CM3B_CORMM
ID CM3B_CORMM Reviewed; 2525 AA.
AC G3J453;
DT 17-JUN-2020, integrated into UniProtKB/Swiss-Prot.
DT 16-NOV-2011, sequence version 1.
DT 03-AUG-2022, entry version 65.
DE RecName: Full=Highly reducing polyketide synthase cm3B {ECO:0000303|PubMed:31926180};
DE Short=HR-PKS cm3B {ECO:0000303|PubMed:31926180};
DE EC=2.3.1.- {ECO:0000305|PubMed:31926180};
DE AltName: Full=Beauveriolides biosynthesis cluster protein B {ECO:0000303|PubMed:31926180};
DE AltName: Full=Cyclodepsipeptides cm3 biosynthesis cluster protein B {ECO:0000303|PubMed:31926180};
GN Name=cm3B {ECO:0000303|PubMed:31926180}; ORFNames=CCM_01282;
OS Cordyceps militaris (strain CM01) (Caterpillar fungus).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Cordycipitaceae; Cordyceps.
OX NCBI_TaxID=983644;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=CM01;
RX PubMed=22112802; DOI=10.1186/gb-2011-12-11-r116;
RA Zheng P., Xia Y., Xiao G., Xiong C., Hu X., Zhang S., Zheng H., Huang Y.,
RA Zhou Y., Wang S., Zhao G.-P., Liu X., St Leger R.J., Wang C.;
RT "Genome sequence of the insect pathogenic fungus Cordyceps militaris, a
RT valued traditional Chinese medicine.";
RL Genome Biol. 12:RESEARCH116.1-RESEARCH116.21(2011).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=14718664; DOI=10.1073/pnas.0307757100;
RA Namatame I., Tomoda H., Ishibashi S., Omura S.;
RT "Antiatherogenic activity of fungal beauveriolides, inhibitors of lipid
RT droplet accumulation in macrophages.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:737-742(2004).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=19396893; DOI=10.1002/cbic.200900139;
RA Witter D.P., Chen Y., Rogel J.K., Boldt G.E., Wentworth P. Jr.;
RT "The natural products beauveriolide I and III: a new class of beta-amyloid-
RT lowering compounds.";
RL ChemBioChem 10:1344-1347(2009).
RN [4]
RP BIOTECHNOLOGY.
RX PubMed=19336931; DOI=10.1248/cpb.57.377;
RA Ohshiro T., Matsuda D., Nagai K., Doi T., Sunazuka T., Takahashi T.,
RA Rudel L.L., Omura S., Tomoda H.;
RT "The selectivity of beauveriolide derivatives in inhibition toward the two
RT isozymes of acyl-CoA: cholesterol acyltransferase.";
RL Chem. Pharm. Bull. 57:377-381(2009).
RN [5]
RP FUNCTION, DOMAIN, AND PATHWAY.
RX PubMed=31926180; DOI=10.1016/j.jbiotec.2020.01.002;
RA Wang X., Gao Y.L., Zhang M.L., Zhang H.D., Huang J.Z., Li L.;
RT "Genome mining and biosynthesis of the Acyl-CoA:cholesterol acyltransferase
RT inhibitor beauveriolide I and III in Cordyceps militaris.";
RL J. Biotechnol. 309:85-91(2020).
CC -!- FUNCTION: Highly reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of beauveriolides I and III,
CC cyclodepsipeptides acting as inhibitors of the acyl-CoA:cholesterol
CC acyltransferase (PubMed:31926180). The HR-PKS cm3B initiates the
CC biosynthesis of beauveriolides by iteratively catalyzing the formation
CC of the linear polyketide chain (Probable). The ATP-dependent acetyl-CoA
CC ligase cm3D converts the polyketide carboxylic acid to a CoA thioester
CC which id shuttled to the first T domain in the NRPS cm3A by the
CC acetyltransferase cm3C (Probable). Cm3A contains 13 domains and
CC assembles the polyketide chain, L-phenylalanine, L-alanine, and D-
CC leucine (or D-allo-isoleucine) to form beauveriolide I (or
CC beauveriolide III). The production of both beauveriolides I and III
CC suggests the substrate adaptability of cm3B, using different amino
CC acids as substrates (Probable). {ECO:0000269|PubMed:31926180,
CC ECO:0000305|PubMed:31926180}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:31926180}.
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.
CC {ECO:0000305|PubMed:31926180}.
CC -!- BIOTECHNOLOGY: Beauveriolides inhibit selectively the acyl-
CC CoA:cholesterol acyl-transferases (ACATs), leading to blocking the
CC synthesis of cholesteryl esters and decreasing the cholesterol
CC concentration, which suggests that beauveriolides are promising as
CC potential lead compounds for antiatherosclerotic agents
CC (PubMed:14718664, PubMed:19336931). Moreover, this activity correlates
CC with inhibitory activities of beauveriolides in the secretion of
CC amyloid-beta-peptide, which suggests that beauveriolides may be an
CC attractive new candidate for the treatment of Alzheimer's disease
CC (PubMed:19396893). {ECO:0000269|PubMed:14718664,
CC ECO:0000269|PubMed:19336931, ECO:0000269|PubMed:19396893}.
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DR EMBL; JH126399; EGX96624.1; -; Genomic_DNA.
DR RefSeq; XP_006666501.1; XM_006666438.1.
DR AlphaFoldDB; G3J453; -.
DR SMR; G3J453; -.
DR STRING; 983644.G3J453; -.
DR EnsemblFungi; EGX96624; EGX96624; CCM_01282.
DR GeneID; 18163313; -.
DR KEGG; cmt:CCM_01282; -.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_000022_31_0_1; -.
DR InParanoid; G3J453; -.
DR OMA; RNWIGAY; -.
DR OrthoDB; 19161at2759; -.
DR Proteomes; UP000001610; Unassembled WGS sequence.
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:0016491; F:oxidoreductase 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 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; 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; 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; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 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; 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; NADP;
KW Oxidoreductase; Phosphopantetheine; Phosphoprotein; Reference proteome;
KW Transferase.
FT CHAIN 1..2525
FT /note="Highly reducing polyketide synthase cm3B"
FT /id="PRO_0000449817"
FT DOMAIN 2411..2489
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..29
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 32..453
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5BA83, ECO:0000255"
FT REGION 560..895
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5BA83, ECO:0000255"
FT REGION 949..1252
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5BA83, ECO:0000255"
FT REGION 1399..1504
FT /note="Methyltransferase (CMet) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5BA83, ECO:0000255"
FT REGION 1799..2111
FT /note="Enoyl reductase (ER) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5BA83, ECO:0000255"
FT REGION 2411..2489
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5BA83, ECO:0000255"
FT COMPBIAS 1..28
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 202
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2449
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2525 AA; 274979 MW; 0505AAF52DDAD377 CRC64;
MQSDTNNSPL SWEELRSGAA SSDANSSPPE PIAIIGMSCR LSGSAQDPSS LWEMLTSGRT
AWTPGPGQRF NMEAFQSSSA DTFGMTNTGG GHFLKEDVAA FDAAFFGIHA VEAKAIDPQH
RLLLEIAYEC FDNSGLNMDS LWGSNTGVYV GQWANDYHEI QTRDIDAPPL YLTTGTGPAI
SSNRISYFFN LRGPSFTVDT GCSSGFVALH QAVQSLRSGE TSQCFVGGVN LMLDPQRFVY
QSKLKMFSNE GRSFAFDSRA NGYGRGEGCT AVMLKPLSAA LRDGDQIRAV IRNSVLNQDG
RTAGITVPSP EAQEEAILKA YGDAMLELRA DYVEAHGTGT KVGDPKEAGA IAAALARGNS
PGAALPIGSI KANIGHTESA AGLAGLIKAV LMLEHGIIPP QANYESPNPD LCLEERGLRV
PTQLERRTLR RISVNSFGYG GTNAHVVVDA SADALCALSS LGRHTSAQRV FFISGASEKA
CQRICARLAK YLARKSAWPE TDTPELLAKL AYTLSKKSIH PYRLALVAQD INELVQQLIS
AAYSPVARQD RKGDTRIGLV FSGQGSQYAE MGRELLSSSA VFSRSIDRAC QHLTELGSGW
NMREELCRPQ ETTRINEPAL SQPLTTAIQL ALVDLLFDLK ISVSAVVGHS SGEIAAAYAA
EAISFEDAMT ASYYRGSLTS SLVVGNPECD GAMLAVGADA DVVNQRISEV GDAHGRMRIA
CFNSPSSVTV SGDAKAVNEL RKLLVAEGTF NRMLPTNGAA YHSHQMESMN KEYTLSLQKK
LSPKKKTSIS AARIFSSVTG KENDLQTPLD GVYWAANLLS PVLFSQALRE MCEAKYDGKA
LDMIIEVGPH SQLGGAVKQT VKALKSSSGI AYTSVLKKGK KARQAFLECL GALHVCTATV
DLNASNGFSA THAPKLLVDL PPYPFDHERS FWHETRISKD YRHRKHAPHE LLGTFAHDTN
RVEPRWRQFL SLKQTPWLKS HAVQGQIVFP GAGFLTMAIQ AMLQHMHATS PLVKVHSLLL
RNVSLSRALV LPADGPDVEI TLTLRPESHT AKSSSAVWSE FRIFTVTSES VWTEHCRGLV
HAETQAADVD EIAADVKDTL EAGETCVHEV TPQKLYHLGS EIGLDWQHPF NNVSNIRTSR
DACVAVARKT VLDSDVGGMG DILHPTVLDS CLFHGLSAVL VLERGSTSTF VPNFIEQLQI
FNRTPDSSAE LLSTSKLSRD TSTCDVVVQE KGCSPGQAVI FAAKGVHTTT LPGDTGLNEV
IDDICHSQDW VTYVDAWTPE HCDRFVQKAV KEVDPERVPD GPRRQFFEWM KIYAETPLDE
QTLPPASISA DHWAFYEGVK RLGPHLADIL VEKTDPLALL TPDNLLGQLY NTERCRRCIV
QMAEYCHALG QQSPGLKVLE VGAGTASATL PAIEALNGRG SINAHSYTFT DLSPAFFDPA
KERLGSFADA VKFDILDIER CPLEQGFQEA GYDLIIASNV IHATQRIDAV LANIKKLLKP
GGKFMLMELT VPTPHYNLLF GVFKGWWAGY DEGRQLSPLI PPSEWVTRLT RAKFSPAELW
FQDYPEENGG TISVLIASAP WDVAQVELPA IDVVTTEYSA LESGDEAVLR TLSSSEELLN
TNISVGCLSD ISSKDNIVII LPEVARYLCQ SLHGSAWERF KHLVLNARAV LLVGCSSSYC
SDFVSGGIWL GFARCLRLEL PRLRVITLDL AVERALMMKR LTSVLPTLMR SIKQGLALDG
RVEVENEFRE SDGQLYVSRL VSNDKMSEYV HRSRQRAQPK LLSFMDPQRP MTAELRVPGL
LESIRWKDDV KATAVGPDEV KLELRAASIN FKDVLIAAGQ LEGINEMRND CSGVVIEVGS
NMCDRFKAGD RVCALYSRSY TNYPVVHGDC CQVVPDSMTY EEATALPVVW TTVYYSLVDA
GRLEQGDKIL IHSAAGAVGQ AAIMLAKHIG AEVFATVGNS EKQTLLRERY GIADDHIFSS
RTPAFHDKIK RLTGGYGVDV VLNSLAGDQF RHSCNLVAPF GRFVEIGRKD LMDDARMSMG
FLLKNVTFAY VDLSLIMEVK RPLARRLLRE VVNLAASGAI RPVTLTTLPI TEIETAFRMI
QAGKHTGKIV LRVAQDQIVK ADPPAPAHAE LKPNATYLLV GGFGGLGRAV ITWMGSRGAK
NILVISRSGS PDKQGQILIK DMEAMGVKVV AEKCDVTAED EVASLSKLAA DRGLPPIRGV
IHSAMVLQDS VLEEMTADEW CRALAPKYAG SLNLHRSFGN EVDFFIFMSS AVALRGNVGQ
SNYAAACSFQ DALARYRTAA GLPAFSINVG PVREVGFVSE NPQVAAALRK QGLGTISMAD
LLTLLNYAVV HRNPEESVCS IGMLPRDTDE SLTDRRFAHL VRHDVVSQTA DAGGVQFADI
PRLLDGAAPG AQLLENISQL VLMQLSKLIA SPVETLSAAQ SLDSYGVDSL VAVELRNWVG
AYLQANVPLM VLRGTSSIHE LAKIIAKESR RPSTLLWRST LLYSYPDLDK LQHDMPAQIS
WPANS
