ADRD_PENRO
ID ADRD_PENRO Reviewed; 2495 AA.
AC A0A1Y0BRF1;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 30-AUG-2017, sequence version 1.
DT 03-AUG-2022, entry version 16.
DE RecName: Full=Non-reducing polyketide synthase adrD {ECO:0000303|PubMed:28529508};
DE EC=2.3.1.- {ECO:0000305|PubMed:28529508};
DE AltName: Full=Andrastin A biosynthesis cluster protein D {ECO:0000303|PubMed:28529508};
GN Name=adrD {ECO:0000303|PubMed:28529508};
OS Penicillium roqueforti.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=5082;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], IDENTIFICATION, FUNCTION, DISRUPTION
RP PHENOTYPE, AND PATHWAY.
RC STRAIN=CECT 2905;
RX PubMed=28529508; DOI=10.3389/fmicb.2017.00813;
RA Rojas-Aedo J.F., Gil-Duran C., Del-Cid A., Valdes N., Alamos P., Vaca I.,
RA Garcia-Rico R.O., Levican G., Tello M., Chavez R.;
RT "The biosynthetic gene cluster for andrastin A in Penicillium roqueforti.";
RL Front. Microbiol. 8:813-813(2017).
CC -!- FUNCTION: Non-reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of andrastins, meroterpenoid compounds
CC that exhibit inhibitory activity against ras farnesyltransferase,
CC suggesting that they could be promising leads for antitumor agents
CC (PubMed:28529508). The first step of the pathway is the synthesis of
CC 3,5-dimethylorsellinic acid (DMOA) by the polyketide synthase adrD via
CC condensation of one acetyl-CoA starter unit with 3 malonyl-CoA units
CC and 2 methylations (By similarity). DMAO is then converted to farnesyl-
CC DMAO by the prenyltransferase adrG (By similarity). The
CC methyltransferase adrK catalyzes the methylation of the carboxyl group
CC of farnesyl-DMAO to farnesyl-DMAO methyl ester which is further
CC converted to epoxyfarnesyl-DMAO methyl ester by the FAD-dependent
CC monooxygenase adrH (By similarity). The terpene cyclase adrI then
CC catalyzes the carbon skeletal rearrangement to generate the andrastin
CC E, the first compound in the pathway having the andrastin scaffold,
CC with the tetracyclic ring system (By similarity). The post-cyclization
CC tailoring enzymes adrF, adrE, adrJ, and adrA, are involved in the
CC conversion of andrastin E into andrastin A. The short chain
CC dehydrogenase adrF is responsible for the oxidation of the C-3 a
CC hydroxyl group of andrastin E to yield the corresponding ketone,
CC andrastin D. The ketoreductase adrE stereoselectively reduces the
CC carbonyl moiety to reverse the stereochemistry of the C-3 position to
CC yield andrastin F. The acetyltransferase adrJ is the acetyltransferase
CC that attaches the acetyl group to the C-3 hydroxyl group of andrastin F
CC to yield andrastin C. Finally, the cytochrome P450 monooxygenase adrA
CC catalyzes two sequential oxidation reactions of the C-23 methyl group,
CC to generate the corresponding alcohol andrastin B, and aldehyde
CC andrastin A (By similarity). {ECO:0000250|UniProtKB:B6HV32,
CC ECO:0000269|PubMed:28529508}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + 3 malonyl-CoA + 2 S-adenosyl-L-methionine = 3,5-
CC dimethylorsellinate + 3 CO2 + 4 CoA + 2 S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:49628, ChEBI:CHEBI:16526, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57288, ChEBI:CHEBI:57384, ChEBI:CHEBI:57856,
CC ChEBI:CHEBI:59789, ChEBI:CHEBI:131856;
CC Evidence={ECO:0000250|UniProtKB:B6HV32};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:49629;
CC Evidence={ECO:0000250|UniProtKB:B6HV32};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:28529508}.
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; a methyltransferase (CMeT) domain that
CC transfers methyl groups to the growing polyketide; and an acyl-carrier
CC protein (ACP) that serves as the tether of the growing and completed
CC polyketide via its phosphopantetheinyl arm.
CC {ECO:0000305|PubMed:28529508}.
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:0000305|PubMed:28529508}.
CC -!- DISRUPTION PHENOTYPE: Drastically reduces the production of andrastin
CC A. {ECO:0000269|PubMed:28529508}.
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DR EMBL; KY349137; ART41209.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A1Y0BRF1; -.
DR SMR; A0A1Y0BRF1; -.
DR UniPathway; UPA00213; -.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0008236; F:serine-type peptidase activity; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IEA:InterPro.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 2.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR013094; AB_hydrolase_3.
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; IPR041068; HTH_51.
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; IPR013217; Methyltransf_12.
DR InterPro; IPR001375; Peptidase_S9.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR032088; SAT.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF07859; Abhydrolase_3; 1.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF18558; HTH_51; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08242; Methyltransf_12; 1.
DR Pfam; PF00326; Peptidase_S9; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR Pfam; PF16073; SAT; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
PE 3: Inferred from homology;
KW Methyltransferase; Multifunctional enzyme; Phosphopantetheine;
KW Phosphoprotein; Transferase.
FT CHAIN 1..2495
FT /note="Non-reducing polyketide synthase adrD"
FT /id="PRO_0000446475"
FT DOMAIN 1651..1725
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 14..252
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255"
FT REGION 386..749
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 913..1222
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1295..1600
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1887..2120
FT /note="Methyltransferase (CMeT) domain"
FT /evidence="ECO:0000255"
FT REGION 2150..2495
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT ACT_SITE 551
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 1000
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 2273
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT ACT_SITE 2432
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT MOD_RES 1685
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2495 AA; 273592 MW; D1BB768F42A27962 CRC64;
MAEPPKTPGR PVCVVFGPQS SEIDETLFYI SRNIDENPSL GFLKDVLQEL PSLWSPITDA
WSSLSSIPGA TQLTVLAECV QGTTAAPKSA MNVFMTPLTV IRQIIDVWKF KEESQNRCRI
VDAQGFCVGF LAAVAVASSN DSNEFEDIAS TMIRLAVCIG AAVDLDGILH GPARSVALRW
KSDSEKEQLD RVLGSSSTAY ISCFTDATSV TVTVAEDEVD DLTKELGGHG LSVKIIDLKG
RFHHSRHVTA VQYLADLCET DARFRLARTS PCVLPLRSNV DGHVIGKRFA IHKTALESIL
TKPSQWAITV SAAFEQARET DDDLAFVVIG TGQFVPRLVR TRVLDHLNNK WSDTKQHAIL
PNGIHRSSST TRSRPSIDMA PIGPTVIPIA ITGMGCRYAQ ADSPEQLWEM LELGRCGVNA
LPNERFKMEN LLREPKGPFW GNYLANPDVF DHRFFGISAR EAEAMDPQQR LLLQVGYEAM
ESAGYCGLRT SNIPTDVGCY VGVGSDDYTD NVGSSNANAF SATGTLQAFC TGRLSHYFGW
TGPSVVVDTA CSSAAVSIHL ACKALQTNEC SIAVAGGVNV MTSPRVTQNL AAASFLSPTG
ASKAFDASAD GYCRGEGAGL VVLRPLKDAI HNGDPILAII GGSAVNQGSN RSPITVPDSD
SQISLYRKAL VTSGVRPEDV TYVEAHGTGT QVGDPIEFES IRKTFGRPAR TERLYVGSVK
DNIGHTETSS GVAGLLKTVL MMQKHQIPKQ ANFVQLNPKI PTLDDAAIAI PTKSIHWPSA
ANSSSTAVAM VTNYGAAGSN AALVVKQYKA KSGLSNPVSP LPSEVPVILA ANTVESLRSY
CKALLSSVCD AQLTSCQDTA YNLAIKQSRD MDYVSAFSIP VDRPNELIAK LESISRETTN
LEKQPAARLP VVLCFGGQNG NEATISEDLF NQCELLQYHL TECEKVCQTL DLPSLFPSIF
QPGPIEDTVS LHCILFSIQY ASAKSWIDSG LQVDRIIGHS FGQLTGLCVG GGLSLSDALY
LVSERAKMIH SMWGSERGAM LLVEGSEVEV QGLLNRAAEH MADVAVDVAC VNGPRNTILA
GDERSLQMIE KLSAKAPSIL RTKRLKNTHA FHSRLVDNIV PPLTKVAQQL QYKPLSIPIE
ACSQYDDWTY VTPGKIVDHS RRRVDFQTAV ERVAQRIQGP AIWLEAGSAS PIIPLVRRVI
DTVAAFSNGH VYQALDLGGA LAHRSLSQAT CNLWSRGVKV QFWQFHDSQA KSYNWINLPP
YQFAQTRHWI GYDPNAFASL PEVKPTVPSS DAPKEFVQLL TKQPTECVFA INTNDPLYQE
CTQGHAVLDQ NLCPASLYFE IIVRAAGLIR PENDISPAMP HLKDLAISAP LVLNPRGNVM
LSLTRARVGD STWSFSLFTR ESNKNKVTTH ATGEISLHPF GQNTPLFVRL HSMNRLIDSS
RVDSIANSRE SSGLKGFAVY QAFRRVVNYA DYYRGVEQVF ATDHEAAGIV NLPSSRTKDA
SCDPMLVDNF IQVAGIHVNC LSETKEDEVF VCTGVGEILI GEAFMTRDPN CSRSWAVYSN
VDRSIKNKIT CDTFVLDRET DKLAVTILSA TFTSVSIAGL SRVLKKLNNQ PDDKKVPLGQ
SLRDDSKVAL NPTPQNALAA VPAPLHSAPD SGHFMVVQEM LCDLLGIASD ELLPSSNLED
IGVDSLMRTE VLVEIKKRFN FTIDTSSFVE IPDILTLVQT IFPDAATAPL TNGVHPSLQI
ETTEAVDSES NTHVIPTPIS DEEIHGLIDI APGLFTDIQR SMVHSQSTQW DGFCESVYPR
QMALVTAYVV EAFKSLGVSL ESFEAEHLIP QVPVLQQHSK VRSQLYSILQ FSNLIRATDH
GFVRTSVPVS TISSDVLHEE IIRLYPQHTS EHNLLRTTGS RLSDCLSGAA DPLSLLFQDA
EARRLMEDVY TNAPMFKAAT NHLAQYLVNL LGRVDTTREI KILEIGGGTG GTTKALLSQL
TAVPGLRFQY TFTDLSSGLL ALARKKFKHY SFMKYQVLNI ERAPTPDMLG QYDIVLSSNC
VHATRSLVQS CSNINKLLRP DGLLCLIELT RNLFWFDLVF GLLEGWWLFE DGRQHALATE
HVWKQTLSQS GFQWVDWTYN DSQESNVLRV ITASPTSAVI LPPSPRSPLY LMNEETIVYG
KNDGVELSAD IYYPRDLQPI GKPRPIALLI HGGGHIMLSR RDIRSKQVRM LLNAGFLPVS
VDYRLCPEVS LTEGPMHDVC DALCWARHVL PSLTLGRPDI QPDGTQAVAV GWSTGAHLAM
TLAWTSQQRG IAPPNAILAF YGPTDYEDSF WSQPNFPYGK NAASPEMRYD LWEGIYETPI
TAYNPPVDQK ALGGWMSPAD PRSRIALHMN WKGQSLPMLL HGGRFWSDHK DGDCGEELPV
PTLEEIQAVS PLAQIRNGHY KTPTFIIHGT LDDLIPVEQA QRTSQELVTK GVEVQLRVVD
KAVHLFDIYP GFEKDQAASR AVEDGYEFLR DHVRY
