PHNA_PENHR
ID PHNA_PENHR Reviewed; 2187 AA.
AC A0A142C799;
DT 16-JAN-2019, integrated into UniProtKB/Swiss-Prot.
DT 08-JUN-2016, sequence version 1.
DT 25-MAY-2022, entry version 24.
DE RecName: Full=Non-reducing polyketide synthase phnA {ECO:0000303|PubMed:26978228};
DE Short=NR-PKS phnA {ECO:0000303|PubMed:26978228};
DE EC=2.3.1.- {ECO:0000269|PubMed:26978228, ECO:0000269|PubMed:28240554};
DE AltName: Full=Phenalenone biosynthesis cluster protein A {ECO:0000303|PubMed:26978228};
GN Name=phnA {ECO:0000303|PubMed:26978228};
OS Penicillium herquei.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=69774;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], CATALYTIC ACTIVITY, FUNCTION, DISRUPTION
RP PHENOTYPE, AND PATHWAY.
RC STRAIN=ATCC 10118 / CBS 336.48 / NBRC 31747 / NRRL 1040;
RX PubMed=26978228; DOI=10.1021/jacs.6b01528;
RA Gao S.S., Duan A., Xu W., Yu P., Hang L., Houk K.N., Tang Y.;
RT "Phenalenone polyketide cyclization catalyzed by fungal polyketide synthase
RT and flavin-dependent monooxygenase.";
RL J. Am. Chem. Soc. 138:4249-4259(2016).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=28240554; DOI=10.1021/jacs.7b01089;
RA Gao S.S., Garcia-Borras M., Barber J.S., Hai Y., Duan A., Garg N.K.,
RA Houk K.N., Tang Y.;
RT "Enzyme-catalyzed intramolecular enantioselective hydroalkoxylation.";
RL J. Am. Chem. Soc. 139:3639-3642(2017).
CC -!- FUNCTION: Non-reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of phenalenones such as herqueinone,
CC compounds that have been reported to treat tumors, bacterial infections
CC and/or mycoses, and rheumatic diseases (PubMed:26978228). The non-
CC reducing polyketide synthase phnA synthesizes the heptaketide backbone
CC and cyclizes it into the angular, hemiketal-containing naphtho-gamma-
CC pyrone prephenalenone. The product template (PT) domain of phnA
CC catalyzes only the C4-C9 aldol condensation, which is unprecedented
CC among known PT domains (PubMed:28240554, PubMed:26978228). The
CC transformation of prephenalenone to phenalenones requires an FAD-
CC dependent monooxygenase phnB, which catalyzes the C2 aromatic
CC hydroxylation of prephenalenone and ring opening of the gamma-pyrone
CC ring simultaneously (PubMed:28240554, PubMed:26978228). Subsequent
CC intramolecular deprotonation of C3 phenolic oxygen accelerates
CC phenalenone ring closure to yield the tricyclic phenalenone core with a
CC C2 hydroxylation (PubMed:28240554, PubMed:26978228). The
CC prenyltransferase phnF further catalyzes reverse C-prenylation of
CC phenalenone by direct electrophilic substitution at C6, or possibly via
CC first a forward O-prenylation of a neighboring phenol in phenalenone,
CC followed by a Claisen rearrangement (PubMed:28240554). The
CC hydroalkoxylation enzyme phnH catalyzes the 5-exo-trigcyclization via
CC acid catalysis after the spontaneous deprotonation of 7-OH, which leads
CC to the formation of the dihydrobenzofuran atrovenetin
CC (PubMed:28240554). Atrovenetin is further converted to deoxyherqueinone
CC by the O-methyltransferase phnC which can methylate C2-OH to stabilize
CC the northern portion of the phenalenone core (PubMed:28240554).
CC Finally, the oxidoreductase phnG converts deoxyherqueinone to
CC herqueinone via C6 hydroxylation (PubMed:28240554).
CC {ECO:0000269|PubMed:26978228, ECO:0000269|PubMed:28240554}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + 5 H(+) + 6 malonyl-CoA = 3,6,7,9-tetrahydroxy-3-
CC methyl-2,3-dihydro-1H-naphtho[2,1-b]pyran-1-one + 6 CO2 + 7 CoA +
CC H2O; Xref=Rhea:RHEA:12060, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288,
CC ChEBI:CHEBI:57384, ChEBI:CHEBI:142802;
CC Evidence={ECO:0000269|PubMed:26978228, ECO:0000269|PubMed:28240554};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12061;
CC Evidence={ECO:0000269|PubMed:26978228, ECO:0000269|PubMed:28240554};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:26978228, ECO:0000269|PubMed:28240554}.
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 2 acyl-carrier protein (ACP) domains
CC that serve as the tethers of the growing and completed polyketide via
CC their phosphopantetheinyl arm. {ECO:0000250|UniProtKB:Q5B0D0}.
CC -!- DOMAIN: The release of the polyketide chain from the non-reducing
CC polyketide synthase is mediated by the thioesterase (TE) domain
CC localized at the C-ter of the protein. {ECO:0000250|UniProtKB:Q5ATJ7}.
CC -!- DISRUPTION PHENOTYPE: Completely abolishes the production of
CC herqueinone. {ECO:0000269|PubMed:26978228}.
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DR EMBL; KU641626; AMP46751.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A142C799; -.
DR SMR; A0A142C799; -.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR Gene3D; 1.10.1200.10; -; 2.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 2.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
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; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR030918; PT_fungal_PKS.
DR InterPro; IPR032088; SAT.
DR InterPro; IPR001031; Thioesterase.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF00550; PP-binding; 2.
DR Pfam; PF14765; PS-DH; 1.
DR Pfam; PF16073; SAT; 1.
DR Pfam; PF00975; Thioesterase; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 2.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR TIGRFAMs; TIGR04532; PT_fungal_PKS; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 2.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 2.
PE 1: Evidence at protein level;
KW Multifunctional enzyme; Phosphopantetheine; Phosphoprotein; Repeat;
KW Transferase.
FT CHAIN 1..2187
FT /note="Non-reducing polyketide synthase phnA"
FT /id="PRO_0000446161"
FT DOMAIN 1684..1758
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 1796..1874
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 17..255
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:26978228"
FT REGION 386..822
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:26978228"
FT REGION 926..1226
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:26978228"
FT REGION 1321..1637
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:26978228"
FT REGION 1652..1681
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1754..1796
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1906..2183
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:26978228"
FT COMPBIAS 1754..1785
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 555
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 555
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 1021
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 2009
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q03149"
FT MOD_RES 1718
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1834
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2187 AA; 237598 MW; 1F9B27F02CC07397 CRC64;
MATTEMNDVQ PVQSQVLLFG DLSLAHVEES LKRLLHVKTN PLLAAFFQRV NHQLRRLLDG
LPLEQQDFFP RFTTLIDLVS RLGETSGTPV LAFFLLSVQQ VAQSIVYFSH GSRIFPPSSA
CIIGPCTGGF AAAALASSQN LVDLVNNGAE ASILAFRTAL VSFLISRSLS NSPQTEGSTS
WSVAVSSRGE QTVEDLAQEY MAAKTPLRHS SLWKSAVTAS LTITLSGQPS ILQGFLETYS
EQLRYKYLDI DSPYHAAHLF SETDVEQIVS HLAGSDTADQ KPRLPVLSSA TGQLISASTF
HGLLHTVVQE TLLKPVCWDL ILDSCQSWLT QGGAQECTIL PFSSNAGTMI ASALTKEKEI
EVTVADATGS GLLDEKPTGR FEHSKIAIVG YSGRFPSAAS NDAFWELLRS GQDVHREVPR
DRFEWEKYYD PTGKKKNTSR VKYGCWIDEP GVFDTRFFNM SPKEAENTDP AQRLAITTTY
EAMEMAGMVR NRTASTQQDR IGVFFGTTSD DWREVNSGQD VGTYFIPGGN RAFVPGRISY
FFRFSGPSLS IDTACSSSFA AIQAACSYLW RGECDAAIAG GTNVLTSPDN FAGLDRAHFL
STTGNCNAFD DEASGYCRSD AVGSVVLKRL EDAEADNDPI FGVILGTNTN HCGQTESITR
PHEGDQISVF KNIIRHSGID PTDVSYIEMH GTGTQAGDAT EMNSVLSAFV PKYKRTEMSP
QRPLFIGSAK ANIGHAESAS GVSSLIKVME MMKHNEIPPH CGIKNRINHN YPLDLAQRGV
NIAFEVKPWL RENSNGGKRR VFLNNFSAAG GNTAMLIEDA PLPKSIAHLT DPRSTHLVSV
SAKSPKSLLA NIKSILASLD MRATPPSVAA LSYTTTARRT QHNYRVIVSG SDLDSVKSSL
RSWTQENEST ISDFKPIPSS AKKQARVAFA FTGQGTLYTA IGAQLFAVNE TFKINIHKLN
RLAEIQGFPS FIGLIDGTIT AEELPNVSPV VTQLALVCVQ VALYELWSSW GLNPAAVIGH
SLGEYPALYA AGVLSSADMI YLVATRATLL EKLCTRGTHS MLAVKASEDV AEKLIRDATA
SPECEIACAN QPAGHVIAGP VGKIDEVAQK AAESGVEVVK LNVPYAFHSP QVEPILVDFL
ESASQGVTYN APTIPVLSPF HGRVVAAGET GVLNAEYLVA ACRGQVNFKQ ALSSAGELTD
ADRTLWLEIG AHPACGGMVK GTIDSRVKTI ASLRQNVDAY QTLTTGLKTL YLAGIDINWN
EYHRHFPASH QMVKLPMYAW DLKNYWIQYK NDFLLYKGGD FPQQIAAAPT PVPVVRKYLS
PCAQQIVEEF HDSQQSTMVV ESDIFDPKLL PVLQGHLVNG AALCPSSMYA DLAYTVADYL
IRHCPTQIPD TTGLDVTNVK VSNPLIAKGN ETTHLFRASV KADWPANRVS IDLFSVGANG
KRTASHAKLD VVLYPGQQWL KEWKRNAHFI TSRIKGLNAA IHSSSTETHL IKRGMAYKLF
ASLVDYKKEY QGMSEIVIDS HELEAVSTVQ FQVGKEEFFL NPRWIDSLGG VAGFIMNAND
GVCSKDQVFI NHGWERMRIA EPFDEKKTYH AYNRMQLVEN TTYAGDTYIM DGDRVIAIFE
GVVFQGVPRR ALDHLLPNAA AKSAAATKAP AKAPVAAVAP PRTPTKAAPQ SRQAAPKQKR
SPVSDVFNRI LGLISEEVGV SLSDLVGDAD FASLGVDSLL SLTITAKIRD EMGLDFPSSL
FVDEPTVADL RTLLSNSDED DTPSGDSSTY EDSESQITSP ASSVGPETPG GGEFGSSESA
RVALVVRQAI CEETQVAMEE LKSFTCLSDI GVDSLLGLTL SSRLQDLLQV DIPGNMLMDF
ETVHDLEEEI YNVMGLEKPQ KKASGPTQVP LAVPQPLAVP AVTSISSLPQ ATSILLSGSI
KTAQTILFLF PDGSGSASSY AHVARAVAPS TFAVYGLNCP WRKTARDMTR LGITMSSMVA
QYLPEVQRMI QKVRSEGNST ATIALGGWSA GGILAFEAIR QMGASTPISH LVLFDSPNPI
GLQNPPQRMF DFFDGLGIFG PPPGKNGEKA KTPEWLLDHF NAFISILDDY EPSPLPNAPA
SLMIYAKDGV CKDPNGPQMD IRPDDPREMI WLLNNRTDFT ADGWASIIGR EKLSITVLDE
VNHFSLMDPG PKMPEMGEAV AEFLGRN
