PKS1_SARSH
ID PKS1_SARSH Reviewed; 2729 AA.
AC A5PHD6; A0A2U8U2L1;
DT 25-OCT-2017, integrated into UniProtKB/Swiss-Prot.
DT 10-FEB-2009, sequence version 2.
DT 03-AUG-2022, entry version 83.
DE RecName: Full=3-methylorcinaldehyde synthase {ECO:0000303|PubMed:17912413};
DE Short=MOS {ECO:0000303|PubMed:17912413};
DE EC=2.3.1.- {ECO:0000269|PubMed:17912413, ECO:0000269|PubMed:20552126, ECO:0000269|PubMed:29773797};
DE AltName: Full=Non-reducing polyketide synthase 1 {ECO:0000303|PubMed:17912413};
DE AltName: Full=Xenovulene A biosynthesis cluster protein aspks1 {ECO:0000303|PubMed:29773797};
GN Name=aspks1 {ECO:0000303|PubMed:29773797};
GN Synonyms=pks1 {ECO:0000303|PubMed:17912413};
OS Sarocladium schorii (Acremonium strictum (strain IMI 501407)).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Sarocladiaceae; Sarocladium;
OC unclassified Sarocladium.
OX NCBI_TaxID=2203296;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], DOMAIN, FUNCTION, CATALYTIC ACTIVITY,
RP AND PATHWAY.
RX PubMed=17912413; DOI=10.1039/b708614h;
RA Bailey A.M., Cox R.J., Harley K., Lazarus C.M., Simpson T.J., Skellam E.;
RT "Characterisation of 3-methylorcinaldehyde synthase (MOS) in Acremonium
RT strictum: first observation of a reductive release mechanism during
RT polyketide biosynthesis.";
RL Chem. Commun. (Camb.) 39:4053-4055(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], INDUCTIONY, FUNCTION, DISRUPTION
RP PHENOTYPE, AND PATHWAY.
RX PubMed=29773797; DOI=10.1038/s41467-018-04364-9;
RA Schor R., Schotte C., Wibberg D., Kalinowski J., Cox R.J.;
RT "Three previously unrecognised classes of biosynthetic enzymes revealed
RT during the production of xenovulene A.";
RL Nat. Commun. 9:1963-1963(2018).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=9262310;
RA Thomas P., Sundaram H., Krishek B.J., Chazot P., Xie X., Bevan P.,
RA Brocchini S.J., Latham C.J., Charlton P., Moore M., Lewis S.J.,
RA Thornton D.M., Stephenson F.A., Smart T.G.;
RT "Regulation of neuronal and recombinant GABA(A) receptor ion channels by
RT xenovulene A, a natural product isolated from Acremonium strictum.";
RL J. Pharmacol. Exp. Ther. 282:513-520(1997).
RN [4]
RP FUNCTION, DOMAIN, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=20552126; DOI=10.1039/c0cc01162b;
RA Fisch K.M., Skellam E., Ivison D., Cox R.J., Bailey A.M., Lazarus C.M.,
RA Simpson T.J.;
RT "Catalytic role of the C-terminal domains of a fungal non-reducing
RT polyketide synthase.";
RL Chem. Commun. (Camb.) 46:5331-5333(2010).
CC -!- FUNCTION: Non-reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of xenovulene A, an unusual
CC meroterpenoid that has potent inhibitory effects on the human gamma-
CC aminobutyrate A (GABAA) benzodiazepine receptor (PubMed:17912413,
CC PubMed:29773797, PubMed:20552126). The first step of xenovulene A
CC biosynthesis is the biosynthesis of 3-methylorcinaldehyde performed by
CC the non-reducing polyketide synthase aspks1 (PubMed:17912413,
CC PubMed:29773797, PubMed:20552126). The salicylate hydroxylase asL1 then
CC catalyzes the oxidative dearomatization of 3-methylorcinaldehyde to
CC yield a dearomatized hydroxycyclohexadione (PubMed:29773797). The 2-
CC oxoglutarate-dependent dioxygenase asL3 further catalyzes the oxidative
CC ring expansion to provide the first tropolone metabolite
CC (PubMed:29773797). The cytochrome P450 monooxygenase asR2 allows the
CC synthesis of tropolone hemiacetal (PubMed:29773797). In parallel, a
CC previously unrecognised class of terpene cyclase, asR6, produces alpha-
CC humulene from farnesylpyrophosphate (FPP) (PubMed:29773797). The
CC putative Diels-Alderase asR5 probably catalyzes the formation of the
CC tropolone-humulene skeleton by linking humulene and the polyketide
CC moiety (PubMed:29773797). Oxidative-ring contractions catalyzed by asL4
CC and asL6 then processively remove carbon atoms from the polyketide to
CC yield xenovulene A (PubMed:29773797). {ECO:0000269|PubMed:17912413,
CC ECO:0000269|PubMed:20552126, ECO:0000269|PubMed:29773797}.
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:17912413, ECO:0000269|PubMed:20552126,
CC ECO:0000269|PubMed:29773797}.
CC -!- INDUCTION: Expression is significantly up-regulated under xenovulene A
CC producing condition. {ECO:0000269|PubMed:29773797}.
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; an acyl-carrier protein (ACP) that serves
CC as the tether of the growing and completed polyketide via its
CC phosphopantetheinyl arm; a C-methylation (C-Met) domain; and a C-
CC terminal reductase (R) domain (PubMed:20552126). Methylation occurs
CC during the processive construction of the carbon backbone, directly
CC after the second extension at the triketide stage (PubMed:20552126).
CC The C-terminal R domain is involved in a reductive release mechanism,
CC reducing the thiolester intermediate to the observed aldehyde and
CC concomitantly releasing the free holo-ACP thiol (PubMed:20552126).
CC {ECO:0000269|PubMed:20552126}.
CC -!- DISRUPTION PHENOTYPE: Leads to the loss of production of xenovulene A
CC and its related compounds. {ECO:0000269|PubMed:29773797}.
CC -!- BIOTECHNOLOGY: Xenovulene A is a natural product exhibiting little
CC structural resemblance with classical benzodiazepines yet is able to
CC displace high-affinity ligand binding to the benzodiazepine site of the
CC gamma-aminobutyrate A (GABAA) receptor and could be potentially used as
CC an anti-depressant with reduced addictive properties.
CC {ECO:0000269|PubMed:9262310}.
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DR EMBL; JQ012797; AFD18255.1; -; Genomic_DNA.
DR EMBL; AM745350; CAN87161.2; -; Genomic_DNA.
DR EMBL; MG736817; AWM95789.1; -; Genomic_DNA.
DR SMR; A5PHD6; -.
DR BioCyc; MetaCyc:MON-19385; -.
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:0031177; F:phosphopantetheine binding; 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: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 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; IPR013120; Far_NAD-bd.
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; IPR036291; NAD(P)-bd_dom_sf.
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; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR032088; SAT.
DR InterPro; IPR016039; Thiolase-like.
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; PF07993; NAD_binding_4; 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 SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme;
KW Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2729
FT /note="3-methylorcinaldehyde synthase"
FT /id="PRO_0000441934"
FT DOMAIN 1750..1824
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:17912413"
FT REGION 99..238
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:17912413"
FT REGION 361..391
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 400..831
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:17912413"
FT REGION 942..1230
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:17912413"
FT REGION 1374..1665
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:17912413"
FT REGION 1682..1726
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1835..1874
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2086..2254
FT /note="Methyltransferase (C-MeT) domain"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:20552126,
FT ECO:0000305|PubMed:17912413"
FT REGION 2344..2599
FT /note="Reductase (R) domain"
FT /evidence="ECO:0000269|PubMed:20552126,
FT ECO:0000305|PubMed:17912413"
FT COMPBIAS 1835..1873
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 571
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 1029
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 1784
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2729 AA; 296115 MW; A78A9A343D58F2A1 CRC64;
MAAHGQTSKR GNNTLLLFGA LVQSHDVSTL RSMRESIVVQ HGEHSWLVDS IKALPQDFEA
ALPHLPFFDQ ATTTTIHQLL VDAVSSFLTG SFETLVSPLP AALLIPLAVA TQLAHYVEYS
RQSPTGLAEG KEALGFCTGI LSAFAVASSH DVCDLAKYGA AAMRLGMLVG LVVDCEDAAA
GQGRYRSVSA GWDSEEKHAA MLKIVQSFEE AYVSVHFDKN RATITTSPGT ISNLTRQLQK
EGLVASDMGL LGRFHFAGST KPREVTVDQL VSFCNSPAGA LFRLPDADSL RLATRINDRD
GGLITQGSLH EHALQSILVK LAAWFETFSS ATTTQANTGA QNGRARPQIV DFGPQNSVPH
SLASTVDINS GNGKTRRVKP ADAQSSANST HTRPWLDTDI AIVGMSCKVP GAENLEEFWD
LLVSGKSQHQ EISGQEGGRF DFGDTAFRTA ADQRRRWFAN LVSNHDQFDH RFFKKSARES
ASMDPQQRHI LQVAYQAVEG SGYFNKSSSS TPTNANIGCY VGLCLGDYES NVASHPATAF
TATGNLQGFV SGKVSHYFGW TGPAVTVNTA CSSSLVAVHL ACQAILSGEC EAALAGGSHI
MTSATWFQNL AGGSFLSPTG ACKPFDSKAD GYCRGEGVGA VFLKRMSQAM ADGDMVLGVV
AATGVQQNQN CTPIFVPNAP SLENLFSRVM TKARVKPADI SVVEGHGTGT AVGDPAEYDA
IRKALGGTTH RSADKPLMLS SVKGLVGHME CTSGVIGMIK LLLMMNKGAL PPQASFQSIN
PALGATPADH MFIPTRPQPW VVPAGGFRAA LLNNYGASGS NASAVLVQSP SMSFRPEITV
GSRPAAGIKF PFWLAAFDKK SLSRYVKALR KWLCRLDGDQ SLASLSFNLA RQSNRTMQAN
LVLTARSIEA LDQSLADFEN GNDGSFIERT PASSQPTVIL CFGGQVSCFV GLDKQVYQDM
ALVRYYLDRV DAVIQCQGGR SIFPGIFNRS PPSKVDIVHL HTMLFAMQYA SARCWIDSGV
KPAALVGHSF GTLTALCISG ILSLEDTIKA IMCRAKLLNE AWGPDQGGMI AVEGDIDVIE
ELLDEANKNH DDKPATIACY NGPTSFTLAG STTAMDAVAA QLKNGAKYSK GMKSKRIYVT
HAFHSVLVDP LLEELTQRVA DSGVRFRKPI IPVELSTEQH MSESELTSEF MANHMRQPVY
FHHAVERLAR RYAGGSSPCV FLEAGTNSSV CNMASRALGS TEFVTKSSSL SFHGVNIANC
DAGWNKLTDT TVNLWETGVR VHHWAHHGVQ QMHQTDIKPL LVPPYQFDPD SRHWIDLKVP
RKALMETDEA DAGGKKQSDA EKLPETILTF HSSDAVGAQK QARFRVNTML EEYKQLLRGH
MTLETAPILS ATLQINLVIE AISSTQPEYK SSKSQPQIQD VVYQSPVCFN SANTLWVEVT
NVSGQWMFQV FSTTTQELSP KSTRMVHTKG TVAFKNPGDA EIRRQLMSYE RLFSHGRATD
LLQNSNASTA PIDEMLGNQS IYRIFSEIVS YGPEFRGLQK MVSRGNETAG HVVHLKHQDS
ASTEAEPWFD PHLADTFCQL GGLWVNCMMP ERERGNGHVY LANGIDQWIR GYPAASTDRP
EAFNVFAVNK QASEQLTLTD VFVFNAADGA LVEVILGIAY VKIARPSMEK LLARLTEPSW
VAGGKTTPQT ATKPAAAPVV ADHTPRTTES ASTVNGVNLD DRKPEGTALP QEMLSDTEEL
RPKAQGQELQ DMIARVKAVM ADISGLDISE IKDDSNLADL GIDSLVGMEM THEIESTLKV
ELPESEIMSV VDMEGLLQCV AGALGLSMTG ASSDTLTASS DSGINSAKSS ILSGTSTSTS
TGTTDTGSDV GQSMKEPSLM LDTVKKAFAQ TKEATDARIK AASNQVSYCS TSLPQQNELS
VLLTITALEA LGAGFSTARP GSQLTRISHA PGHEQFVTHL YKEIETATQI IKIDGHGAQA
VITRTAVPLP DVESRQVALC EQMLRGDPEQ VGTMELIKHA GENLHRVLSG ETDGAKVIFG
SKTGSKLVSQ WYAQWPLNRS LIAQMGDFLT AVVAGIQADE DMPFSEINPL RIMETGAGTG
GTTKQIVPLL ARLGLPVVYT FTDLAPSFVA AARKTWGKEY PWMQFRTLDM EKTPPSVEDG
LPLQHFIVSA NAVHATKSIS ATTGNLRKAL RTDGFLLMME MTRTPFWVDL IFGLFEGWWL
FEDGRKHALT HEALWDQELS KVGFGYVDWT EGMTAESEIQ KIILASADAN TRLERVRLPA
SHTDYHLNQV GVENEARELM VADYVSTLTK EFNKTMTQYT DAGLSLSSRT SQTPMSSQKR
CILITGGTGG LGAHLVAEAA LLPDVNMVIC LNRPNRKQEA RERQLVSLEK KGLILSPEAL
AKITVFETDL SQPGSLGLSD DKYNLLRGNV THIIHNAWLM HSKWPVRRFE PQLRIMAHML
NLAADIATCQ RTQGQRQPGP PVSFVFVSSI ATVGYHPVVT NPGNPAVPET RIPISSVLPT
GYGEAKYICE RMLDATLHQY PAQFRASAVR LGQIAGSEIN GHWNSAEHIS FLVKSSQSIG
ALPALPGPMG WTPADYVARG LVEIATQPDN IELYPIYHIE NPVRQPWDEA LAVLADEMGI
SSEALPFQEW VQTVRDWPRQ GDNTAAGANP AYLLVDFLED HFLRMSCGGL LLGTAKAREH
SPSLAGMGPV SDELLRLFVR SWKEVGFLL
