CM3A_CORMM
ID CM3A_CORMM Reviewed; 4760 AA.
AC G3J456;
DT 17-JUN-2020, integrated into UniProtKB/Swiss-Prot.
DT 16-NOV-2011, sequence version 1.
DT 25-MAY-2022, entry version 55.
DE RecName: Full=Nonribosomal peptide synthetase cm3A {ECO:0000303|PubMed:31926180};
DE EC=6.3.2.- {ECO:0000305|PubMed:31926180};
DE AltName: Full=Beauveriolides biosynthesis cluster protein A {ECO:0000303|PubMed:31926180};
DE AltName: Full=Cyclodepsipeptides cm3 biosynthesis cluster protein A {ECO:0000303|PubMed:31926180};
GN Name=cm3A {ECO:0000303|PubMed:31926180}; ORFNames=CCM_01285;
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: Nonribosomal peptide synthetase; 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: 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 epimerase (E) domains (responsible for L- to D-amino acid conversion)
CC are present within the NRP synthetase. Cm3A has the following module
CC architecture: T-C-A-T-C-C-A-T-C-A-T-C-C. {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}.
CC -!- SIMILARITY: Belongs to the nrps family. {ECO:0000305}.
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DR EMBL; JH126399; EGX96627.1; -; Genomic_DNA.
DR RefSeq; XP_006666504.1; XM_006666441.1.
DR SMR; G3J456; -.
DR STRING; 983644.G3J456; -.
DR EnsemblFungi; EGX96627; EGX96627; CCM_01285.
DR GeneID; 18163316; -.
DR KEGG; cmt:CCM_01285; -.
DR eggNOG; KOG1178; Eukaryota.
DR HOGENOM; CLU_000022_60_0_1; -.
DR InParanoid; G3J456; -.
DR OMA; ERLWFIH; -.
DR OrthoDB; 4243at2759; -.
DR Proteomes; UP000001610; Unassembled WGS sequence.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR Gene3D; 1.10.1200.10; -; 4.
DR Gene3D; 3.30.300.30; -; 3.
DR Gene3D; 3.30.559.10; -; 6.
DR Gene3D; 3.40.50.12780; -; 3.
DR InterPro; IPR010071; AA_adenyl_domain.
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 Pfam; PF00501; AMP-binding; 3.
DR Pfam; PF00668; Condensation; 6.
DR Pfam; PF00550; PP-binding; 4.
DR SMART; SM00823; PKS_PP; 4.
DR SUPFAM; SSF47336; SSF47336; 4.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 3.
DR PROSITE; PS00455; AMP_BINDING; 3.
DR PROSITE; PS50075; CARRIER; 4.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Ligase; Phosphopantetheine; Phosphoprotein; Reference proteome; Repeat.
FT CHAIN 1..4760
FT /note="Nonribosomal peptide synthetase cm3A"
FT /id="PRO_0000449816"
FT DOMAIN 19..95
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 1120..1197
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 2684..2762
FT /note="Carrier 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 3783..3857
FT /note="Carrier 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..24
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 142..570
FT /note="Condensation 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31926180"
FT REGION 178..571
FT /note="Condensation 1"
FT /evidence="ECO:0000250|UniProtKB:C8VPS9, ECO:0000255"
FT REGION 591..984
FT /note="Adenylation 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31926180"
FT REGION 1210..1654
FT /note="Condensation 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31926180"
FT REGION 1689..2125
FT /note="Condensation 3"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31926180"
FT REGION 2171..2551
FT /note="Adenylation 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31926180"
FT REGION 2811..3203
FT /note="Condensation 4"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31926180"
FT REGION 3255..3647
FT /note="Adenylation 3"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31926180"
FT REGION 3869..4296
FT /note="Condensation 5"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31926180"
FT REGION 4340..4757
FT /note="Condensation 6"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31926180"
FT COMPBIAS 1..22
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 56
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1158
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 2721
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 4760 AA; 527912 MW; 167406FAE544D813 CRC64;
MKHLASSENM PTPAQDRAPS PSAMQQEIVD MCAQVLGRPI TRMRTSKSFV ALGGDSLLAI
KLMAHCREAG YTISIAKILQ TASIEELSRS AECQLISSSG EGPVPDPNRP GEPIATSLSL
LNNELVLDQV RNITAEPLED IQDIFPCSRT QEVFLISQHA NPEMYQCVVV AEIKCMKPGL
SLNDDRLQNA WICVAQRHPA LRTVFIESIQ RPGHFDQVIM KHEAVPLECQ LSSAQCEESA
EGMFSRRVSI SKEKGTTGRA TILRRSENSA VFRLEVSHAL MDGQSFGIIF HDFAQAYLQN
ELPSPTAFSY DSFVAYQEEI DRESVRAYWS SHLAGAQPTR FPTNGNRKLE DLKTLRFRIE
LDAAALQKVC LEYDATSANL CQVAWAVVLG SYTGSKDVCF SYVNSGRHAP LSSIENAVGA
FVDVMVCRMK LPETAKISQM LSKAKQDVIQ GLSHPGSLLF EEKKHGHGVS DLRGNTIITF
QMGVRDEESA GSDLQIVMLD EITASDYDIS LNIQPCHGGL DIRLDYWLSR IDQEIIESVA
ESFQTALACM CSDDIPLRDV NVVCTQEIEQ LRRRNSYTAT EIGSLLHDKV DEQARLCPDA
LAVQGWDGEL TYRALNEEAS KLASYLQHLG AQQDILICTC FEKSKWAAIS QLAVLKSGAA
VVPLGTNQPM KRLEMMITNT GADIVLTTSN FASRFVTLFK HVVVIDGASM AKLPLAATVS
CSATPDSLAY VIFTSGSTGV PKGVMLTHDS VSTSLRHSVE RLNPGPDTRM LQFSAYTFDA
AIYEFFFTWH IGACVCIVSE HDRINRLEPA MGELNVNWAL LTPTMAEMIS PGQVPSLKHL
MLIGEAIKPG VLHRWIDHVE LWNGYGPSEC SIISSCKLLT RECNTTNIGF PITGAFWVVD
ATNPDRLAPT GAIGELLIQG SHLARGYLND EQKTSQAFVP PPAWVSKYAF SGSTRYYRTG
DLVQRNKDGS ITFVGRRDTQ VKLRGQRVEF EDIEQHLKDH DAVVEAAIVL AADGPCQGQL
VAVVALEAFI SQEMHPKTLS PVDQQQIARA KLQTAILGDW LSDRVPEYMV PTMWIPVTSR
LLQTDSGKLD RVRLGRCVDS VDVSWVEAFA SAGEELTQER EATTLQLQIR DIWAEILLLS
IPQVPINRRS FLSLGGDSIL AMKAVSRART QGITLTVPDI LQSKSIAKLT EKLGVPEENF
LSYTSASKPF PLSPTQKWYF DRVHPLGSGI RHGYCRSVCL QANQKLAEKH VSTSFSTLVS
MHPMLRARFL ADAANGWQQQ VVGHSDDAYG FAVSHLNGFE EIHDIAESTE QGLNIENGPV
FSVQFMHLHA GKEEGKQLLF ITGHHLVMDE ISLCIIIEDL ERLLYQDSTV ALVVERPSFQ
AWVEGIAKTT KEEGPEPTSA SLTPGLKPLM SKLDLEFGSL TSNEPVYDET NTKVLQFDEF
DTMVLLGNAN QALRTEPVEL ILAALVMSFT TTFPSQCIPV LLEGSRGRSL NHGSIDNSKT
VGCFTTTMPL RFPVANMDDA VKSTKQIKNA RRNTKFRRLH DSQNRNARNY ETISSLNRET
MEIFFNFDDS SQQIQEQSTL FKQQLLPRRQ KLSTGVQKTR HSEIDVDATI LQSRLHVAFH
FNHRMNHGSD VERWSCEFPK TLRALVATLL KTPSMLTLSD FPLVELTDQK LKILEGQTLP
RVGVQPENVE DMYPCTPMQN GILMSQARSP GMYQTQVVWQ LQSPDSRINL DVERIMHAYQ
TLTDRHPMLR TIFVPRTSNA GDGAFDQIVI RRYRINVVHQ VCEQDSVEAL LATMTNPSAV
DYGDGPNHKF MVYSTPSNLT YGHLVINHAL SDGFSLSLLE KELTEAYEGT LTPDSKAPPY
SAYLSFLKQR STKEALQYWI NNLESAEACF LPAMVERKIQ NESETDIVSL PAPSRRQSTT
ASLEGVESLR KFSEKHSVTM ANVFQLAWAL VLSKFVRSDD VLFGYVSSGR DVPVHEAHQI
FGPFVNILVS RIKLDWDSSI AESLQSVQKR FFENLGQQRT PLVDIWHALK TGGRGLFNTY
LSYRQLSSAD GQRSGLFQHT IAILGDSEYD AGVDIVASSN KVSVTLDYLP SFMGHDAATR
IVDCLLQTVQ SLTQSEAFLL RNVTTTTGQD IRQICQWNSE VPLVTVQHCV HDTVYSKCCL
DPSAKAICAW DGDLTYFELD QLGEQLAFYL TSNLSVTPET MIGVCFDKSR WAIVAQLAIL
KSGGAIVPIN PMEPMQRLET ILRESGICTL LTTSCYGDRF LEIIPNVVAV DSNSPFFHGA
MPTERVHSTA NPDNAAVVIH TSGSTGNPKG VVLTHRSIAS SLEAQGKIFG LSSRTRTLQF
VSYTFDLSIG DIWGTLSHGG CVCVMSEDDR MNNIQGAIQI YGATLVIMTP TVATLLDVSK
LPSLETLVLG GEALKPAFVE KHLEARQIKI FNGYGPSECS MITTCNGPIQ HKNEAPKIGR
PLLGSVWLVD DTDKICPIGA VGEIWVEGPL VARGYLNKKD LTDKGFPVDP PWAASAGLQG
KRFYRTGDMA RQNAKGDLFY VDRKDWQIKI RGNRVELSEI EHAIKEILSG LQNVAACLVS
SNQRGPLIAA VLEQNCDTLG LQADVAGFHF ERLSPGFQKE LVLLKKALAG VLPSHMIPNL
YVPTTRLPLT ASGKVNRQAL RQSLESFSEQ EALHYTLADA AKTLPSSETE KTVRALWAAV
LQHELDQVGV EDNFFHLGGD SYLAMRLVAS SQADDSRVHF TVSDVLQHPT IRELAHAIDQ
RSTHSRASDR ETARFSLWKE YQELNKSQES GHAKALLDQI AAQCDVPIDD VEDIYPCTPL
QEGLMVVTAQ QPRAYIARWA FQMPDNINLE RFQGAWQTLS RAVPILRTRI VPGRLSGALQ
VVVRGDCKWH TSHDLDQYLS DDVAQSMAYG TSLIRLAYIN HSNGCRDFVW TAHHSIYDGW
SLPMLLEALS RIYLFNEVPE SFPPYSNFIQ YIQAQDLAEA TAFWRSELQG NLGEPFPALP
KPSYQPEPAR IIRCTINVES VNRLVTLASL LRAAWAATVS SHTGGTALFA MPLSGRNAPV
KGILDMMAPT VTTVPVRIQV DEKQAVHDYL AAVQQQASNM VPFEHSGLHH VRSMVGRDIN
PQHLFAIQSA PPGKATFEEL LGMKELTLPM DGFDNYALIV ECFINSREGA SIEILARFDD
NVLSHTQVQH LLSRFKHIFG QLSQVSAGNN DNTSSMLMGG LEYISPEEVA QLAILNREVA
ADAPCLVHDL VLRYSATTPD RPAVCAWDGE MSFQQLDQLS EALANRLVEL GVTIESPVMI
CCDKSKWAVV GILAILRAGG TVVPVRAAPV ARLQAIMEAT GSRVVVTMSE FISQLQGIAD
HVVSMDSVPV TKPEIPQGPV KQHPSTKSVS FIMFTSGSTG SPKGIVLEHG SMSIAIQSHV
KRFGVNRHTR GFQFASFTFD MSLHDILTPL AGGGCVCLPS EVERVNNLAH AMRRFRVNYS
MLTPRVLHTI KPSECPEIRT LLVGGERCDT EQLKLWLPQA KVWHVYGPVE CSIISTAAEF
TGSDTLSLGL ALVGAVWVTN KDNCNQLCPI GAVGELLVEG PLVARGYLRD EAKTSAVFID
YPPWRKQHGL APNSQSQRMY RTGDLVVQHE DGSLIFVGRA DQQLKIRGQR VEVGDIEHHI
GLQPEVEDGV VLYPQNGPCR SQLIGLVTLH EHMSATDLSE VQPSSADDLA KAITQTEIIR
SRLSDVLPDY MVPNVWISMA CLPQSAHHKV DRRKLMDWVQ SLDAEYFRRI TGAKQEAPEK
PTTRTEELMQ SVLADVLGLS PEDVSMGRSF LSMGGDSITS MQVVSQCRSR YGLSLHVRDI
LQSKSITQLA QRATTDAAIA PLLPASDGEF RLSPIQRLFF RSFAARGLQS EDEFRFNQSV
CLTVNKHIDT EQIKHAARGV VSAHPMLRAR FTVSGKRWRQ RIEDDVDASC HVVFHQVENQ
AELEDVIWAG QRSLSVEQGR VFSVHCIETT TTGSQLLFLV AHHLVVDIVS WQIILRDLDN
LIQHPKLTAP VESTTFQHWL QLQASRAQNV GSPHQLVHAQ MPIADWSYWG VTPENNTYGH
RINEQFILED CASVLFGDKQ PLRSEPVEVL LAALFHSFHQ IFPDRAVPTV FNEGHGREPW
SDAIDLSNTV GWFTTMTPIH VPVGTSDVVD VLKRTKDLRR SIPERGFAYF TSRFLTRDGQ
HAFASHDQPE VMFNFGGRYR DDKHSRSLFR MSNEFNSSHI SGIGNNVKRI AVFEVEASIQ
QENLAVTLGF SKNMQNPERI TRWIQAYQDS LKTLLCQLST LPTFLSLADV PLLNITYDDL
DRLQSERLPL VGINDIDCIE DIYPCSPAQE SILRSQARDS STFHVRSACE FRAREAVVNP
EALIRAWQTV VARHAILRTV CVPPTCDGES FYQAVLKQYE PQVSTVRCET AEDVDEAFKD
EGGLRYPKWK PEHQLTLCLT STGQVFFRLL INHTLVDVSS LQLIMNEVTL AYEDGILDTA
APSFSKYIAF LQESSVSESM KYWTSRLAGA QPHCLPVSAT VGDGQSRDNA HLEMSNLEPL
WRFRDRYGIT IANILQLAWA FVLAKHSGSR DVVFGYVANG RDAPVDGVSH MAGPLINVMV
SRIWLGDKQR SVAKTAEQVQ NDFMEAFRYQ RVSLADIEQV TGLSERQMLH TVVSIVRDPG
SRRSSDAGVS VHGQSATSLA EYDVSLNAAC GEDAIKLSLE YSSRYPGSVS AKGLLDNLQK
AVLDLAENGE ASIEEMGLRC
