CDME_TALVE
ID CDME_TALVE Reviewed; 2592 AA.
AC A0A3G9GQ29;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 13-FEB-2019, sequence version 1.
DT 03-AUG-2022, entry version 17.
DE RecName: Full=6-hydroxymellein synthase cdmE {ECO:0000303|PubMed:30417647};
DE AltName: Full=Highly reducing polyketide synthase cdmE {ECO:0000303|PubMed:30417647};
DE EC=2.3.1.- {ECO:0000269|PubMed:30417647};
DE AltName: Full=chrodrimanin B biosynthesis cluster protein E {ECO:0000303|PubMed:30417647};
GN Name=cdmE {ECO:0000303|PubMed:30417647};
OS Talaromyces verruculosus (Penicillium verruculosum).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Trichocomaceae; Talaromyces;
OC Talaromyces sect. Talaromyces.
OX NCBI_TaxID=198730;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DOMAIN, CATALYTIC ACTIVITY,
RP AND PATHWAY.
RC STRAIN=TPU1311;
RX PubMed=30417647; DOI=10.1021/acs.orglett.8b03268;
RA Bai T., Quan Z., Zhai R., Awakawa T., Matsuda Y., Abe I.;
RT "Elucidation and heterologous reconstitution of chrodrimanin B
RT biosynthesis.";
RL Org. Lett. 20:7504-7508(2018).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=26115570; DOI=10.1016/j.bmcl.2015.06.026;
RA Yamazaki H., Nakayama W., Takahashi O., Kirikoshi R., Izumikawa Y.,
RA Iwasaki K., Toraiwa K., Ukai K., Rotinsulu H., Wewengkang D.S.,
RA Sumilat D.A., Mangindaan R.E., Namikoshi M.;
RT "Verruculides A and B, two new protein tyrosine phosphatase 1B inhibitors
RT from an Indonesian ascidian-derived Penicillium verruculosum.";
RL Bioorg. Med. Chem. Lett. 25:3087-3090(2015).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=25902139; DOI=10.1371/journal.pone.0122629;
RA Xu Y., Furutani S., Ihara M., Ling Y., Yang X., Kai K., Hayashi H.,
RA Matsuda K.;
RT "Meroterpenoid Chrodrimanins Are Selective and Potent Blockers of Insect
RT GABA-Gated Chloride Channels.";
RL PLoS ONE 10:E0122629-E0122629(2015).
CC -!- FUNCTION: Highly reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of chrodrimanin B, a meroterpenoid that
CC acts as a potent blocker of insect GABA-gated chloride channels
CC (PubMed:30417647). The first step of the pathway is the biosynthesis of
CC 6-hydroxymellein by the polyketide synthase cdmE (PubMed:30417647). The
CC prenyltransferase cdmH acts as a 6-hydroxymellein 5-farnesyltransferase
CC and produces the hydrophobic metabolite verruculide C
CC (PubMed:30417647). The FAD-dependent monooxygenase cdmI further
CC converts verruculide C into verruculide B (PubMed:30417647). The
CC terpene cyclase cdmG then produced the pentacyclic molecule 3-
CC hydroxypentacecilide A, the backbone structure of chrodrimanin B, via
CC folding the farnesyl moiety of the substrate into the chair-boat
CC conformation (PubMed:30417647). The short-chain dehydrogenase/reductase
CC cdmF functions as the 3-OH dehydrogenase that oxidizes the C-3 hydroxyl
CC group of 3-hydroxypentacecilide A and produces chrodrimanin C, the
CC dehydrogenated product of 3-hydroxypentacecilide A (PubMed:30417647).
CC The cytochrome P450 monooxygenase cdmJ then accepts both 3-
CC hydroxypentacecilide A and chrodrimanin C and functions as a C-7-beta-
CC hydroxylase to produce respectively chrodrimanin H and chrodrimanin F
CC (PubMed:30417647). The dioxygenase cdmA accepts chrodrimanin H to
CC afford chrodrimanin E, which is further transformed to chrodrimanin A
CC by the dioxygenase cdmD (PubMed:30417647). CdmA can also accept
CC chrodrimanin C as substrate to convert it into verruculide A, which is
CC further converted into chrodrimanin T by cdmD (PubMed:30417647). The
CC last step of the biosynthesis is proposed to be performed by the
CC acetyltransferase cdmC which acetylates chrodrimanin A to yield
CC chrodrimanin B (Probable). The pathway may also lead to the production
CC of additional shunt products, including chrodrimanins T and U
CC (PubMed:30417647). {ECO:0000269|PubMed:30417647,
CC ECO:0000305|PubMed:30417647}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=AH2 + 5 H(+) + 5 malonyl-CoA = 6-hydroxymellein + A + 5 CO2 +
CC 5 CoA + H2O; Xref=Rhea:RHEA:65248, ChEBI:CHEBI:13193,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:16368,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:17499, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57384; Evidence={ECO:0000269|PubMed:30417647};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:65249;
CC Evidence={ECO:0000269|PubMed:30417647};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:30417647}.
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; a methyltransferase
CC (CMeT) domain responsible for the incorporation of methyl groups; an
CC enoylreductase (ER) domain that reduces enoyl groups to alkyl group; a
CC ketoreductase (KR) domain that catalyzes beta-ketoreduction steps; and
CC an acyl-carrier protein (ACP) that serves as the tether of the growing
CC and completed polyketide via its phosphopantetheinyl arm (Probable).
CC The DH and CMeT domains are inactive due to mutations of their
CC catalytic residues, as consistent with the required reactions to
CC synthesize 6-hydroxymellein (Probable). The ER domain could be active,
CC but it should not affect the PKS chemistry due to the inactive DH
CC domain (Probable). {ECO:0000305|PubMed:30417647}.
CC -!- BIOTECHNOLOGY: Compounds in the chrodrimanin family such as
CC chrodrimanin A or verruculide A exhibit strong inhibitory activities
CC against protein tyrosine phosphatase 1B (PTP1B) and therefore, they
CC could potentially be developed into drugs for the treatment of type 2
CC diabetes or obesity (PubMed:26115570). Furthermore, chrodrimanin B, the
CC end product of the pathway involving chrodrimanin A or verruculide A,
CC does not exhibit the PTP1B inhibitory activity, while it functions as a
CC potent blocker of insect GABA-gated chloride channels
CC (PubMed:25902139). {ECO:0000269|PubMed:25902139,
CC ECO:0000269|PubMed:26115570}.
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DR EMBL; LC422696; BBG28484.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A3G9GQ29; -.
DR SMR; A0A3G9GQ29; -.
DR UniPathway; UPA00213; -.
DR GO; GO:0016746; F:acyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; 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:0044281; P:small molecule metabolic 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; -; 1.
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; IPR013149; ADH-like_C.
DR InterPro; IPR011032; GroES-like_sf.
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; 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; IPR029063; SAM-dependent_MTases_sf.
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; 1.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF08242; Methyltransf_12; 1.
DR Pfam; PF00550; PP-binding; 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; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS50075; CARRIER; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme; NADP;
KW Oxidoreductase; Phosphopantetheine; Phosphoprotein;
KW S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..2592
FT /note="6-hydroxymellein synthase cdmE"
FT /id="PRO_0000449130"
FT DOMAIN 2509..2586
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..25
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 35..459
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 589..910
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 978..1291
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255"
FT REGION 1483..1591
FT /note="Methyltransferase (CMeT) domain"
FT /evidence="ECO:0000255"
FT REGION 1887..2199
FT /note="Enoyl reductase (ER) domain"
FT /evidence="ECO:0000255"
FT REGION 2223..2398
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255"
FT ACT_SITE 205
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT BINDING 1462
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019"
FT BINDING 1484
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019"
FT MOD_RES 2546
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2592 AA; 284655 MW; B24DC3B1259E294E CRC64;
MVLHPSDRRF PETNGVGGHS KDSSAKSGYT SLEPLAIVGF ASHLAGDATD NENLWKHILE
GQSASGPFPQ NRLQGNQYFH PDPEHGGTCA TKGGYFLKKD IDTFDASFFR LSEYDIAAMD
PQQKILLENV YHAVENAGLP MESLAGSRTS VYVGSSTNDH AALTNEDLDF TIKNKATGTL
PSLLANRVSW FYDLKGASIV IDTACSSSLV ALHMACLDIR AGGSEMAIVS GINLLQHPAS
LMLLSNLGVL SPDGRSYAFD DRANGYGRGE GVITVVVKSL QAAIRDGDRV RALVRASGVS
SDGKTAGITL PSEEEQKVLI RNVYASANLD VNETTYVEAH GTGTPVGDPL ECKAIMSAFR
TQRRKQTLYI GSIKANIGHL EGGAGLAGLV KAIMMLEKQI IPPIAGLQRL NPLISQDGHN
VCFTREAIPW PKSHVRRASV NSFGFGGTNA HVVLESPDMF LHGRSLDTTS TSLVRLPNGY
LNGINGQKTP PEDSPKSYVF MISANDENGI QRNAMLLKKY IDNYLKTQCS FSEDQFMKDL
VYTLSEKRSR LKWRASIIAS SLTELSQQLT GGTLPKFRAA NTEPGISFVF TGQGAQWPGM
GKMLMEFPIF RQSVEAASLH LQKQGSQWTL HDAFDPIEDS KTDINNPIQS QTACTVLQVA
LVDLLQSWNI SPSIVIGHSS GEIAAAYCAG AISREAAWNI SYYRGLVSSI LVKGGGGAMI
AVGLHPQEAQ KYINQLSPEL QCMVQIGCYN SPNNTTITGE RNAILILQAL LDENGVFNRV
LATPVAYHSQ YMQPVADTYS TLLRLSDLSV GRMRQPQIDE EIVMISSVTG EPIGAKRLQD
PQYWTQNLIS PVKFMNALHQ LKNFAPQFNL QELLELGPHS ALQSAIRESM ADGQSTAPQI
RYSHTITRKK MTYSTILSTA AGLFCRGYPV NLVATSCTDS HHGTLLTDLP GYEFNHDAGL
RAESRRMKNS RLPEFPRHEL LGSPDPDWDR REPRWRNFLR TSELPWLRDN KVNGGIIFPG
VGYSIMAMEA VKQISDRSIS IAGYRLKQIS MEAALIVPDT RDGLEVMTSL REVYDEGSTT
SPKYQFSVKT HDTMRNEWIE HCSGFIESKC ESDSIEDMGT WRPLPWDAVH DLQFSEESCT
QIGSISAFYD ALERSGFDLG PTLKNLVDVR TSATSPHCMT KMAAPSIAEH MPKGYNFPYI
IHPSTMESMA HAILHVCTTK EAPVGSALLA RYIDNIWISN KIPMDPGHLF VTVADGEQVS
PGKWRCAITV WNDATKEVVI QIRGTELCLL SAGRGDQKTV PECFLVKWYP SLDLVTDKLP
FASLSSPETG VTEARHAHKT YEQLCTLYIA RALKSLHGYD RKLLPQHLQQ YLDWMVRQTM
DSDAHTMRAI LVENEVKLKE ESGMLEALRT QAQGLGSRGE LLVNVGDHIV PLIKGEKDPQ
SIIIGGNDLR PWTLDQDLSG NIKNVLSDNL KALRHGQGQL KVLEIGTGFG SVTAHIIKAL
TSVEDMSQTV FGKYQYTNKH NSSFEDVRQK CGDWLSLMDF QVLDVDQSVA EQGFEEHSYD
LVISAHAFTR TVSLERSLKN AHSLLKPGGK LLVIENVQPQ YKSTPFVYGL FPGWWHSTEP
FRSTTPLVSE DKWVELLEAT GFTTSSVKDV ENEKSNETCL FLSTAIRTKE LIAAPPFDDI
VLTHHAYDPK NLVSSLLAAI KQISGLPVIV VPFSQLSHRK MERSFCIVVG ELGQGYLDLS
CVNEDIYREM KRLLLTCQNL LWISLDDVDY PKAALSTGLV RTLRWEREMD KINFLTLKFA
QSSSHVPEIV SAVTSLYQHY FDGKVEASPN SEFLYKDGSF WVNRLYPAKT ANNFLQSHIS
EAPQSQMLGD NVDRSLKARF KGSGRQGLLV WSDDEALSQP LSASEIQIDV QASGLTFQDG
MAIRGDIDQH VFGKQVAGTV TQVGQKVEAL EPGDHVMALL VGSEQHSLSR SIRVNANFAQ
RLSPDADFME AATIPTTFTA VHYALHNVAR VMESEKVLVH GAMQAAGQAA IQLAKLAGAD
VFVTVKTFEQ KQKIETKYGI PENHVFIANE HLDAGIKEAT GGASGVDIVL NFLHGSATRS
AWQCVGMMGR FVDMALKAPG RHRGLDMSPF SRNAMYIGVD IAALGTAHHP SIMKAFSKVG
ELFRQRLIFG PGHKPFSYNN FGAAMIHIQN DSNMDTAVIV PKADDVIQVV PCKYTAYEFP
TDATYVIAGG LGGLGRSAAR WMCSKGARHL ILISRSGART ASAKELLQDL ASQGCKIKIC
QCDITDKDNL QIAMRECASG MPPIKGCLQS TMLLQDSIFE NMSFQQFMAG IHPKVQGSLN
VLDAIPDQLD FFLVLSSAAS IVGNRGQANY NSANAFQDSL AEHLTSKGIP GMSVNLGNML
SVGWVAENEG ALPLDLVYSS IDEPEFHALL EYHLDPRWGA SQSVETCHTI AGVRSATRFN
EDRTPIPSFM NDPLFTIIRE STNGTTDNGE QEREISISTL LKESSSVQVA ASHVTEAIIC
KLSSVMSFPA AEIDPSQGLA SYGVDSLVTV DFRTWIAKDM GANLSTADIL DDGNIIGLSE
KIARQSKFVK VA
