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PATH_PENEN
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   03-AUG-2022, entry version 31.
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:30100914, PubMed:25625822,
CC       PubMed:30680886). PatH catalyzes the conversion of m-cresol into m-
CC       hydroxybenzyl alcohol (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. The 6-
CC       methylsalicylic acid decarboxylase patG then catalyzes the
CC       decarboxylation of 6-methylsalicylic acid to yield m-cresol (also known
CC       as 3-methylphenol). These first reactions occur in the cytosol. The
CC       intermediate m-cresol is then transported into the endoplasmic
CC       reticulum where the cytochrome P450 monooxygenase patH converts it to
CC       m-hydroxybenzyl alcohol, which is further converted to gentisyl alcohol
CC       by the cytochrome P450 monooxygenase patI. The oxidoreductases patJ and
CC       patO further convert gentisyl alcohol to isoepoxydon in the vacuole.
CC       PatN catalyzes then the transformation of isoepoxydon into phyllostine.
CC       The cluster protein patF is responsible for the conversion from
CC       phyllostine to neopatulin whereas the alcohol dehydrogenase patD
CC       converts neopatulin to E-ascladiol. The steps between isoepoxydon and
CC       E-ascladiol occur in the cytosol, and E-ascladiol is probably secreted
CC       to the extracellular space by one of the cluster-specific transporters
CC       patC or patM. Finally, the secreted patulin synthase patE catalyzes the
CC       conversion of E-ascladiol to patulin (PubMed:30680886) (Probable).
CC       {ECO:0000269|PubMed:25625822, ECO:0000269|PubMed:30100914,
CC       ECO:0000269|PubMed:30680886, ECO:0000305|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}.
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DR   EMBL; KF899892; AIG62144.1; -; Genomic_DNA.
DR   EMBL; JQFZ01000262; KGO52627.1; -; Genomic_DNA.
DR   RefSeq; XP_016595357.1; XM_016745544.1.
DR   AlphaFoldDB; A0A075TRL5; -.
DR   SMR; A0A075TRL5; -.
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:0005783; C:endoplasmic reticulum; IDA:GO_Central.
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; IDA:GO_Central.
DR   GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR   GO; GO:0140723; P:patulin biosynthetic process; IDA:GO_Central.
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   BINDING         442
FT                   /ligand="heme"
FT                   /ligand_id="ChEBI:CHEBI:30413"
FT                   /ligand_part="Fe"
FT                   /ligand_part_id="ChEBI:CHEBI:18248"
FT                   /note="axial binding residue"
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
 
 
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