreductase; Reference proteome. FT CHAIN 1..298 FT /note="Short-chain dehydrogenase/reductase prx6" FT /id="PRO_0000451218" FT ACT_SITE 174 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10001" FT ACT_SITE 178 FT /note="Lowers pKa of active site Tyr" FT /evidence="ECO:0000250|UniProtKB:O93868" FT BINDING 27 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:L0E2Z4" FT BINDING 70 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:L0E2Z4" FT BINDING 97 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:O93868" FT BINDING 174 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:O93868" FT BINDING 178 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:O93868" FT BINDING 208 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:O93868" FT BINDING 210 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:L0E2Z4" SQ SEQUENCE 298 AA; 32254 MW; 6FE84E5075846846 CRC64; MGSYTEPRVA IVAGATSLTR DPLQSGIGID LAKDLCSKGW KVACVGRRQE AGEALLKDLP QDRAYFFAAD VSNYEQYASV FSKVHHLWGR IDALCANAGI VDTSSLYIYG SKNNGVDNIP PAPDLSVVDI NYKGVVYGTQ LAIHFMRHNP QPGGRIVVTG SIGAVFPHKT YPVYCGTKAA VNHFIRGVAP LLKQKENISI NCVMPGIVNT PIVPPEMIAA VTPECITPVQ TVLRGYETFL EDSTGMAGEI LECSADKLIY YHMPKPGNGH ITKRAVTVWE PLFRMSHGEV SGLPDAIP //