PATK_PENEN
ID PATK_PENEN Reviewed; 1776 AA.
AC A0A075TRC0; A0A0A2JCW7;
DT 05-DEC-2018, integrated into UniProtKB/Swiss-Prot.
DT 29-OCT-2014, sequence version 1.
DT 03-AUG-2022, entry version 37.
DE RecName: Full=6-methylsalicylic acid synthase {ECO:0000303|PubMed:25120234};
DE Short=6MSAS {ECO:0000303|PubMed:25120234};
DE EC=2.3.1.165 {ECO:0000269|PubMed:30680886};
DE AltName: Full=Non-reducing polyketide synthase patK {ECO:0000305};
DE AltName: Full=Patulin biosynthesis cluster protein K {ECO:0000303|PubMed:25120234};
GN Name=patK {ECO:0000303|PubMed:25120234}; ORFNames=PEX2_082880;
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, DISRUPTION PHENOTYPE, 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).
RN [10]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=35339702; DOI=10.1016/j.fgb.2022.103689;
RA Clemmensen S.E., Kromphardt K.J.K., Frandsen R.J.N.;
RT "Marker-free CRISPR-Cas9 based genetic engineering of the phytopathogenic
RT fungus, Penicillium expansum.";
RL Fungal Genet. Biol. 160:103689-103689(2022).
CC -!- FUNCTION: 6-methylsalicylic acid synthase; part of the gene cluster
CC that mediates the biosynthesis of patulin, an acetate-derived
CC tetraketide mycotoxin produced by several fungal species that shows
CC antimicrobial properties against several bacteria (PubMed:30100914,
CC PubMed:25625822, PubMed:30680886, PubMed:35339702). PatK catalyzes the
CC first step of the pathway which is the synthesis of 6-methylsalicylic
CC acid via condensation of 1 acetate and 3 malonate units
CC (PubMed:30680886). The pathway begins with the synthesis of 6-
CC methylsalicylic acid by the polyketide synthase (PKS) patK via
CC condensation of acetate and malonate units. The 6-methylsalicylic acid
CC decarboxylase patG then catalyzes the decarboxylation of 6-
CC methylsalicylic acid to yield m-cresol (also known as 3-methylphenol).
CC These first reactions occur in the cytosol. The intermediate m-cresol
CC is then transported into the endoplasmic reticulum where the cytochrome
CC P450 monooxygenase patH converts it to m-hydroxybenzyl alcohol, which
CC is further converted to gentisyl alcohol by the cytochrome P450
CC monooxygenase patI. The oxidoreductases patJ and patO further convert
CC gentisyl alcohol to isoepoxydon in the vacuole. PatN catalyzes then the
CC transformation of isoepoxydon into phyllostine. 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. The steps between isoepoxydon and E-ascladiol occur in the
CC cytosol, and E-ascladiol is probably secreted to the extracellular
CC space by one of the cluster-specific transporters patC or patM.
CC Finally, the secreted patulin synthase patE catalyzes the conversion of
CC E-ascladiol to patulin (PubMed:30680886) (Probable).
CC {ECO:0000269|PubMed:25625822, ECO:0000269|PubMed:30100914,
CC ECO:0000269|PubMed:30680886, ECO:0000269|PubMed:35339702,
CC ECO:0000305|PubMed:30680886}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + 3 H(+) + 3 malonyl-CoA + NADPH = 6-
CC methylsalicylate + 3 CO2 + 4 CoA + H2O + NADP(+);
CC Xref=Rhea:RHEA:12240, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:36658, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57288, ChEBI:CHEBI:57384, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; EC=2.3.1.165;
CC Evidence={ECO:0000269|PubMed:30680886};
CC -!- PATHWAY: Mycotoxin biosynthesis; patulin biosynthesis.
CC {ECO:0000269|PubMed:30680886}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {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 -!- DOMAIN: Multidomain protein; including a starter unit:ACP transacylase
CC (SAT) that selects the starter unit; a ketosynthase (KS) that catalyzes
CC repeated decarboxylative condensation to elongate the polyketide
CC backbone; a malonyl-CoA:ACP transacylase (MAT) that selects and
CC transfers the extender unit malonyl-CoA; a product template (PT) domain
CC that controls the immediate cyclization regioselectivity of the
CC reactive polyketide backbone; and an acyl-carrier protein (ACP) that
CC serves as the tether of the growing and completed polyketide via its
CC phosphopantetheinyl arm. {ECO:0000250|UniProtKB:Q5B0D0}.
CC -!- DISRUPTION PHENOTYPE: Completely abolishes the production of patulin
CC and shows significant slower colony expansion.
CC {ECO:0000269|PubMed:25625822, ECO:0000269|PubMed:30680886,
CC ECO:0000269|PubMed:35339702}.
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 -!- SEQUENCE CAUTION:
CC Sequence=KGO52641.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; KF899892; AIG62146.1; -; Genomic_DNA.
DR EMBL; JQFZ01000262; KGO52641.1; ALT_SEQ; Genomic_DNA.
DR RefSeq; XP_016595371.1; XM_016745558.1.
DR AlphaFoldDB; A0A075TRC0; -.
DR SMR; A0A075TRC0; -.
DR EnsemblFungi; KGO43545; KGO43545; PEXP_094460.
DR EnsemblFungi; KGO52641; KGO52641; PEX2_082880.
DR GeneID; 27680978; -.
DR HOGENOM; CLU_000022_35_3_1; -.
DR OrthoDB; 19161at2759; -.
DR UniPathway; UPA00918; -.
DR PHI-base; PHI:3299; -.
DR PHI-base; PHI:4505; -.
DR Proteomes; UP000030143; Unassembled WGS sequence.
DR GO; GO:0005829; C:cytosol; IDA:GO_Central.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0050641; F:6-methylsalicylic acid synthase activity; IDA:GO_Central.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:0140723; P:patulin biosynthetic process; IDA:GO_Central.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR InterPro; IPR001227; Ac_transferase_dom_sf.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR014043; Acyl_transferase.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR018201; Ketoacyl_synth_AS.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR032821; PKS_assoc.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF51735; SSF51735; 2.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Multifunctional enzyme; NADP; Phosphopantetheine;
KW Phosphoprotein; Reference proteome; Transferase.
FT CHAIN 1..1776
FT /note="6-methylsalicylic acid synthase"
FT /id="PRO_0000445925"
FT DOMAIN 1700..1774
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..26
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 35..460
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 567..880
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 925..1196
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255"
FT REGION 1205..1657
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT COMPBIAS 1..21
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 1734
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 1776 AA; 190701 MW; 0E11675586B03011 CRC64;
MHSVSPSTYP SGGTSPAPAD TPGTEYSEYE FSNDVAVVGM ACRVAGGNHN PELLWQSLLS
QKSAVGEIPE MRWEPYYRRD PRNAKELKKT TSRGYFLDRL EDFDCQFFGI SPKEAEQMDP
QQRVSLEVAS EALEDAGIPA KSLSGSDTAV FWGVNSDDYS KLVLEDLPNV EAWMGIGTAY
CGVPNRISYH LNLMGPSTAV DAACASSLVA VHHGVQAIRL GESQVAIVGG VNALCGPGLT
RVLDKAGAIS SDGSCKSFDD DAHGYARGEG AGALVLKSLH RALLDHDNVL AVIKGSAVAQ
DGKTNGIMAP NAKAQQLAAR TALNVAGVDP STVRYVEAHA TSTPLGDPTE ISAIAGVYGT
NRPADDPCYI GSIKPNIGHL EAGAGVMGFI KAILTIQKGV LPPQANLTNL NSRIDWKTAG
VKVVQEATPW PSSDPIRRAG VCSYGYGGTV SHAVIEEFNP ILRPDPLDDG AATGPGLLLL
SGPQEKRLAL QAKTLREWMT ADGKDNNLSE ILTTLATRRD HHDYRAALVV DDHLDATQVL
QALANGTDHS FTTQSRVLGA DVSKDVVWVF SGHGAQWPDM GKQLIHNPVF FAAIQPLDEL
IQAEIGLSPI ELLRTGDFES SDRVQILTYL MQIGLSAILQ SNGITPQAVI GHSVGEIAAS
VVAGALTSAE GALIVTRRAL LYRQVMGKGG MILVNLPSAE TEEILGRRQD LVVAIDSSPS
SCVVAGDKDI VAETAEAFKA RGVKTFTVKS DIAFHSPTLN VLMDPLRDAL GQALAPTVHI
KLYSTALVDP RGQDVRDLEY WTGNMVNRVR LTSAIQAAVE DGYRLFLEVS THPVVSHSIN
ETLMDAGLED FAVIPTLLRK KPTEKHILHS IAQLHCRGAE VNWAAQMPGR WATGLPTTTW
MHKPIWRKIE TAPLHTGLTH DVEKHTLLGQ RIPVPGTDTF VYTSRLDNET KPFPGSHPLH
GTEIVPAAGL INTFLKGTGG QMLQNVVLRV PVAINAPRSV QVVVQQDQVK VVSRLISSDP
SLSDDDASWV THTTAYWDRK VLGSADRIDL AAVKARLTTK LADNFSIDYL DKVGVSAMGF
PWAVTEHYRD TKQMLARVDV NPAVLGDDPL PWDSSSWAPV LDAATSVGST VFQTAALRMP
AQIERVEIFT SEDPPKISYL FVEEASDSVP TSHVSVLSET GEVLAKFTAM RFSEIEGTPG
VSGSMESLVH QIAWPPATPA EEPLLITKVI LVSPDATARA QYAATLPTQV QSFQFSTTED
FFSNASSLPL EKGTVVAYIP GEVASLAEVP AASESFTWNL LELIKFIVNG SLPIKVFTLT
SSVGDGQTPT ALAQSPLIGL ARIIASEHPD LGSLIDIEEP KIPLSTMRYI QGADVIRISD
GIARVSRFRS LPRTKLRPAS EGPRLLPRPD GTYLITGGLG ILGLEVADFL VEKGARRLLL
ISRRALPPRR TWDQVSEDLQ PTIAKIRLLE SRGASVHVLP LDITKPDAVE QLSTALDRLS
LPAVQGVVHA AGVLDNEMVL QTTRDAFNRV LAPKIAGALA LHEVFPPKSV DFFVMFSSCG
NLVGFTGQAS YGSGNAFLDT LATHRARLGD SGAVAFQWTA WRGLGMGSST DFINAELEAK
GITDVTRDEA FAAWQHLAKY DIDHGVVLRS LAIDDGEPVP VPILNDIVVR RVSELSGSAQ
AAAGSSGNDA VPSSGPELKA YLDEKIRGCV AKVLQMTAED VDSKAALADL GVDSVMTVTL
RRQLQQTLKI PVPPTLTWSH PTVSHLVVWF AEKIGK
