MILA_CORMM
ID MILA_CORMM Reviewed; 2465 AA.
AC G3JUI8;
DT 03-AUG-2022, 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 milA {ECO:0000303|PubMed:34548637};
DE Short=HR-PKS milA {ECO:0000303|PubMed:34548637};
DE EC=2.3.1.- {ECO:0000269|PubMed:34548637};
DE AltName: Full=Cordypyrones biosynthesis cluster protein A {ECO:0000303|PubMed:34548637};
GN Name=milA {ECO:0000303|PubMed:34548637}; ORFNames=CCM_09346;
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 FUNCTION, DOMAIN, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=34548637; DOI=10.1038/s41429-021-00478-3;
RA Gao Y.L., Yu C., Li L.;
RT "Heterologous expression of a natural product biosynthetic gene cluster
RT from Cordyceps militaris.";
RL J. Antibiot. 75:16-20(2022).
CC -!- FUNCTION: Highly reducing polyketide synthase (HR-PKS); part of the
CC gene cluster that mediates the biosynthesis of cordypyrones A and B, 2
CC pyrones that show modest activities against pathogenic bacteria
CC including methicillin-resistant Staphylococcus aureus (MRSA),
CC Mycobacterium tuberculosis and Bacillus cereus (PubMed:34548637). The
CC HR-PKS milA catalyzes the formation of cordypyrones A via condensation
CC of one acetate with 10 malonate units (PubMed:34548637). Since milA
CC lacks an enoyl reductase domain, the 2 beta-keto processing domains DH
CC and KR of milA collaborate with the trans-enoyl reductase milB to
CC catalyze the different levels of reduction (PubMed:34548637). The
CC cytochrome P450 monooxygenase milC then hydroxylates the C-22 of
CC cordypyrones A to yield cordypyrones B (PubMed:34548637).
CC {ECO:0000269|PubMed:34548637}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + 3 AH2 + 18 H(+) + 10 malonyl-CoA + 8 NADPH = 3 A
CC + 10 CO2 + 11 CoA + cordypyrone A + 8 H2O + 8 NADP(+);
CC Xref=Rhea:RHEA:71139, ChEBI:CHEBI:13193, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, ChEBI:CHEBI:17499,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57288, ChEBI:CHEBI:57384,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:190187;
CC Evidence={ECO:0000269|PubMed:34548637};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:71140;
CC Evidence={ECO:0000269|PubMed:34548637};
CC -!- COFACTOR:
CC Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942;
CC Evidence={ECO:0000255};
CC Note=Binds 1 phosphopantetheine covalently. {ECO:0000255};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:34548637}.
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 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.
CC {ECO:0000305|PubMed:34548637}.
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DR EMBL; JH126407; EGX87724.1; -; Genomic_DNA.
DR RefSeq; XP_006674543.1; XM_006674480.1.
DR STRING; 983644.G3JUI8; -.
DR EnsemblFungi; EGX87724; EGX87724; CCM_09346.
DR GeneID; 18171349; -.
DR KEGG; cmt:CCM_09346; -.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_000022_31_0_1; -.
DR InParanoid; G3JUI8; -.
DR OMA; ESMDPQH; -.
DR OrthoDB; 19161at2759; -.
DR Proteomes; UP000001610; Unassembled WGS sequence.
DR GO; GO:0016746; F:acyltransferase 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:0009058; P:biosynthetic process; IEA:UniProt.
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; 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; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
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; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Multifunctional enzyme; NADP; Oxidoreductase;
KW Phosphopantetheine; Phosphoprotein; Reference proteome; Transferase.
FT CHAIN 1..2465
FT /note="Highly reducing polyketide synthase milA"
FT /id="PRO_0000455745"
FT DOMAIN 2384..2459
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 4..437
FT /note="Ketoacyl synthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:34548637"
FT REGION 567..888
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:34548637"
FT REGION 957..1265
FT /note="Dehydratase (DH) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:34548637"
FT REGION 2095..2269
FT /note="Ketoreductase (KR)domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:34548637"
FT MOD_RES 2419
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2465 AA; 265234 MW; 09D80C74EBB8ABBC CRC64;
MEPIAIVGSA CRFPGDATSP SKLWELLKAP RDLSQEVKRF NAKGFYHENG HHHGASNVMA
AYTLESDPME FDPQFFNIQP GEAESMDPQH RLLLETTYEG LEQAGIPIES LRGSDTSAFI
GVMSADYTTM VFFDSECTPT YSATGTSRAI LSNRLSHAFD WRGASMTLDT ACSSSLVAIH
LAVRELRSGS SRVAVAGGTN LILSADPFIS ETNLDMLSPQ GKCHMWDARA NGYARGEGIS
VVVLKTLRDA LADGDHIECI IRETGVNQDG HTPGITMPNP EAQTRLIRDV YSRAGLDLSK
PEDRCQYFEA HGTGTKAGDK VESRAIHDAF FPETGGEQAP LEPLYVGSVK TIIGHTEGTA
GVAGVLRASL AIQNGTIPPN LHFESLNPEL KPYYGNLQIA TEAIPWPELH GGVRRASVNS
FGFGGANCHV ILEGYLPSYG DDALREVVSK PSLSSSPSLS PTSTSPPTPR TPANSLPFLI
SASSEKTLRK LVQRYIDHVG QNPNVDMGNL AWTLFKNRSA LNFRLAVPAP TPEALITTLE
SVLKQPAGGP KSSIIRTVSQ PKRLLGVFTG QGAQWATMGR QLVQKSARAA ATVDRLDAAL
AALPDPYRPT WSLKAQILAE KKASRIDESA VSQPLCTVIQ IILVDLLRNA GVDFDGVLGH
SSGEIAAAYA AGFLSAEDAV KIAYTRGLCA HLARGQQGEK GGMIAAGMTH PDAKDLCENE
AVLGRISVAA YNSPTSVTLS GDSDVIDQVS VVLEDEDKFN RVLRVQTAYH SHHMEACVGL
YRKALAACNI TVLNPAQHVP WFSSVYGGSV MSATSNIASE YWIQNMVQPV LFSEAVAAAS
QTEHQDALPT LAEIGPHPAL KSPVLETLKS LGIDKVAYCG TLSRAVDDVD ALSAFFGWFW
SVSAQSGLQL DRYAAQFSQN KLVSLRNLPS YPWDHTHSYE FESRESHAHR FRELPCHPLL
GVRTNTCGDA EYRWKNFLST EEIPWLTGHQ IQGQTLVPAA MFLIMAAEAA TIAAGSLGLQ
VRLIELHDST IHRALALDDD KSTETLFYLS GVEVTSSPNE GSILSATYHC DAATSKSSSR
LTSIASGKVQ LFVGGDASRT LPNSALGSGQ LNEIDVDTFY DNLRTIGYNY NGAFRSIASL
QRTTNWANGT IAAPTSTDPA TSPSWVPLHP AVLDVSFQAV FAALSYPGDG RLQTLHVPTT
IKRLTISPAA LSSGAIPAGG FAFNAVSYML DRRTICGDIE VGIAGQEESI FKVEGLTVSP
VAPVTADDDK HMFADMVLCV AEPSTALLPD VPEQLLANTL SQNYGEAENA VSNKHSSLEN
GHLTNGHCLA NGGHSTNGLT NGHASTNGHG STNGHISTNG HSTNGDVLTN GHSVNGHAHS
NGHSENGAIS VNKPTAGGYT ADKARSYHIV AGLLKQITDR YPKARILERV TDNASEVLNV
FTAIGGRLSS YALDGIAESE FDAIADSRDD GSSLKRVSLQ LESPSFLETN AGGEYDVVVL
RDGHATDKGT LQLLRHLLRP GGYLLLIHEL DQSLASLEGD SELWSGRFTE AGFSKMEAQG
SSKSGRFSIM ATMATNDAVD ALRQPMVSVG AKIPTLIIIG GETPVTVDLI GKIRALLAPF
CQVVQTVKSL AHLDDSAVAE KAFVLSLTEL DSDLYRDLSE KTFTKLQELT TRSDRLIWVV
SGSQGRNPYA NMIKGTLRCL IEECSHLVTQ ILDIEDNVSG AGQFISDAVL RLHNLHSMEN
ASKTLWSHEP ELHLRNGQPF ISRYLPNKQL DLGYNSLQRH VQVELQPTAG VLQLSADKSA
LSLERLRVAA LPSSHLAANE LETEIIVRYS QSVAVHVPAL GYLYPVTGTD VQTGRVVAAL
STENRSRVSV HKATLVPLIG LSDDQERSLP ERLQAFFLAA TIMQRCPPFT SAVVHEASNS
LTQLLVDAGR KSGVQFIFTT SDASRVDEIQ EQGWKFIARH GSTRQLSKLV QPDTLMCVDC
TQTGSGDSLA AMGLQVPSGV AVLTASDFVR PQSFKYRKIE DQAVHEALKA AVAETTSLAA
EKSDLGADGM IQIQDLPQSF AFGVPAKTIS WVNELPVRAT VLPALEECHF NPDRTYFLVG
MAGSLGLSTV SYMISRGARH FALSSRNPQV DAAWIAAQRT KYGAVVNTFA LDITDKAALT
KTIAAIRATM PPIGGVANGA LIIEDSLFAD LTYKQMTRAL GPKVDGSRYL DEAFGQDDLE
FFILYSSLVS IAGNTGQIAY AVANSFMVSL AHQRRQRGLA ASVINLTGVS GIGFITRTGH
NIIARSKALG YDIISESDYC YIFAESVLAS PSTSPHGPEV SSSLRYVDVA RDKVVPPWAY
DAKFGHYLLD RQAPATNGAA GESDNGGHLS LDVLKAAPPA ECYDMIFRAF QTVLQKLLRL
PADQPVPAEV QILDLGVDSL VAVKMRQWFL KELQVNMPVM KLIGGATVSQ VVWSVVHQIL
PESAK
