BSLS_BEAB2
ID BSLS_BEAB2 Reviewed; 3147 AA.
AC J5JV76;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 31-OCT-2012, sequence version 1.
DT 03-AUG-2022, entry version 50.
DE RecName: Full=Bassianolide nonribosomal cyclodepsipeptide synthetase {ECO:0000303|PubMed:19285149};
DE Short=BSLS {ECO:0000303|PubMed:19285149};
DE Includes:
DE RecName: Full=Nonribosomal peptide synthetase {ECO:0000303|PubMed:19285149};
DE EC=6.1.2.- {ECO:0000269|PubMed:23608474, ECO:0000269|PubMed:23727842, ECO:0000269|PubMed:29163920, ECO:0000269|PubMed:31388353, ECO:0000269|PubMed:31471217};
DE Includes:
DE RecName: Full=S-adenosyl-L-methionine-dependent N-methyltransferase {ECO:0000303|PubMed:19285149};
DE EC=2.1.1.- {ECO:0000269|PubMed:29163920, ECO:0000269|PubMed:31388353, ECO:0000269|PubMed:31471217};
GN Name=BSLS {ECO:0000303|PubMed:19285149}; ORFNames=BBA_02630;
OS Beauveria bassiana (strain ARSEF 2860) (White muscardine disease fungus)
OS (Tritirachium shiotae).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Cordycipitaceae; Beauveria.
OX NCBI_TaxID=655819;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ARSEF 2860;
RX PubMed=22761991; DOI=10.1038/srep00483;
RA Xiao G., Ying S.-H., Zheng P., Wang Z.-L., Zhang S., Xie X.-Q., Shang Y.,
RA St Leger R.J., Zhao G.-P., Wang C., Feng M.-G.;
RT "Genomic perspectives on the evolution of fungal entomopathogenicity in
RT Beauveria bassiana.";
RL Sci. Rep. 2:483-483(2012).
RN [2]
RP FUNCTION, DISRUPTION PHENOTYPE, DOMAIN, AND BIOTECHNOLOGY.
RX PubMed=19285149; DOI=10.1016/j.fgb.2009.03.001;
RA Xu Y., Orozco R., Kithsiri Wijeratne E.M., Espinosa-Artiles P.,
RA Leslie Gunatilaka A.A., Patricia Stock S., Molnar I.;
RT "Biosynthesis of the cyclooligomer depsipeptide bassianolide, an
RT insecticidal virulence factor of Beauveria bassiana.";
RL Fungal Genet. Biol. 46:353-364(2009).
RN [3]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=23608474; DOI=10.1016/j.ymben.2013.04.001;
RA Yu D., Xu F., Zi J., Wang S., Gage D., Zeng J., Zhan J.;
RT "Engineered production of fungal anticancer cyclooligomer depsipeptides in
RT Saccharomyces cerevisiae.";
RL Metab. Eng. 18:60-68(2013).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, AND DOMAIN.
RX PubMed=23727842; DOI=10.1039/c3cc42425a;
RA Yu D., Xu F., Gage D., Zhan J.;
RT "Functional dissection and module swapping of fungal cyclooligomer
RT depsipeptide synthetases.";
RL Chem. Commun. (Camb.) 49:6176-6178(2013).
RN [5]
RP INDUCTION.
RX PubMed=25912088; DOI=10.1016/j.jip.2015.04.004;
RA Lobo L.S., Luz C., Fernandes E.K., Juarez M.P., Pedrini N.;
RT "Assessing gene expression during pathogenesis: Use of qRT-PCR to follow
RT toxin production in the entomopathogenic fungus Beauveria bassiana during
RT infection and immune response of the insect host Triatoma infestans.";
RL J. Invertebr. Pathol. 128:14-21(2015).
RN [6]
RP BIOTECHNOLOGY.
RX PubMed=27676608; DOI=10.1016/j.bioorg.2016.09.008;
RA Mun B., Park Y.J., Sung G.H., Lee Y., Kim K.H.;
RT "Synthesis and antitumor activity of (-)-bassianolide in MDA-MB 231 breast
RT cancer cells through cell cycle arrest.";
RL Bioorg. Chem. 69:64-70(2016).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, AND DOMAIN.
RX PubMed=29163920; DOI=10.1039/c7sc03093b;
RA Steiniger C., Hoffmann S., Mainz A., Kaiser M., Voigt K., Meyer V.,
RA Suessmuth R.D.;
RT "Harnessing fungal nonribosomal cyclodepsipeptide synthetases for
RT mechanistic insights and tailored engineering.";
RL Chem. Sci. 8:7834-7843(2017).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, AND DOMAIN.
RX PubMed=31471217; DOI=10.1016/j.chembiol.2019.08.005;
RA Steiniger C., Hoffmann S., Suessmuth R.D.;
RT "Probing Exchange Units for Combining Iterative and Linear Fungal
RT Nonribosomal Peptide Synthetases.";
RL Cell Chem. Biol. 0:0-0(2019).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, DOMAIN, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=31388353; DOI=10.1186/s13036-019-0195-y;
RA Xu F., Butler R., May K., Rexhepaj M., Yu D., Zi J., Chen Y., Liang Y.,
RA Zeng J., Hevel J., Zhan J.;
RT "Modified substrate specificity of a methyltransferase domain by protein
RT insertion into an adenylation domain of the bassianolide synthetase.";
RL J. Biol. Eng. 13:65-65(2019).
CC -!- FUNCTION: Bassianolide nonribosomal synthetase that mediates the
CC biosynthesis of bassianolide (BSL), a non-ribosomal cyclodepsipeptide
CC that shows insecticidal and cancer cell antiproliferative activity
CC (PubMed:19285149, PubMed:23608474, PubMed:23727842, PubMed:29163920,
CC PubMed:31471217, PubMed:31388353). BSLS first catalyzes the iterative
CC synthesis of an enzyme-bound dipeptidol monomer intermediate from D-2-
CC hydroxyisovalerate and L-leucine before performing the condensation and
CC cyclization of 4 dipeptidol monomers to yield the cyclic tetrameric
CC ester bassianolide (PubMed:23608474, PubMed:23727842, PubMed:29163920,
CC PubMed:31471217, PubMed:31388353). The N-methyltransferase MT domain is
CC responsible for the methylation of the leucine residues of bassianolide
CC (PubMed:29163920, PubMed:31388353). BSLS is flexible with both the
CC amino acid and hydroxyl acid precursors, and produces bassianolide as
CC the major product (containing N-methyl-L-Leu), together with small
CC amounts of beauvericin and its analogs beauvericins A-C (containing N-
CC methyl-L-Phe) (PubMed:31388353). {ECO:0000269|PubMed:19285149,
CC ECO:0000269|PubMed:23608474, ECO:0000269|PubMed:23727842,
CC ECO:0000269|PubMed:29163920, ECO:0000269|PubMed:31388353,
CC ECO:0000269|PubMed:31471217}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.46 uM for L-phenylalanyl-N-acetyl-cysteamine thioester (by the
CC MT domain) {ECO:0000269|PubMed:31388353};
CC KM=2.8 uM for L-leucyl-N-acetyl-cysteamine thioester(by the MT
CC domain) {ECO:0000269|PubMed:31388353};
CC Vmax=0.41 uM/min/mg enzyme toward L-phenylalanyl-N-acetyl-cysteamine
CC thioester (by the MT domain) {ECO:0000269|PubMed:31388353};
CC Vmax=0.05 uM/min/mg enzyme toward L-leucyl-N-acetyl-cysteamine
CC thioester (by the MT domain) {ECO:0000269|PubMed:31388353};
CC -!- INDUCTION: Expression is induced during insect infection.
CC {ECO:0000269|PubMed:25912088}.
CC -!- DOMAIN: NRP synthetases are composed of discrete domains (adenylation
CC (A), thiolation (T) or peptidyl carrier protein (PCP) and condensation
CC (C) domains) which when grouped together are referred to as a single
CC module. Each module is responsible for the recognition (via the A
CC domain) and incorporation of a single amino acid into the growing
CC peptide product. Thus, an NRP synthetase is generally composed of one
CC or more modules and can terminate in a thioesterase domain (TE) that
CC releases the newly synthesized peptide from the enzyme. Occasionally,
CC additional domains required for further modifications are also present
CC (Probable). Bassianolide synthetase has the C1-A1-T1-C2-A2-MT-T2a-T2b-
CC C3 domain organization. During catalysis, C3 and C2 take turns to
CC incorporate the two biosynthetic precursors into the growing
CC depsipeptide chain that swings between T1 and T2a/T2b with C3 cyclizing
CC the chain when it reaches the full length (PubMed:23727842,
CC PubMed:29163920, PubMed:31471217, PubMed:31388353). The N-
CC methyltransferase MT domain in module 2 is responsible for the
CC methylation of the leucine residues integrated in the backbone
CC structure (PubMed:29163920, PubMed:31388353).
CC {ECO:0000269|PubMed:23727842, ECO:0000269|PubMed:29163920,
CC ECO:0000269|PubMed:31388353, ECO:0000269|PubMed:31471217, ECO:0000305}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of bassianolide but does
CC not affect the biosynthesis of beauvericin (PubMed:19285149).
CC Attenuates the virulence against insects, including the corn earworm
CC (Helicoverpa zea), the fall armyworm (Spodoptera exigua) and the
CC greater wax moth (Galleria mellonella) (PubMed:19285149).
CC {ECO:0000269|PubMed:19285149}.
CC -!- BIOTECHNOLOGY: Shows insecticidal activity and contributes to the
CC virulence of the fungus against insects including the corn earworm
CC (Helicoverpa zea), the fall armyworm (Spodoptera exigua) and the
CC greater wax moth (Galleria mellonella) (PubMed:19285149). Bassianolide
CC possesses antitumor activities and displays significant cytotoxicity
CC against several human tumor cell lines, including A549, SK-OV-3, HepG2,
CC HCT-15, MCF-7 and MDA-MB 231 cell lines with IC(50) values of 7.24,
CC 8.44, 15.39, 6.40, 11.42 and 3.98 ug/ml respectively (PubMed:27676608).
CC Bassianolide especially induces G0/G1 arrest associated with a decrease
CC of cyclin A, D1 and an increase of p53, MDM2, and p21 expression in
CC human breast adenocarcinoma cell lines (PubMed:27676608).
CC {ECO:0000269|PubMed:19285149, ECO:0000269|PubMed:27676608}.
CC -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR EMBL; JH725154; EJP68628.1; -; Genomic_DNA.
DR RefSeq; XP_008595949.1; XM_008597727.1.
DR SMR; J5JV76; -.
DR STRING; 655819.J5JV76; -.
DR EnsemblFungi; EJP68628; EJP68628; BBA_02630.
DR GeneID; 19885642; -.
DR HOGENOM; CLU_000022_60_1_1; -.
DR InParanoid; J5JV76; -.
DR Proteomes; UP000002762; Unassembled WGS sequence.
DR GO; GO:0016853; F:isomerase activity; IEA:UniProtKB-KW.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0043604; P:amide biosynthetic process; IEA:UniProt.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:1901566; P:organonitrogen compound biosynthetic process; IEA:UniProt.
DR Gene3D; 1.10.1200.10; -; 2.
DR Gene3D; 3.30.300.30; -; 3.
DR Gene3D; 3.30.559.10; -; 3.
DR Gene3D; 3.40.50.12780; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR010071; AA_adenyl_domain.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR042099; ANL_N_sf.
DR InterPro; IPR023213; CAT-like_dom_sf.
DR InterPro; IPR001242; Condensatn.
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 Pfam; PF00501; AMP-binding; 2.
DR Pfam; PF00668; Condensation; 2.
DR Pfam; PF00550; PP-binding; 3.
DR SMART; SM00823; PKS_PP; 3.
DR SUPFAM; SSF47336; SSF47336; 3.
DR SUPFAM; SSF53335; SSF53335; 1.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 2.
DR PROSITE; PS00455; AMP_BINDING; 2.
DR PROSITE; PS50075; CARRIER; 3.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 3.
PE 1: Evidence at protein level;
KW Isomerase; Ligase; Methyltransferase; Multifunctional enzyme;
KW Phosphopantetheine; Phosphoprotein; Reference proteome; Repeat;
KW S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..3147
FT /note="Bassianolide nonribosomal cyclodepsipeptide
FT synthetase"
FT /id="PRO_0000448665"
FT DOMAIN 1015..1091
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 2515..2589
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 2615..2689
FT /note="Carrier 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..23
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 69..454
FT /note="Condensation 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:19285149"
FT REGION 495..887
FT /note="Adenylation 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:19285149"
FT REGION 1109..1538
FT /note="Condensation 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:19285149"
FT REGION 1567..1973
FT /note="Adenylation 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:19285149"
FT REGION 2041..2181
FT /note="S-adenosyl-L-methionine-dependent N-
FT methyltransferase (MT)"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:31388353"
FT REGION 2735..3139
FT /note="Condensation 3"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:19285149"
FT COMPBIAS 1..22
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 1052
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 2549
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 2649
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 3147 AA; 348346 MW; B8F4C5057B6E0FBA CRC64;
MEPPNNANTG QLGPTLPNGT VDLPTDLSRE ITRHFGLEQD EIEEILPCTP FQRDVIECAS
DDKRRAVGHV VYEIPEDVDT ERLAAAWKAT VRYTPALRTC IFTSETGNAF QVVLRDCFIF
ARMYCPSAHL KSAIVKDEAT AAVAGPRCNR YVLTGEPNSK RRVLVWTFSH SFVDSAFQGR
ILQQVLAAYK DEHGRVFSLQ PTTDLVESEN GDCLSTPASE RTVGIERATQ FWQEKLHGLD
ASVFPHLPSH KRVPAIDARA DHYLPCPPFI QHEWSSTTVC RTALAILLAR YTHSSEALFG
VVTEQSHEEH PLLLDGPTST VVPFRVLCAP NQSVSEVMEA ITTYDHDMRQ FAHAGLCNIS
RIGDDASAAC GFQTVLMVTD SRTASADEIH HVLEEPEKFI PCTDRALLLS CQMTDEGVLL
VARYDQSILE PLQMARFLRQ LGFLINKLQS TDGSPCVGQL DVLAPEDRTE IEGWNSEPLQ
TQDCLIHSEV VKNADDTPNK PAVCAWDGEW TYSELNNVSS RLASYISSLD LGQQLIVPIY
LEKSKWVMAA ILAVLKAGHA FTLIDPNDPP ARTAQIIKQA SASIALTSAL HQSKMQTVVG
RCITVDDDLF QTLTTFEGSQ VASAAKPGDL AYVIFTSGST GDPKGIMIEH RAFYSSVVKF
GKALGIRSST RALQFATHGF GAFLLEVLTT LIHGGCICIP SDHDRMHNIP GFIRQSQINW
MMATPSYMTT MKPEDVPGLE TLVLVGEQMS SSINDVWLSE LQLLDGYGQS ESSSICFVGK
ISDSSRDPNN LGRAIGSHSW IVNPDNPDQL VPIGAIGELL IESPGIARGY LFSQSTETPF
LERAPAWYAS KQPPYGVKFY RTGDLARYAP DGTVICLGRM DSQVKIRGQR VELDAIENLL
RRQFPSDVTV VAEAVKRSDL PSSVVITGFL ISSEYVVGAP STEDTYILDQ AVTQEINAKM
RQILPAHSIP SFYICMKSLP RTATGKVDRR KLRSIGSSLL ALQAQSTAPR SSQAPDASAG
VTKLEEVWMD IFNLTPNSHN IGGNFFALGG DSITAIKMVN MARAAGIQLK VSDIFQNPTL
ASLQAAIGGS SMTVTSIPAL ALDGPVEQSY SQGRLWFLDQ LEIGANWYTI PYAVRLRGPL
DVDALNRALL ALEKRHETLR TTFEDQDGVG VQIIHETLLD QLRIINADHA DYVQLLKQEQ
TAPFNLASES GWRVSLIRLD DDDNILSIVM HHIISDGWSI DVLRRELGQL YAAALHGADL
FGSALSPLPI QYRDFSVWQK QDAQVAEHER QLQYWQKQLA DCSPAKLPTD FHRPALLSGK
ATTVPVTITS ELYYRLQEFC STFNTTSFVV LLATFRAAHY RLTGVDDAVI GTPIANRNRH
ELENLIGFFV NTQCMRITIN EDEETFESLV RQVRSTTTAA FEHEDVPFER VVSAMLPGSR
DLSQNPLAQL VFAIHSHKDL GKFELEALES EPLQNEVYTR FDAEFHFFQA PDGLTGYINF
ATELFKVETI QNVVSVFLQI LRHGLEHPQT LISVVPLTDG LAELRSMGLL EIKKVEYPRD
SSVVDVFATQ VASYPDTLAV VDSSSRLTYA ELDHQSDLLA TWLRQQNLPT EALVVVLAPR
SCETIITFLG ILKANLAYLP LDIRSPITRM RDVLSTLPGR TIALLCSDEV APDFQLPSIE
LVRIADALEE AAGMTSLNGH EHVPVPSPSP TSLAYVLYTS GSTGRPKGVM IEHRAIVRLA
RSDIIPDYRP ACGDTMAHMF NTAFDGATYE IYTMLLNGGT LVCVDYMDTL SPKSLEAVFK
KEQVNATIMA PALLKLYLAD ARDALKGLDV LISGGDRFDP QDAVDAQSLV RGSCYNGYGP
TENGVFSTVY KVDKNDPFVN GVPLGRAVNN SGAYVVDRNQ QLVGPGIIGE LVVTGDGLAR
GYTERAFDQN RFIQLKIEGQ SVRGYRTGDR VRYRVGEGLI EFFGRMDFQF KIRSNRIEAG
EVEAAILSHP AVRNAAVILH VQEKLEPEIV GFVVAEHDDT AEQEEAGDQV EGWQAFFEST
TYTELDTVSS SEIGKDFKGW TSMYDGNEID KAEMQEWLDD TIHTLTDGQA LGHVLEIGTG
SGMVLFNLGS GLQSFVGLEP SKSAAAFVNN AIKSTPALAG KAHVFVGTAT DTNKLDDLHP
DLVIFNSVLQ YFPTRDYLEQ VVDALVHLRS AKRIFFGDVR SYATNRHFLA ARAIYTLGNH
TTKDEVRKKM AEMEEREEEF LVEPAFFTTL VNRLPDVRHV EIIPKNMQAT NELSAYRYAA
VVHLRGPDEL TRPVHLIKMD DWVDFQASHM HKDALREYLR LAENTKTVAI SNIPYGKTIF
ERQVVESLDD TSEDAPHASL DGAAWISAVR SDAKARSSLS VPDLVLLAKE TGFRVEVSAA
RQWSQSGALD AVFHRYHPAE PDVRTLFQFP TDNDVRMSAL LTNQPLQRLQ KRRVAVQVRE
WLQDRIPSYM IPSHIVALDQ MPLNTSGKVD RKELSRQAKA IKKVQKSAPP TAPAFPLSEV
EVMLCEELTK TFEMDVNITD DFFQLGGHSL LATRLVARIS HRLGARLTVK DVFDYPVFSE
LADIIRQQLA SKNTLLPTAS AGGGGQDKKE SAGVAPTTDM EAMLCEEFAN ILGMDVGITD
NFFDLGGHSL MATRLAARIG HRLNTTISVK DIFSHPVIFQ LSAKLEVSQL ESSSGGTDIK
MPDYTAFQLI PAADAEKFMQ DHIYPQINFS QDMVQDVYLA THLQQCFLRD VFGRPKPLVP
FYVEFPPDSN PHTLATACTS LVDKYDIFRT IFVEAEGNLY QVVLKHLNLD IDVVETDANV
HKTSSDLVDA IAKEPVRLGQ PMIQVKVLKQ TSSVRVLLWL SHALYDGLSW EHIVRDLHIL
SKERSLPPAT QFSRYMQYVD HTRGPGCDFW RDVLQNAPIT NLSDAGSGGR PTKAGDPRVW
HAGKVISGPS QAIRSSITQA TVFNAACAIV LSKETGTDNV VFGRIVSGRQ GLPVRWQNII
GPCTNAVPVR AVVDAHGNHQ QMLRDLQEQY LLSLPYETIG FDEIKRSCTD WPDSARNYGC
CVTYQNFEYH PESEVDQQRV EMGILAKKAE LIKEEPLYNV AIAGEVEPDG VHLQVTVVVD
SQLFSQEGAT HLMEQVCNTF QALNASL
