ID PATH_PENEN Reviewed; 524 AA. AC A0A075TRL5; DT 05-DEC-2018, integrated into UniProtKB/Swiss-Prot. DT 29-OCT-2014, sequence version 1. DT 22-APR-2020, entry version 28. DE RecName: Full=Cytochrome P450 monooxygenase patH {ECO:0000303|PubMed:25120234}; DE EC=1.-.-.- {ECO:0000269|PubMed:30680886}; DE AltName: Full=Patulin biosynthesis cluster protein H {ECO:0000303|PubMed:25120234}; DE AltName: Full=m-cresol hydrolase {ECO:0000303|PubMed:25120234}; GN Name=patH {ECO:0000303|PubMed:25120234}; ORFNames=PEX2_082740; OS Penicillium expansum (Blue mold rot fungus). OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes; OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium. OX NCBI_TaxID=27334; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], IDENTIFICATION, AND INDUCTION. RC STRAIN=NRRL 35695; RX PubMed=25120234; DOI=10.1016/j.ijfoodmicro.2014.07.028; RA Tannous J., El Khoury R., Snini S.P., Lippi Y., El Khoury A., Atoui A., RA Lteif R., Oswald I.P., Puel O.; RT "Sequencing, physical organization and kinetic expression of the patulin RT biosynthetic gene cluster from Penicillium expansum."; RL Int. J. Food Microbiol. 189C:51-60(2014). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=MD-8; RX PubMed=25338147; DOI=10.1094/mpmi-09-14-0261-fi; RA Ballester A.R., Marcet-Houben M., Levin E., Sela N., Selma-Lazaro C., RA Carmona L., Wisniewski M., Droby S., Gonzalez-Candelas L., Gabaldon T.; RT "Genome, transcriptome, and functional analyses of Penicillium expansum RT provide new insights into secondary metabolism and pathogenicity."; RL Mol. Plant Microbe Interact. 28:232-248(2015). RN [3] RP BIOTECHNOLOGY. RX PubMed=15082620; DOI=10.1093/ije/dyh028; RG Patulin Clinical Trials Committee, Medical Research Council; RT "Clinical trial of patulin in the common cold. 1944."; RL Int. J. Epidemiol. 33:243-246(2004). RN [4] RP BIOTECHNOLOGY. RX PubMed=22222931; DOI=10.1016/j.fct.2011.12.022; RA de Melo F.T., de Oliveira I.M., Greggio S., Dacosta J.C., Guecheva T.N., RA Saffi J., Henriques J.A., Rosa R.M.; RT "DNA damage in organs of mice treated acutely with patulin, a known RT mycotoxin."; RL Food Chem. Toxicol. 50:3548-3555(2012). RN [5] RP BIOTECHNOLOGY. RX PubMed=26619846; DOI=10.1007/s13277-015-4474-z; RA Boussabbeh M., Ben Salem I., Rjiba-Touati K., Bouyahya C., Neffati F., RA Najjar M.F., Bacha H., Abid-Essefi S.; RT "The potential effect of patulin on mice bearing melanoma cells: an anti- RT tumour or carcinogenic effect?"; RL Tumor Biol. 37:6285-6295(2016). RN [6] RP INDUCTION. RX PubMed=27528575; DOI=10.1111/mpp.12469; RA Kumar D., Barad S., Chen Y., Luo X., Tannous J., Dubey A., Glam Matana N., RA Tian S., Li B., Keller N., Prusky D.; RT "LaeA regulation of secondary metabolism modulates virulence in Penicillium RT expansum and is mediated by sucrose."; RL Mol. Plant Pathol. 18:1150-1163(2017). RN [7] RP FUNCTION, AND INDUCTION. RX PubMed=30100914; DOI=10.3389/fpls.2018.01094; RA Kumar D., Tannous J., Sionov E., Keller N., Prusky D.; RT "Apple intrinsic factors modulating the global regulator, LaeA, the patulin RT gene cluster and patulin accumulation during fruit colonization by RT Penicillium expansum."; RL Front. Plant Sci. 9:1094-1094(2018). RN [8] RP FUNCTION, AND INDUCTION. RX PubMed=25625822; DOI=10.1094/mpmi-12-14-0398-fi; RA Li B., Zong Y., Du Z., Chen Y., Zhang Z., Qin G., Zhao W., Tian S.; RT "Genomic characterization reveals insights into patulin biosynthesis and RT pathogenicity in Penicillium species."; RL Mol. Plant Microbe Interact. 28:635-647(2015). RN [9] RP FUNCTION, DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, RP INDUCTION, AND PATHWAY. RX PubMed=30680886; DOI=10.1111/1462-2920.14542; RA Li B., Chen Y., Zong Y., Shang Y., Zhang Z., Xu X., Wang X., Long M., RA Tian S.; RT "Dissection of patulin biosynthesis, spatial control and regulation RT mechanism in Penicillium expansum."; RL Environ. Microbiol. 21:1124-1139(2019). CC -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene cluster that CC mediates the biosynthesis of patulin, an acetate-derived tetraketide CC mycotoxin produced by several fungal species that shows antimicrobial CC properties against several bacteria (PubMed:25120234, PubMed:30100914, CC PubMed:25625822, PubMed:30680886). The pathway begins with the CC synthesis of 6-methylsalicylic acid by the polyketide synthase (PKS) CC patK via condensation of acetate and malonate units (PubMed:30680886). CC The 6-methylsalicylic acid decarboxylase patG then catalyzes the CC decarboxylation of 6-methylsalicylic acid to yield m-cresol (also known CC as 3-methylphenol) (PubMed:30680886). These first reactions occur in CC the cytosol (PubMed:30680886). The intermediate m-cresol is then CC transported into the endoplasmic reticulum where the cytochrome P450 CC monooxygenase patH converts it to m-hydroxybenzyl alcohol, which is CC further converted to gentisyl alcohol by the cytochrome P450 CC monooxygenase patI (PubMed:30680886). The oxidoreductases patJ and patO CC further convert gentisyl alcohol to isoepoxydon in the vacuole CC (PubMed:30680886). PatN catalyzes then the transformation of CC isoepoxydon into phyllostine (PubMed:30680886). The cluster protein CC patF is responsible for the conversion from phyllostine to neopatulin CC whereas the alcohol dehydrogenase patD converts neopatulin to E- CC ascladiol (PubMed:30680886). The steps between isoepoxydon and E- CC ascladiol occur in the cytosol, and E-ascladiol is probably secreted to CC the extracellular space by one of the cluster-specific transporters CC patC or patM (PubMed:30680886). Finally, the secreted patulin synthase CC patE catalyzes the conversion of E-ascladiol to patulin CC (PubMed:30680886). {ECO:0000269|PubMed:25120234, CC ECO:0000269|PubMed:25625822, ECO:0000269|PubMed:30100914, CC ECO:0000269|PubMed:30680886}. CC -!- CATALYTIC ACTIVITY: CC Reaction=3-methylphenol + O2 + reduced [NADPH--hemoprotein reductase] = CC 3-hydroxybenzyl alcohol + H(+) + H2O + oxidized [NADPH--hemoprotein CC reductase]; Xref=Rhea:RHEA:62208, Rhea:RHEA-COMP:11964, Rhea:RHEA- CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, CC ChEBI:CHEBI:17069, ChEBI:CHEBI:17231, ChEBI:CHEBI:57618, CC ChEBI:CHEBI:58210; Evidence={ECO:0000269|PubMed:30680886}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62209; CC Evidence={ECO:0000269|PubMed:30680886}; CC -!- COFACTOR: CC Name=heme; Xref=ChEBI:CHEBI:30413; CC Evidence={ECO:0000250|UniProtKB:P04798}; CC -!- PATHWAY: Mycotoxin biosynthesis; patulin biosynthesis. CC {ECO:0000269|PubMed:30680886}. CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:30680886}; Single-pass membrane protein CC {ECO:0000269|PubMed:30680886}. CC -!- INDUCTION: Expression is correlated with the production of patulin CC (PubMed:25120234). Expression is positively regulated by the secondary CC metabolism regulator laeA (PubMed:27528575, PubMed:30100914). CC Expression is strongly decreased with increased sucrose concentrations. CC This decrease is lost in the presence of malic acid (PubMed:30100914). CC Expression is increased with pH changes from 2.5 to 3.5 in the presence CC of a limiting concentration of sucrose, 50 mM (PubMed:30100914). CC Natural phenols present in apple fruits such as chlorogenic acid or the CC flavonoid epicatechin modulate patulin biosynthesis. They increase CC expression in the absence of sucrose, have little impact in the CC presence of 15 mM sucrose, and decrease expression in 175 mM sucrose CC (PubMed:30100914). Expression is positively regulated by the patulin CC cluster-specific transcription factor patL (PubMed:25625822). Finally, CC expression is also positively regulated by the velvet family proteins CC transcription regulators veA, velB, velC, but not vosA CC (PubMed:30680886). {ECO:0000269|PubMed:25120234, CC ECO:0000269|PubMed:25625822, ECO:0000269|PubMed:27528575, CC ECO:0000269|PubMed:30100914, ECO:0000269|PubMed:30680886}. CC -!- DISRUPTION PHENOTYPE: Completely abolishes the production of patulin CC and leads to the production of a distinct dark-red pigment. CC {ECO:0000269|PubMed:30680886}. CC -!- BIOTECHNOLOGY: Patulin was originally used as an antibiotic and CC specifically trialed to be used against the common cold, but it is no CC longer used for that purpose since it has been shown to induce CC immunological, neurological and gastrointestinal effects CC (PubMed:15082620). Genotoxic effects of patulin with dose-dependent CC increase in DNA strand breaks in brain, liver and kidneys have been CC detected in mice (PubMed:22222931). However, more recently, it has been CC proposed that patulin might also have anti-tumor properties CC (PubMed:26619846). {ECO:0000269|PubMed:15082620, CC ECO:0000269|PubMed:22222931, ECO:0000269|PubMed:26619846}. CC -!- SIMILARITY: Belongs to the cytochrome P450 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; KF899892; AIG62144.1; -; Genomic_DNA. DR EMBL; JQFZ01000262; KGO52627.1; -; Genomic_DNA. DR RefSeq; XP_016595357.1; XM_016745544.1. DR EnsemblFungi; KGO43531; KGO43531; PEXP_094320. DR EnsemblFungi; KGO52627; KGO52627; PEX2_082740. DR EnsemblFungi; KGO64340; KGO64340; PEX1_046480. DR GeneID; 27680964; -. DR HOGENOM; CLU_001570_2_1_1; -. DR OrthoDB; 702827at2759; -. DR PhylomeDB; A0A075TRL5; -. DR UniPathway; UPA00918; -. DR Proteomes; UP000030143; Unassembled WGS sequence. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. 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 Gene3D; 1.10.630.10; -; 1. DR InterPro; IPR001128; Cyt_P450. DR InterPro; IPR002401; Cyt_P450_E_grp-I. DR InterPro; IPR036396; Cyt_P450_sf. DR Pfam; PF00067; p450; 1. DR PRINTS; PR00463; EP450I. DR SUPFAM; SSF48264; SSF48264; 1. PE 1: Evidence at protein level; KW Endoplasmic reticulum; Glycoprotein; Iron; Membrane; Metal-binding; KW Monooxygenase; Oxidoreductase; Reference proteome; Transmembrane; KW Transmembrane helix. FT CHAIN 1..524 FT /note="Cytochrome P450 monooxygenase patH" FT /id="PRO_5007956284" FT TOPO_DOM 1..4 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 5..22 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 23..524 FT /note="Lumenal" FT /evidence="ECO:0000305" FT METAL 442 FT /note="Iron (heme axial ligand)" FT /evidence="ECO:0000250|UniProtKB:P04798" FT CARBOHYD 266 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498" SQ SEQUENCE 524 AA; 60202 MW; 96C747028DE5F15C CRC64; MEPFLLLLLV LLPAIVLVRY AFTYGHRTST MPIGPPTLPF IGNIHQITKK YTHIKFTEWA AQYGGLYMLK IGNGNMAVIT DRRLVKEVLD RKSGIYSHRP HSFVSHDLIT KGNHLLVMHY GDQWRTFRRL VHQHLMETMV ENHHTKIVNA EAIQLVRDYM IDPEHHMAHP KRYSNSITNS IVFGIRTANR EGANMRRLYK LMEEWSEVME TGATPPVDLF PWLKLLPQWL FNNYIDRAKA IGVQMETLYV DILNKVIKRR EDGHNNGTFM DKVLDSQEKH NLPWHQLAFI GGVLMEGGSD TSSSLTLAIV QALIQNPDVQ RKAHAEIDAV VGHNRSPVWE DFEKLPYINM IIKEGHRWRP ILPLCFPHAL GEDDWVDGKF LPKGTIVVVN TWGMHMDPSQ PDDPAAFIPE RFAKHPQLAP DYVPGTWERR DHYGYGVGRR ICPGIHLAER NMFLGIAKLL WAFDFQPGEG PIDSDPVTGY HNGFLYCAKD YSCRPVIRNE VIRDTIEREY ATATADVFSR FTEG //