ADRD_PENRW
ID ADRD_PENRW Reviewed; 2496 AA.
AC B6HV32;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 10-APR-2019, sequence version 2.
DT 03-AUG-2022, entry version 65.
DE RecName: Full=Non-reducing polyketide synthase adrD {ECO:0000303|Ref.2};
DE EC=2.3.1.- {ECO:0000305|Ref.2};
DE AltName: Full=Andrastin A biosynthesis cluster protein D {ECO:0000303|Ref.2};
GN Name=adrD {ECO:0000303|Ref.2}; ORFNames=Pc22g22850;
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 IDENTIFICATION, FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX DOI=10.1016/j.tet.2013.07.029;
RA Matsuda Y., Awakawa T., Abe I.;
RT "Reconstituted biosynthesis of fungal meroterpenoid andrastin A.";
RL Tetrahedron 69:8199-8204(2013).
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 (Ref.2). The first step of the pathway is the synthesis of 3,5-
CC 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 (Ref.2). DMAO is then converted to farnesyl-DMAO by
CC the prenyltransferase adrG (Ref.2). The methyltransferase adrK
CC catalyzes the methylation of the carboxyl group of farnesyl-DMAO to
CC farnesyl-DMAO methyl ester which is further converted to epoxyfarnesyl-
CC DMAO methyl ester by the FAD-dependent monooxygenase adrH (Ref.2). The
CC terpene cyclase adrI then catalyzes the carbon skeletal rearrangement
CC to generate the andrastin E, the first compound in the pathway having
CC the andrastin scaffold, with the tetracyclic ring system (Ref.2). The
CC post-cyclization tailoring enzymes adrF, adrE, adrJ, and adrA, are
CC involved in the conversion of andrastin E into andrastin A. The short
CC chain 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 (Ref.2). {ECO:0000269|Ref.2}.
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; Evidence={ECO:0000305|Ref.2};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:49629;
CC Evidence={ECO:0000305|Ref.2};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000305|Ref.2}.
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. {ECO:0000305|Ref.2}.
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|Ref.2}.
CC -!- CAUTION: Pc22g22850 has first been identified as a mannose-ethanolamine
CC phosphotransferase-like protein. However, resequencing of the region
CC showed that it correspond actually to a non-reducing polyketide
CC synthase. {ECO:0000269|Ref.2}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAP99573.1; Type=Miscellaneous discrepancy; Note=Probable sequencing or genome assembly error.; Evidence={ECO:0000305|Ref.2};
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DR EMBL; AM920437; CAP99573.1; ALT_SEQ; Genomic_DNA.
DR RefSeq; XP_002566179.1; XM_002566133.1.
DR AlphaFoldDB; B6HV32; -.
DR SMR; B6HV32; -.
DR GeneID; 8309011; -.
DR KEGG; pcs:Pc22g22850; -.
DR eggNOG; KOG2125; Eukaryota.
DR HOGENOM; CLU_000022_6_3_1; -.
DR OrthoDB; 848878at2759; -.
DR BioCyc; PCHR:PC22G22850-MON; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000000724; Contig Pc00c22.
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:0031177; F:phosphopantetheine binding; IEA:InterPro.
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; IPR020806; PKS_PP-bd.
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; SM00826; PKS_DH; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 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 1: Evidence at protein level;
KW Methyltransferase; Multifunctional enzyme; Phosphopantetheine;
KW Phosphoprotein; Reference proteome; Transferase.
FT CHAIN 1..2496
FT /note="Non-reducing polyketide synthase adrD"
FT /id="PRO_0000446474"
FT DOMAIN 1652..1726
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 15..254
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255"
FT REGION 387..750
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 914..1223
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1296..1601
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1615..1645
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1888..2121
FT /note="Methyltransferase (CMeT) domain"
FT /evidence="ECO:0000255"
FT REGION 2151..2496
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT COMPBIAS 1625..1644
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 552
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 1001
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 2274
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT ACT_SITE 2433
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT MOD_RES 1686
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2496 AA; 272705 MW; 4D88582E36BCF307 CRC64;
MVDLSQTSPG RPVCLVFGPQ IAEIDESLFY ISRNIDENPA LHFLKDVLRE LPSLWSTISD
TWAPLSSIPG AAQLTALADC VQGGPIATHE NPTNVLLTPL TVIRQIIDAW KFKEKSQNKC
RIMDAQGFCV GFLAAVAVAC SNDAKEFADI ASTMVRLAVC IGTAVDLDGI SHGQARSVAV
RWKSASENEQ LNRLLTSSST AYVSCFTDTN SATVTVAEDA VDDLIKELGS HGLSVKIIDL
KGRFHHASHI TAVQYLSSLC DTDDRLRLAG TGTCVLPLRS NVDGHLIGKI SDIHKIALES
ILTKPSQWAM TVSAAVEHSR ETNDDLSLAA IGTGQFVPRL VRNRVLDHTN NSLWDTKHEM
LPNGIHKSSF PTESMQSTNM AAMAGTATPI AITGMGCRYA QADSPEQLWE MLELGQCGVS
ALPNERFKMD KLRREPKGPF WGNYLANPDV FDHRFFGISA READAMDPQQ RLLLQVGYEA
MESAGYCGLR NPNVPTDIGC YVGVGSDDYT ENVGSTHANA FSATGTLQAF CTGRLSHYFG
WTGPSVVVDT ACSSAAVSIH LACKALQTNE CSIAVAGGVN VMTSPRVTQN LAAASFLSPT
GASKAFDATA NGYCRGEGAG LVVLRPLADA IRNGDPILAV IGGSAVNQGS NCSPITVPDS
NSQRSLYRKA LLASGIPPED VTYVEAHGTG TQVGDPIEFD SIRKAFGGPG RSEKLHVGSI
KDNIGHTETA SGVAGLLKTV LMMQKQQIPK QANFVQLNPK IPALDDAEIA IPTKSIHWPS
AATSSSNAVA MVTNYGAAGS NAALVVKQYK APSEPSNRAS LLPSEVPIIL AANSVESLRS
YCKVLLPSVR NAQLGSCQDI AYNLAVKQSR DMDYISTLTV PADQPNELIA KLESMSTETT
NPKKQPSSRL PVILCFGGQN GNETTLSEDL FNQCELLQYH LMECEKVCRT RDLPSLFPRI
FQTGPIEDTV SLHCILFSIQ YASAMSWISS GLQVDRIIGH SFGQLTGLCV AGGLNLSDAL
YLVSERARMI QSMWGSERGA MLLVEGTEAD VQSLLNRATQ QMADAAVDVA CVNGPRNIIL
AGDERSLQMI QKLSAETPSI LRTKRLKNTH AFHSRLVDSI VPSLSKVAQQ LQYTPLSIPL
EACWQDGDWS FVSPDKIVAH SRGRVDFQTA VERVAQRIQG PAIWLEAGSA SPIIPLVRRV
IDTVTASSKD HLYQSLDLGG PQGQKNLSQA TCNLWSRGAK VQFWQFHGSQ AKSYNWINLP
PYQFAQTRHW IAYDPNAFAP LPEDKPTVPS SGGPKEFVQL LTKQPTECVF AINTKDHLYQ
ECTQGHAVLD QNLCPASLYF EVIVRAAGLV RPENDTSPSM PHLQNLAISA PLVLNPTGNV
LLSLTRARAG DSPWSFSLYT REPNTNLVTT HATGEISLHP FGQNTPLFVR LHSMNRLIDS
SRVDSIANSR ESSGLKGFAV YQAFRRVVNY ADCYRGVERV FATEHEAAGI VNLLSSKTKD
AACDPMLVDN FIQVAGIHVN CLSETNEDEV FVCTGVGEIL IGEAFMTRDP KSSRSWGVYS
NMDRSVKNKI ACDTFVLDRE TGKLAVTILS AEFTSVSIAG LARVLKKLNN QADDEKASPD
LSLRNDSKVD VNPTPQNTAP VVQPTRQAAA EPGYFVVVQE MLCDLLGIVS EELLPSSNLE
EIGVDSLMRT EVLVEIKKRF NVSIDASTLT EIPNIQALVQ TIFPDAATAP LTHGVHPSLE
IETTDVPDSE NNTHVIPTPI SDADVHGLID IAPTLFTDIQ RSTSHSEMTQ WNGFCESVYP
KQMALVTAYV VEAFKSLGVS LDKFEAEGVI PQVPVLKQHG KVRNQLYSIL EFSNLIRATD
RGFVRTTIPV PTISSDVLHE EIIRLYPQHR SEHHLLKTTG SRLSDCLSGA ADPLSLLFQD
AEARRLMEDV YTNAPMFKGA TNHLAQYLVN LLGRMDTTRE INILEIGGGT GGTTKALLNQ
LTAVPGLRFQ YTFTDLSSGL LTLARKKFKH YNFMKYQVLN VEQTPTPDMV GQYDIILSSN
CVHATRNLVQ SCSNINKLLR PDGILCLIEL TRNLFWFDLV FGLLEGWWLF EDGRQHALAT
EHMWKQTLVQ SGFQWVDWTH NDSEESNVLR VITASPTSAV ILPPTPGSPL RVMNEETVPY
GKNGAVELSA DIYYPRDLQP IGKPRPIALL IHGGGHIMLS RRDVRSKQVK MLLDAGFLPV
SVDYRLCPEV SLSEGPMHDV CDALSWARNV LPKLSLCRPD IQSDGTQVVA VGWSTGAHLA
MTLAWTAEQR GIEPPQAILA FYGPTDYEDP FWSKPNFPYG KSAASPEMSY NLWEGMHETP
ITAYNPPANQ NALGGWMSPA DPRSRIALHM NWKGQSLPML LHGGHFWSAH KDGDCGEDLP
VPTLKEIQAV SPLAQIRNGC YKTPTFIIHG TLDDLIPVEQ AQRTSQELVT KGVEVELRIV
DKAVHLFDIY PGFEKDHAAA QAVQDGYEFL RDHVRY
