ID ROQA_PENRW Reviewed; 2372 AA.
AC B6HJU6;
DT 08-JUN-2016, integrated into UniProtKB/Swiss-Prot.
DT 16-DEC-2008, sequence version 1.
DT 24-JAN-2024, entry version 86.
DE RecName: Full=Nonribosomal peptide synthase roqA {ECO:0000303|PubMed:22118684};
DE EC=2.3.2.- {ECO:0000269|PubMed:22118684, ECO:0000269|PubMed:23776469, ECO:0000269|PubMed:24225953};
DE AltName: Full=Roquefortine/meleagrin synthesis protein A {ECO:0000303|PubMed:23776469};
GN Name=roqA {ECO:0000303|PubMed:23776469};
GN Synonyms=rds {ECO:0000303|PubMed:22118684}; ORFNames=Pc21g15480;
OS Penicillium rubens (strain ATCC 28089 / DSM 1075 / NRRL 1951 / Wisconsin
OS 54-1255) (Penicillium chrysogenum).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium;
OC Penicillium chrysogenum species complex.
OX NCBI_TaxID=500485;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 28089 / DSM 1075 / NRRL 1951 / Wisconsin 54-1255;
RX PubMed=18820685; DOI=10.1038/nbt.1498;
RA van den Berg M.A., Albang R., Albermann K., Badger J.H., Daran J.-M.,
RA Driessen A.J.M., Garcia-Estrada C., Fedorova N.D., Harris D.M.,
RA Heijne W.H.M., Joardar V.S., Kiel J.A.K.W., Kovalchuk A., Martin J.F.,
RA Nierman W.C., Nijland J.G., Pronk J.T., Roubos J.A., van der Klei I.J.,
RA van Peij N.N.M.E., Veenhuis M., von Doehren H., Wagner C., Wortman J.R.,
RA Bovenberg R.A.L.;
RT "Genome sequencing and analysis of the filamentous fungus Penicillium
RT chrysogenum.";
RL Nat. Biotechnol. 26:1161-1168(2008).
RN [2]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=22118684; DOI=10.1016/j.chembiol.2011.08.012;
RA Garcia-Estrada C., Ullan R.V., Albillos S.M., Fernandez-Bodega M.A.,
RA Durek P., von Doehren H., Martin J.F.;
RT "A single cluster of coregulated genes encodes the biosynthesis of the
RT mycotoxins roquefortine C and meleagrin in Penicillium chrysogenum.";
RL Chem. Biol. 18:1499-1512(2011).
RN [3]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=24225953; DOI=10.1074/jbc.m113.512665;
RA Ries M.I., Ali H., Lankhorst P.P., Hankemeier T., Bovenberg R.A.,
RA Driessen A.J., Vreeken R.J.;
RT "Novel key metabolites reveal further branching of the
RT roquefortine/meleagrin biosynthetic pathway.";
RL J. Biol. Chem. 288:37289-37295(2013).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, INDUCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23776469; DOI=10.1371/journal.pone.0065328;
RA Ali H., Ries M.I., Nijland J.G., Lankhorst P.P., Hankemeier T.,
RA Bovenberg R.A., Vreeken R.J., Driessen A.J.;
RT "A branched biosynthetic pathway is involved in production of roquefortine
RT and related compounds in Penicillium chrysogenum.";
RL PLoS ONE 8:E65328-E65328(2013).
RN [5]
RP DISRUPTION PHENOTYPE.
RX PubMed=25766600; DOI=10.1002/cbic.201402686;
RA Ouchaou K., Maire F., Salo O., Ali H., Hankemeier T., van der Marel G.A.,
RA Filippov D.V., Bovenberg R.A., Vreeken R.J., Driessen A.J.,
RA Overkleeft H.S.;
RT "A mutasynthesis approach with a Penicillium chrysogenum DeltaroqA strain
RT yields new roquefortine D analogues.";
RL ChemBioChem 16:915-923(2015).
RN [6]
RP BIOTECHNOLOGY.
RX PubMed=26692349; DOI=10.1016/j.bmc.2015.11.038;
RA Mady M.S., Mohyeldin M.M., Ebrahim H.Y., Elsayed H.E., Houssen W.E.,
RA Haggag E.G., Soliman R.F., El Sayed K.A.;
RT "The indole alkaloid meleagrin, from the olive tree endophytic fungus
RT Penicillium chrysogenum, as a novel lead for the control of c-Met-dependent
RT breast cancer proliferation, migration and invasion.";
RL Bioorg. Med. Chem. 24:113-122(2016).
CC -!- FUNCTION: Dipeptide synthase; part of the gene cluster that mediates
CC the biosynthesis of the mycotoxins roquefortine C and meleagrin
CC (PubMed:22118684, PubMed:23776469). The first stage is catalyzed by the
CC dipeptide synthase roqA which condenses histidine and tryptophan to
CC produce histidyltryptophanyldiketopiperazine (HTD) (PubMed:22118684,
CC PubMed:23776469). HTD is then converted to roquefortine C through two
CC possible pathways (PubMed:23776469). In the first pathway,
CC prenyltransferase roqD transforms HTD to the intermediate roquefortine
CC D, which is in turn converted to roquefortine C by the cytochrome P450
CC monooxygenase roqR (PubMed:23776469). In the second pathway, HTD is
CC first converted to the intermediate dehydrohistidyltryptophanyldi-
CC ketopiperazine (DHTD) by roqR which is then prenylated by roqD to form
CC roquefortine C (PubMed:23776469). Roquefortine C can be further
CC transformed to meleagrin via three more reactions including oxydation
CC to glandicolin A by roqM, which is further reduced to glandicoline B by
CC roqO (PubMed:23776469). Finally, glandicoline B is converted to
CC meleagrin by the glandicoline B O-methyltransferase roqN
CC (PubMed:22118684, PubMed:23776469). More studies identified further
CC branching and additional metabolites produced by the
CC roquefortine/meleagrin cluster, including roquefortine F, roquefortine
CC L, roquefortine M, roquefortine N and neoxaline (PubMed:24225953).
CC {ECO:0000269|PubMed:22118684, ECO:0000269|PubMed:23776469,
CC ECO:0000269|PubMed:24225953}.
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000269|PubMed:22118684,
CC ECO:0000269|PubMed:23776469, ECO:0000269|PubMed:24225953}.
CC -!- INDUCTION: Expression is decreased in presence of phenylacetic acid
CC (PAA) (PubMed:23776469). {ECO:0000269|PubMed:23776469}.
CC -!- DISRUPTION PHENOTYPE: Decreases the production of roquefortine C and
CC meleagrin, as well as of all their intermediates HTD, DHTD,
CC roquefortine D and glandicoline B (PubMed:22118684, PubMed:23776469,
CC PubMed:25766600). {ECO:0000269|PubMed:22118684,
CC ECO:0000269|PubMed:23776469, ECO:0000269|PubMed:25766600}.
CC -!- BIOTECHNOLOGY: The indole alkaloid meleagrin was shown to be a good
CC candidate to control c-Met-dependent breast cancer proliferation,
CC migration and invasion (PubMed:26692349).
CC {ECO:0000269|PubMed:26692349}.
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DR EMBL; AM920436; CAP96445.1; -; Genomic_DNA.
DR RefSeq; XP_002568558.1; XM_002568512.1.
DR AlphaFoldDB; B6HJU6; -.
DR SMR; B6HJU6; -.
DR STRING; 500485.B6HJU6; -.
DR GeneID; 8315549; -.
DR KEGG; pcs:Pc21g15480; -.
DR VEuPathDB; FungiDB:PCH_Pc21g15480; -.
DR eggNOG; KOG1178; Eukaryota.
DR HOGENOM; CLU_000022_60_2_1; -.
DR OMA; IQRRNDH; -.
DR OrthoDB; 2787863at2759; -.
DR BioCyc; PCHR:PC21G15480-MONOMER; -.
DR Proteomes; UP000000724; Contig Pc00c21.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0016740; F:transferase activity; IEA:UniProtKB-KW.
DR GO; GO:0018130; P:heterocycle biosynthetic process; IEA:UniProt.
DR GO; GO:1901576; P:organic substance biosynthetic process; IEA:UniProt.
DR CDD; cd05918; A_NRPS_SidN3_like; 2.
DR CDD; cd19542; CT_NRPS-like; 1.
DR CDD; cd19545; FUM14_C_NRPS-like; 1.
DR Gene3D; 3.30.300.30; -; 2.
DR Gene3D; 3.40.50.980; -; 2.
DR Gene3D; 1.10.1200.10; ACP-like; 2.
DR Gene3D; 3.30.559.10; Chloramphenicol acetyltransferase-like domain; 2.
DR Gene3D; 3.40.50.12780; N-terminal domain of ligase-like; 1.
DR Gene3D; 3.30.559.30; Nonribosomal peptide synthetase, condensation domain; 2.
DR InterPro; IPR010071; AA_adenyl_domain.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR025110; AMP-bd_C.
DR InterPro; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig_com.
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 NCBIfam; TIGR01733; AA-adenyl-dom; 2.
DR PANTHER; PTHR45527:SF1; FATTY ACID SYNTHASE; 1.
DR PANTHER; PTHR45527; NONRIBOSOMAL PEPTIDE SYNTHETASE; 1.
DR Pfam; PF00501; AMP-binding; 2.
DR Pfam; PF13193; AMP-binding_C; 1.
DR Pfam; PF00668; Condensation; 2.
DR Pfam; PF00550; PP-binding; 2.
DR SMART; SM00823; PKS_PP; 2.
DR SUPFAM; SSF56801; Acetyl-CoA synthetase-like; 2.
DR SUPFAM; SSF47336; ACP-like; 2.
DR SUPFAM; SSF52777; CoA-dependent acyltransferases; 4.
DR PROSITE; PS00455; AMP_BINDING; 2.
DR PROSITE; PS50075; CARRIER; 2.
DR PROSITE; PS00697; DNA_LIGASE_A1; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Ligase; Phosphopantetheine; Phosphoprotein; Reference proteome; Repeat;
KW Transferase.
FT CHAIN 1..2372
FT /note="Nonribosomal peptide synthase roqA"
FT /id="PRO_0000436344"
FT DOMAIN 750..823
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 1819..1895
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 217..610
FT /note="Adenylation 1"
FT /evidence="ECO:0000255"
FT REGION 723..745
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 856..1122
FT /note="Condensation 1"
FT /evidence="ECO:0000255"
FT REGION 1290..1679
FT /note="Adenylation 2"
FT /evidence="ECO:0000255"
FT REGION 1962..2227
FT /note="Condensation 2"
FT /evidence="ECO:0000255"
FT MOD_RES 784
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1856
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2372 AA; 262822 MW; 18EC92731F80B66F CRC64;
MDSYLGRDTI SFPLSKELEA EWTDNGEVLL RSHLLKACWA LLLGRLSETH TITFAVLEQL
VAPPRDACSK LVASSPHLET WQISDRPDSL LVDAAKETHR EPLSGTQTST AVVIRWHDEL
NGPTSLPYAF NAIVVLDCSI SPAKVYMEYS RASLTVNQAW SQLTATVHIL EQLVMSPGIS
LRELDFLGSY STKLILQWNN PYSLARPQVC IHTLILEHCR SQPDAEALCA WDGSVTYAEL
DRFSLAVAHQ LLSLGVGPES VVPLYFEKSR WTVVAMLGVL RAGGAFVLLD PSHPMPRLAE
ICSEVQATVV ITSESLQELG RKLGPRAVTI LDTINSHVDT GRNAFNTSVK PSNAAYVAFT
SGSTGKPKGI VIEHQCFVAN TLAQNAVQNI NSQTRAFQFA SYGFDSSILE TLMTLVAGGC
VCIPSEKQRL NGLADAIRGM RANWLELTPS VARFINPEEV PDVSSVLLVG EPMSQDHITQ
WSGSGKIQLL NAYGPAECSV VATVQPNVQL EDPQNIGCSY SSHCWITNPQ DHDQLEPLGA
VGELLISGPI VARGYLNQPH QKSFISNPRW ATRFGIPPGE RVYKTGDLVR YNLDDGALRY
VGRKDREVKI HGQRVDLHEI EHHASRFQKG MLAVADVLQV NGGSAGKLLA LFIVADNDET
RMTKESFVVP MNDTLLDLVT SIKHWLRDCL PPYMIPTKYT FVNRFPLTRT GKLDRRALVD
LGAASSHSST REQPSNQRDK EDVELDPGLS AKENTLCSVF AEALGCLAIN IGPEDGFYDM
GGNSLAAIEL VARARNHGLE ITVADVIRLQ NPRKIARCTA ESKDVREISP FSLLVDTEQS
LSAATAQCGI GREMIEDIYP CTPLQEGLMH LSITNPGAFM GTYRFSLAPS TDLYRVWAAW
EQLWLVHPIL RTRIIQLQDG QKLQVVTKQK LPFEDISGMD NCQPMNLGTP LARVTYHRGR
GSSGSDSGIF LLTMHHALFD GWSYLQMLGD LQVIYAGDKL SPRPSFKHAI NYISKLSIEE
GRSFWSQELK DFQATMFPTS SRRPTTSPHW QVRSQQIILA ESDMNWTLAN KIKLAWTLVI
SSQTHSNDVV YGLTVSGRNA PVPEIDRIVG PTFATFPFRT QLEDDISVED MLVQMRQHDV
SIMPFEHVGL RRIAESSSDA ALACGFQNLL TIRLQSLQMP PGALIELPEN ENHDLKFASY
ALSIVAQQEG TSLGVKAIFN SCILGADRTE ALLEQFDTLL QRILREPGTK MKDLRTQLSP
EWQQLAAINK KSPSHLRCLH DIINHFSITQ PNSEAVCAWD GSLTYSELVA LARRLAGLLQ
SFGSGSEPGA VIGICVERSK WFPVAILGVM MSGAAMVLLE PNFPTQRLRH ILRDAGARTM
ICSTVFQEKC AGLVDDMLVL THDIVTQADY DAWTPSAVSH HDPMYVAFTS GSTGAPKGVV
IEHGMVYSML KAHKDIIGAS IASRGLLFAS PAFDICLAEI VLILCSGGCV CVPSEAQRMN
SLAKTMTTMQ VNMAMLTPSV ARTLAPAAIP CLQTLILGGE APSASDLETW ASRVKLHQSY
GPAECAMYTT TTHPLTSSSD LGNVGSSQNA SCWIVDPDNH DELQPVGSIG ELLIGGPIVG
RGYINRAQES AAAFICDPVW SENFPFLQGA RLYKTGDLAI LNADGSLNLV GRKDTQVKLN
GQRIELHEIE HCAERYQHGT AVIAELIKPV GIQRPRLIMF VYDPATVETT VGIDSTCHDH
RGLFLPPSRQ NQAYLEGVRD HLNQHLPPYM IPSHFLSLSR LPLSPSGKAD RKTLRQVASK
MDRETLEMYL DNPVAEKRKP TTEQERFVRA SFATALSLNE EAIGMDDSFF ALGGDSITAM
RVLTLCRRRN MAISMQEFLS KNTVTLFCKH VILIQGQAVD SKRQKLLDSQ DLVRGEDHLV
QFQHLDYQLD MVRSQLNLLK SDSIQEIYPC SDAHSGVLEL YTSNYTSTAI FEIRATGSVT
PMQVSNAWSQ LVHRHVALRT VLMKEPKVHA DYLHVVLDKG PAQILALPRS KNALSELKGL
EPVKSWGLSP PHRLIIGHDH SGTLFMRLET GYALIDAFSM TILLEELSLL LQGQPLPERG
VSYREYLSNL RSQSSAETLQ YWTQVLYGVY PSHLPRVPVT QSPLPEPRSQ SRCLPFAQSK
RLDSFWRSNN LTITNVFQLA WALTLAHYTN SRDVCFGTIT SGRDIPHLEV WNIVGSFFNV
LPCRIAIEPT RTVIDTLRQN QEDIQRRNDH QYCSIPDMIR KSGIRSLDNN QQLFNTVLTV
QNPFSIQSST AKDGSNEIDV KLIDLEDATE YDLCVAILPS PSHLKVELRY WSTTVSEGYA
SDILDRLFSQ LEQIVHHATK PDFVQVYECT KH
//
