DMXL2_CRYX8
ID DMXL2_CRYX8 Reviewed; 2406 AA.
AC A0A4P8DJV2;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 31-JUL-2019, sequence version 1.
DT 03-AUG-2022, entry version 13.
DE RecName: Full=Highly reducing polyketide synthase dmxL2 {ECO:0000303|PubMed:30996871};
DE EC=2.3.1.- {ECO:0000305|PubMed:30996871};
DE AltName: Full=Dimeric xanthone biosynthesis cluster protein L2 {ECO:0000303|PubMed:30996871};
GN Name=dmxL2 {ECO:0000303|PubMed:30996871};
OS Cryptosporiopsis sp. (strain 8999).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Leotiomycetes;
OC Helotiales; Dermateaceae; Cryptosporiopsis; unclassified Cryptosporiopsis.
OX NCBI_TaxID=2572248;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DISRUPTION PHENOTYPE, AND
RP PATHWAY.
RC STRAIN=8999;
RX PubMed=30996871; DOI=10.1039/c8sc05126g;
RA Greco C., de Mattos-Shipley K., Bailey A.M., Mulholland N.P., Vincent J.L.,
RA Willis C.L., Cox R.J., Simpson T.J.;
RT "Structure revision of cryptosporioptides and determination of the genetic
RT basis for dimeric xanthone biosynthesis in fungi.";
RL Chem. Sci. 10:2930-2939(2019).
CC -!- FUNCTION: Highly reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of the dimeric xanthones
CC cryptosporioptides (PubMed:30996871). The pathway begins with the
CC synthesis of atrochrysone thioester by the polyketide synthase dmx-
CC nrPKS (Probable). The atrochrysone carboxyl ACP thioesterase dmxR1 then
CC breaks the thioester bond and releases the atrochrysone carboxylic acid
CC from dmx-nrPKS (Probable). Atrochrysone carboxylic acid is
CC decarboxylated by the decarboxylase dmxR15, and oxidized by the
CC anthrone oxygenase dmxR16 to yield emodin (Probable). Emodin is then
CC reduced to emodin hydroquinone by the oxidoreductase dmxR7 (Probable).
CC A-ring reduction by the short chain dehydrogenase dmxR18, dehydration
CC by the scytalone dehydratase-like protein dmxR17 and probable
CC spontaneous re-oxidation, results in overall deoxygenation to
CC chrysophanol (PubMed:30996871). Baeyer-Villiger oxidation by the
CC Baeyer-Villiger monooxygenase (BVMO) dmxR6 then yields monodictylactone
CC in equilibrium with monodictyphenone (PubMed:30996871). In the case of
CC the cryptosporioptides biosynthesis, monodictylactone is reduced at C-
CC 12 to an alcohol (by the short chain dehydrogenases dmxR12 or dmxR8)
CC and hydroxylated at C-5 by dmxR9, yielding the electron-rich aromatic
CC which could eliminate H(2)O to form the ortho-quinonemethide, followed
CC by tautomerisation to paraquinone and complete the formal reduction to
CC produce the 10-methylgroup (Probable). Conjugate addition of C-4a-OH to
CC the resulting paraquinone by the monooxygenase dmxR10 then gives
CC cyclohexadienone, which is then reduced at C-5 by the short chain
CC dehydrogenase dmxR3 to give the dihydroxanthone (Probable). The 6,7-
CC epoxide in the cryptosporioptides could be introduced by the cytochrome
CC P450 monooxygenase dmxL3 (Probable). The highly reducing PKS dmxL2
CC manufactures butyrate, which is further carboxylated by dmxL1 to form
CC ethylmalonate (PubMed:30996871). It is not yet clear whether the
CC carboxylation occurs while the butyrate is attached to the ACP of
CC dmxL2, but this unusual fungal metabolite could then be esterified to
CC O-5 by the O-acetyltransferase dmxR13 (PubMed:30996871). Finally,
CC dimerization performed by dmxR5 gives the observed dimers
CC cryptosporioptides A, B and C as the final products of the pathway
CC (PubMed:30996871). {ECO:0000269|PubMed:30996871,
CC ECO:0000305|PubMed:30996871}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:30996871}.
CC -!- DOMAIN: Multidomain protein; including a ketosynthase (KS) that
CC catalyzes repeated decarboxylative condensation to elongate the
CC polyketide backbone; a malonyl-CoA:ACP transacylase (MAT) that selects
CC and transfers the extender unit malonyl-CoA; a dehydratase (DH) domain
CC that reduces hydroxyl groups to enoyl groups; an enoyl reductase (ER)
CC domain that reduces enoyl groups to alkyl group; a ketoreductase (KR)
CC domain that catalyzes beta-ketoreduction steps; 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}.
CC -!- DISRUPTION PHENOTYPE: Abolished production of cryptosprioptide B and C,
CC and produces exclusively cryptosporioptide A.
CC {ECO:0000269|PubMed:30996871}.
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DR EMBL; MK182094; QCL09089.1; -; Genomic_DNA.
DR SMR; A0A4P8DJV2; -.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 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; IPR013149; ADH-like_C.
DR InterPro; IPR011032; GroES-like_sf.
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; IPR032821; PKS_assoc.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR020843; PKS_ER.
DR InterPro; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR002364; Quin_OxRdtase/zeta-crystal_CS.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00107; ADH_zinc_N; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 2.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00829; PKS_ER; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF50129; SSF50129; 1.
DR SUPFAM; SSF51735; SSF51735; 2.
DR SUPFAM; SSF52151; SSF52151; 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.
DR PROSITE; PS01162; QOR_ZETA_CRYSTAL; 1.
PE 3: Inferred from homology;
KW Acyltransferase; Multifunctional enzyme; NADP; Oxidoreductase;
KW Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2406
FT /note="Highly reducing polyketide synthase dmxL2"
FT /id="PRO_0000453498"
FT DOMAIN 2318..2395
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..402
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 414..476
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 574..911
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 964..1273
FT /note="Dehydratase (DH) domain"
FT /evidence="ECO:0000255"
FT REGION 1694..2006
FT /note="Enoylreductase (ER) domain"
FT /evidence="ECO:0000255"
FT REGION 2032..2210
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255"
FT COMPBIAS 416..470
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 130
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 130
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 665
FT /note="For malonyltransferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 994
FT /note="For beta-hydroxyacyl dehydratase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2355
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2406 AA; 260448 MW; F2F8725A5229E81A CRC64;
MEAFWSASKK RSTSVAKGAH FLRQDISRFD ANFFGLPKHE ADAMDPQQRI MMEVAYEALE
GAGLPLDQIA GSRTGVFVGH FSNDYRDMIC RDPDDAPLYS FTGTSTASLA NRLSYLWDLR
GPSFSINTAC SSSLVALHLA CQSLQRGECE IAIVGGSNLL LNPEMFMFLS NQGFLSPDGK
CKSFDESANG YGRGEGFGCV ILKRVDDAVL AGDAIRAVIR GTGSNQDGRT KGLTTPSAEA
QRALIEEVYQ RAGLDFKTTG YTEAHGTGTQ AGDSQEMNAL AKTIAATHTA ESKLIVGSVK
SNVSQSSAQN SCRFLTCLQI GHLEAAAGIA SVIKAVLMLE RGLIPPTIHF KKGNPKIPFD
EWNIRVPTTL TPWPTDGVRR ISINSFGYSG TNAHAVLDDA YHYLEAKKHA FDKGHASNGT
NGTLTNGHIL NGEHTSNGMN GTLTNGHASN DEHALNGTND ALTNGHGPTD GPTSRPRLFI
WSAQDKDGLK RVREPLAQYI QAKAAEYQQD QSLKTEETFM SELAYTLSER RSRLQWKTYT
IASSPSTLSA SLSLGEEASA TPVALSSRNP RIGFVFTGQG AQWPRMGAEL MAYPAFRECI
EAAGSYLQGV CGCPWSAAEE LQKHKSISLV NSSAYSHALC TILQVALVDL LRTWGITPTA
VVGHSGGEIA SAYAFGALTR EDAWRVAYHR GRLSAAIKTK APGLNGAMMA VALSPEQAAE
WISKVTDGHL VVACINSPTS VTIAGDSLGI DQLLGMLQEK GGIFARKLLV DTAYHSPHMK
IIADDYHAMI SDVMPRAAQG GCIMSSSVTG AVVEATQLGA DYWTASLTSP VRFSEAIYDM
LRPIRGKTRL EENTVDVLVE VGPHSALQGP ATQSIKVHNI ANVPYYSVLR RNQDAVDTAL
NLAGSLFTQG YKVDIRQVND DGDAHFAAPL TDLPTYSWNH SQRFWHESRM EREFRSRAAP
KPSLLGSPSP SLAEGERIWR GFIRPAEAPW VNDHKIHGAV LYPGAGYLAM ALEAATQTAD
TTRRVVAYKL RDIQLTAAAL VADGANLEYI VQLRPHVVGN RDSTAAWTEF IVTTAPDGKA
LVQNCRGLLV IEYEAAEGSD TSRERSLELQ GWKTQYVDAQ QACVHRLDPS GFYSDMRSWG
LDYGPAFANV CEVRNRDGQS VGSVRIPDIP APIVDGSDRP HVVHPGTLDA VFHLAFAAAK
GGAYAPSTAM VPKSIDAITI AANVPFQAGT RLPGFSRAGR HGLNELVADI VMLDDTEHLP
AIVIEGFLCA EIAGASSNSA DNSAKSLASR VTWRPALGLL SSDDLCSALS AHIGEAKLVE
YLKLFHHSNP VLSVLEVAAV PNPQEPTPTP LLQRECLASV AKTWDVTTAC RDETLKTSMR
QEAALEVLDF GQDLDTDVPE AYDLLIASDL SLYASDPVPA VERMCKVLKQ GGAICILTTD
SIFLRIQPFL DACHMEVTVL PNPHGSDAAP SQDPSLIIAK KSLPYTNGIN GAAARPQQVT
LIQAAHPTEA AIAMASQLTV SLEEHGYEAH VVSWGSDMST LAGKSCISLV EFQKTLLQDL
AVDDFQSVKK LLLETGKLLW VTALDDPSAA MIDGLVRVVR NETPGLSLRV FHADEPTLAP
AERLAGMLAK AFLWTGQDNE FRVQGNLLHV SRIEEDTTLN EEIHGLLPGA ARTISRIPLK
DVQYPVKLCV QTPGMLGSVC LEPDDSAETV LGPDFIEIHV KATALNFREV MVAMGQMADS
KLGIDAAGVV RRVGSSVTKF KVGDKVAMYG HGAHRTIHRS RADYCALIPD GMSFEEAATI
PAVHGTAWNA LVRLARVQKG QSILIHAAAG GVGQVAVQIA RHTGMEIFAT VSSEAKRKLL
RDEYGVPDDH IFNSRDLSFV KGVKRMTNGR GVDVVLNSLA GEALRQTWHC IAPFGYFVEI
GVRDIINNTG LDMRPFMQDA TFSFFNLTHI EQDRPDIMGA IIQGAFDFLR RGITQLVTPM
VTFPISDVEG ALRLMQTGKH LGKIALSWDE DHAEPISVVQ PRMRAPKLDP DGVYLLVGGL
GGLGRSLSSK LVSLGARRLC FLSRSGARSA NAKDLIDKLE QQQVRVQIQT CDVADESAIA
SAVDRCTREL GKIRGVFQCA MVLRDGLFAN MTHQQWVEST RPKVQGSWNL HQHLPDDLDF
FITLSSFTAT FGSRGQSNYA AAGAYEDALA YHRRTRGRHA TTVDLGIMRD VGVLAETGMT
DAFREWEKPY GIRESEFLVL MERVIDRDIA AIMPPQVLTG FATGGSVSSA GISTPYYMED
ARFSILARTG VRDDGASAAS TDAVPAYTLV SQAKSFQEAS DSVLEALVRQ VAKMFQTPPS
EIDTSRFLHS YGIDSLVAIE IVNWVMREAK STMTVFDVLA GVPMTTFCNR IAAKSTVLPK
ELVPVH
