PENN_PENTH
ID PENN_PENTH Reviewed; 2797 AA.
AC A0A1B2CTC5;
DT 25-MAY-2022, integrated into UniProtKB/Swiss-Prot.
DT 02-NOV-2016, sequence version 1.
DT 03-AUG-2022, entry version 29.
DE RecName: Full=Nonribosomal peptide synthetase penN {ECO:0000303|PubMed:25859931};
DE Short=NRPS penM {ECO:0000303|PubMed:25859931};
DE EC=6.3.2.- {ECO:0000305|PubMed:25859931};
DE AltName: Full=Penigequinolones biosynthesis cluster protein N {ECO:0000303|PubMed:25859931};
GN Name=penN {ECO:0000303|PubMed:25859931};
OS Penicillium thymicola.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=293382;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DISRUPTION PHENOTYPE, AND
RP PATHWAY.
RC STRAIN=IBT 5891 / CBS 111225;
RX PubMed=25859931; DOI=10.1021/jacs.5b03022;
RA Zou Y., Zhan Z., Li D., Tang M., Cacho R.A., Watanabe K., Tang Y.;
RT "Tandem prenyltransferases catalyze isoprenoid elongation and complexity
RT generation in biosynthesis of quinolone alkaloids.";
RL J. Am. Chem. Soc. 137:4980-4983(2015).
RN [2]
RP FUNCTION.
RX PubMed=28114276; DOI=10.1038/nchembio.2283;
RA Zou Y., Garcia-Borras M., Tang M.C., Hirayama Y., Li D.H., Li L.,
RA Watanabe K., Houk K.N., Tang Y.;
RT "Enzyme-catalyzed cationic epoxide rearrangements in quinolone alkaloid
RT biosynthesis.";
RL Nat. Chem. Biol. 13:325-332(2017).
CC -!- FUNCTION: Nonribosomal peptide synthetase; part of the gene cluster
CC that mediates the biosynthesis of penigequinolones, potent insecticidal
CC alkaloids that contain a highly modified 10-carbon prenyl group
CC (PubMed:25859931). The first stage is catalyzed by the nonribosomal
CC pepdide synthetase penN that condenses anthranilic acid and O-methyl-L-
CC tyrosine to produce 4'-methoxycyclopeptin (By similarity). 4'-
CC methoxycyclopeptin is then converted to 4'-methoxydehydrocyclopeptin by
CC the ketoglutarate-dependent dioxygenase penM through dehydrogenation to
CC form a double bond between C-alpha and C-beta of the O-methyltyrosine
CC side chain (By similarity). PenM also converts its first product
CC methoxydehydrocyclopeptin to 4'-methoxycyclopenin (By similarity). The
CC following conversion of 4'methoxycyclopenin into 4'-methoxyviridicatin
CC is catalyzed by the cyclopenase penL (By similarity). 4'-
CC methoxyviridicatin is the precursor of quinolone natural products, and
CC is further converted to quinolinone B (Probable). The prenyltransferase
CC penI then catalyzes the canonical Friedel-Crafts alkylation of
CC quinolinone B with dimethylallyl cation to yield dimethylallyl
CC quinolone, which is subjected to FAD-dependent dehydrogenation by the
CC FAD-linked oxidoreductase penH to yield conjugated aryl diene
CC (PubMed:25859931). The delta(3') double bond then serves as the site of
CC the second alkylation with DMAPP catalyzed by the prenyltransferase
CC penG to yield a carbenium ion intermediate, which can be attacked by
CC H(2)O to yield a styrenyl quinolone containing a C3'-hydroxyprenyl
CC chain, or undergo cyclization to yield yaequinolones J1 and J2
CC (PubMed:25859931). The conversion of the styrenyl quinolone into the
CC tetrahydrofuran-containing yaequinolone C is performed by the FAD-
CC dependent monooxygenase penE and involves epoxidation of the terminal
CC C7'-C8' olefin, followed by epoxide ring opening initiated by the C3'
CC hydroxyl group (PubMed:25859931). The predicted cysteine hydrolase penJ
CC acts as an epoxide hydrolase that enhances the rate of the 5-exo-tet
CC cyclization step, increasing the yield of yaequinolone C
CC (PubMed:25859931, PubMed:28114276). PenF catalyzes the cationic
CC rearrangement of the epoxide formed by penE (before ring opening to
CC produce yaequinolone C) into yaequinolone D (PubMed:28114276). Finally,
CC the short-chain dehydrogenase/reductase (SDR)-like reductase penD,
CC catalyzes both the dehydration of yaequinolone D and the reduction of
CC the resulting oxonium to yield penigequinolone (PubMed:28114276).
CC {ECO:0000250|UniProtKB:C8VJQ3, ECO:0000250|UniProtKB:Q5AR53,
CC ECO:0000250|UniProtKB:Q5AR54, ECO:0000269|PubMed:25859931,
CC ECO:0000269|PubMed:28114276, ECO:0000305|PubMed:25859931}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:25859931}.
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000269|PubMed:25859931}.
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:25859931}.
CC -!- DOMAIN: NRP synthetases are composed of discrete domains (adenylation
CC (A), thiolation (T) or peptidyl carrier protein (PCP) and condensation
CC (C) domains) which when grouped together are referred to as a single
CC module. Each module is responsible for the recognition (via the A
CC domain) and incorporation of a single amino acid into the growing
CC peptide product. Thus, an NRP synthetase is generally composed of one
CC or more modules and can terminate in a thioesterase domain (TE) that
CC releases the newly synthesized peptide from the enzyme. Occasionally,
CC methyltransferase domains (responsible for amino acid methylation) are
CC present within the NRP synthetase. PenN has the following
CC architecture:A-T-C-A-M-T-C. {ECO:0000305|PubMed:25859931}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of penigequinolones A
CC and B. {ECO:0000269|PubMed:25859931}.
CC -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR EMBL; KX528209; ANY57892.1; -; Genomic_DNA.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0043604; P:amide biosynthetic process; IEA:UniProt.
DR GO; GO:1901566; P:organonitrogen compound biosynthetic process; IEA:UniProt.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.30.300.30; -; 3.
DR Gene3D; 3.30.559.10; -; 2.
DR Gene3D; 3.40.50.12780; -; 2.
DR Gene3D; 3.40.50.150; -; 1.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR010071; AA_adenyl_domain.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR042099; ANL_N_sf.
DR InterPro; IPR023213; CAT-like_dom_sf.
DR InterPro; IPR001242; Condensatn.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR Pfam; PF00501; AMP-binding; 2.
DR Pfam; PF00668; Condensation; 2.
DR Pfam; PF00550; PP-binding; 2.
DR SMART; SM00823; PKS_PP; 2.
DR SUPFAM; SSF47336; SSF47336; 2.
DR SUPFAM; SSF53335; SSF53335; 1.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 2.
DR PROSITE; PS00455; AMP_BINDING; 2.
DR PROSITE; PS50075; CARRIER; 2.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 3: Inferred from homology;
KW Ligase; Phosphopantetheine; Phosphoprotein; Repeat.
FT CHAIN 1..2797
FT /note="Nonribosomal peptide synthetase penN"
FT /id="PRO_0000455370"
FT DOMAIN 751..824
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 2277..2351
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 239..625
FT /note="Adenylation 1"
FT /evidence="ECO:0000255"
FT REGION 830..856
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 870..1299
FT /note="Condensation 1"
FT /evidence="ECO:0000255"
FT REGION 1328..1731
FT /note="Adenylation 2"
FT /evidence="ECO:0000255"
FT REGION 1857..1953
FT /note="Methyltransferase"
FT /evidence="ECO:0000255"
FT REGION 2516..2658
FT /note="Condensation 2"
FT /evidence="ECO:0000255"
FT COMPBIAS 841..856
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 785
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 2311
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2797 AA; 307817 MW; 9A6EDB04B5C690FD CRC64;
MYHQLESHGV FPTLGDDAAK LVRTTHVQEI AFTPISEIQR FCEAQNISCD SFYLNVWSLV
LRAFAETNSV CVGFGDFRPS GARLDQALFK ILQTTLSPKS SILSILQGFK QDERAFSVNH
REPAHNTGVV FISEASGPLD LASLGKLKYD LLMVVSFDSK SIPISLFLVY RPSTLSQSHA
ENLSSNITQA MQQVLARPNS FVNDVELFST FNKSLVLCWN GLERKAASLL EVIQGHVRSR
PDHPAICAWD GTISYSQLDM LTTQWASYLQ SRGVQPGCLV PIMMEHSKWA IIGEIAILKA
GAAFVPIDPA HPVSRLKGIV QRTKANIAVS SGHLIDKLSS LVDTVVEISD QTTSGLPEAV
RHGAANPVPF DRTAYVLFTS GSTGQPKGCV VSYRALSDVV HQTTALNIDS ESRVLQFASY
TYGMSLIEVH CTLAAGATIC IPSDYHRLNA LSSAIQSTQV TWAILTASTT LTIAETARYL
RTLVVAGEPM GIDHVRSLAD KVELLQAFGL TEWGGICCVS QRIRSEGDVR LIGRSPTANL
WLIDPTDGSK LAPVGAAAEL FVEGPALADG YLEDPHQTAA VFIKRPPWIP APTGVRLYRT
GDLVRYTGDG NLLYIARKDS QVKIRGMRVE LGEVEYQIRQ AFPALGEAIA VATTTKESSG
MPILAAFLHM ENQLDLSGQS FSHMIDTIKT SLRKTLPDYM WPSIYIPLDS VPLTISRKID
RKDLQLRVQK STRMELEENQ VSSACIVAPL TDTERHVHRF VAELLHLDPL SFGMNQNFIN
LGGDSVSAMR LVNKCKYQGY RVTVGEILEV RTLSDIVSLV RTATTSSSVP SAGAEISRSD
APTESPATGS FEGSGYTTIP RLSQSGPIEQ SFSQARMWFL EELHPGSSWY ILPYATRLQG
PLQLDHLEAA LSALSERHET LRTTFESRDG TGLQIVAPFR PKPLEVIEVT SDSSIAALRT
ALQEQMKPFD LTKDTWRSAV LRLSPTDHVF SVVFHHIISD GWSVDVFMKT LETFYSAVIR
GQPPLHITKP LQIQYRDFSI WQRQEQSRIH QKQIAYWIQQ LHGSKPAEFL CDKPRPTKPS
IAAGSMDVKI DGELYQALQG FCRSRQVTPF TTLLAAFRTT HYRLTGASDA TIGIPSASRT
RPELEELIGY FGNVQCIRTV IDSRGQSFQQ LVQQVQSATT AASQNQDVPF DQVVSRLLKD
RDMSRHPLVQ VTFVLHPQAN FGQLHLEGLR AEHLHLPQVT RLDLEFHLYP GDGCLQGDIL
YSADLFNPET IRTLRSVFYD VLSEGLCHPD IEIGSLLLTD AYPVLDQRGL IYTAHEAPFQ
GCSIIDMFHQ QVAAHGDQMA IKDTHTQLTY CELDRRSDML ATWLKNSFLF VEETPVGVFG
NRSCESIVTI LGILKAGLAY VPLDADAPPQ RTEMILSCLP SCQLVLLLSG LMAPPTLPSN
IKFAYVSNSS DVKVEEVDAF LTHTPTPRAT NLAYIVFTSG TTGTPKGVMV EHRGVVRLAK
DPEIVAHTRD FKVASHVLNP AFDASGFEVY ATLLNGGTLV CIDKNIVWDY AALGATLVKH
GVQRAFFTTA VLKQCLLSAP YIMSDLEILY VGGDKLDPHD MAVARRFGKV RIFNVYGPTE
NSVVSTRYAI PDGEAAVNGM PIGRSIAGSG AYVMDPNLRL VPIGAMGELV VTGLGLARGY
TNPEQNIGRF VTVSIGGQVV HAYRTGDMVR YRPSDAQLEF FGRMDQQVKI RGYRVELAEI
DNALALNSLV SSAVTVLQTQ EDQEQELVSF VTIQDTAANV ENLEEHISNA HVNSWKDHAE
GGDHYGKLGA VDPATLGRDF LGWVSMYDGE AIDTEVMTEW LEDTIAAIHL CDAASALEIG
TGTGMILFNL IDSLKEYYGL EPSRQAVEFV QRAVRCVPKA ASKVRIQQGT ASALVGLKAT
GPIDLAVVNS VAQYFPSAKY MTRVIKQLIQ LHDLNCIFFG DIRSYGLYEE FQASKVLHLY
GHTLSAREFS QKMAEIVQLE KELLIDPAFF TALATEFPEL IEHVEIMPKR MKTTNELSCY
RYTAILHIRR PSQSLLVHEV EQSSWLDFEA SGLDYRSLTQ MLKTSNDVSV LAFSNIPFKK
TIMERHVVNF LRHLPTGAGS AGWSMDVCQQ ALVCPAIDAT ELIDVAQLTG WQVEISWARQ
HSQFGGLDAI FHRLKPEDNG SRVFFQFPTD HGRRGLSCAF SNDPLALQRN QRIENELLEN
LRARLPSYMV PKRIRVLDRM PINNIGKVDR QALAKRVDIP PPAGVLTARS SPRNDMSFTD
DIERAMWEEF AGVLGVEVGI ADSFFDCGGH SLMAIKLVSR INKRLQSTVP VSDLFQYPSV
SRLAGRVRGF RAPSNSTVSY QPFSLLPGSL SRLPYIDSPY GSEPHLPPST EIIDMLPVTE
SQAWFLADWS LVSHSFRIEG ALDVDGLRAA CQAVVRHHAT LRTVFTKLLG RLVQVVCGSV
DAPFAHVYTD GDLESECRSL CAADGGAPSG LTTGFTLLSR STIEHIFILR FSHAQYDGIS
LSSILSDLAA AYAGTAPLPT TAPFSGYVHV AALSRSVALD FWKKYLEGSV LTTLRPSNTA
INARVVDLTR EAVGKLHQLA DITFPTIVNA AIAITLASLV KRNDVTFACV MSSRGVLSQG
ADSVQGPCVN RTLIRVQLSP DSTALGFCRG LRKNQARVSA ENHLELGDVL ENCTSWSSSD
RLAPWITHLP ADKATSTLAL PGACITYRST DVRINPRNQI LVRSVITDQQ QACIQVQVSS
TVMDGSYAFS LASKILNTAQ ALSMSAERTL SSIDVHE
