CALA_PENDC
ID CALA_PENDC Reviewed; 2910 AA.
AC A0A1V6PAF7;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 07-JUN-2017, sequence version 1.
DT 03-AUG-2022, entry version 26.
DE RecName: Full=Highly reducing polyketide synthase calA {ECO:0000303|PubMed:30598828};
DE Short=HR-PKS calA {ECO:0000305};
DE EC=2.3.1.- {ECO:0000305|PubMed:30598828};
DE AltName: Full=Calbistrin biosynthesis cluster protein A {ECO:0000303|PubMed:30598828};
GN Name=calA {ECO:0000303|PubMed:30598828}; ORFNames=PENDEC_c013G00595;
OS Penicillium decumbens.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=69771;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=IBT 11843;
RX PubMed=28368369; DOI=10.1038/nmicrobiol.2017.44;
RA Nielsen J.C., Grijseels S., Prigent S., Ji B., Dainat J., Nielsen K.F.,
RA Frisvad J.C., Workman M., Nielsen J.;
RT "Global analysis of biosynthetic gene clusters reveals vast potential of
RT secondary metabolite production in Penicillium species.";
RL Nat. Microbiol. 2:17044-17044(2017).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=8436557; DOI=10.7164/antibiotics.46.34;
RA Jackson M., Karwowski J.P., Humphrey P.E., Kohl W.L., Barlow G.J.,
RA Tanaka S.K.;
RT "Calbistrins, novel antifungal agents produced by Penicillium restrictum.
RT I. Production, taxonomy of the producing organism and biological
RT activity.";
RL J. Antibiot. 46:34-38(1993).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=24287995; DOI=10.3390/molecules181214629;
RA Bladt T.T., Duerr C., Knudsen P.B., Kildgaard S., Frisvad J.C.,
RA Gotfredsen C.H., Seiffert M., Larsen T.O.;
RT "Bio-activity and dereplication-based discovery of ophiobolins and other
RT fungal secondary metabolites targeting leukemia cells.";
RL Molecules 18:14629-14650(2013).
RN [4]
RP IDENTIFICATION, FUNCTION, DOMAIN, DISRUPTION PHENOTYPE, INDUCTION, AND
RP PATHWAY.
RX PubMed=30598828; DOI=10.1186/s40694-018-0063-4;
RA Grijseels S., Pohl C., Nielsen J.C., Wasil Z., Nygaard Y., Nielsen J.,
RA Frisvad J.C., Nielsen K.F., Workman M., Larsen T.O., Driessen A.J.M.,
RA Frandsen R.J.N.;
RT "Identification of the decumbenone biosynthetic gene cluster in Penicillium
RT decumbens and the importance for production of calbistrin.";
RL Fungal Biol. Biotechnol. 5:18-18(2018).
CC -!- FUNCTION: Highly reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of calbistrin A and related compounds.
CC Calbistrin A is a secondary metabolite with an interesting structure
CC that was recently found to have bioactivity against leukemia cells. It
CC consists of two polyketides linked by an ester bond: a bicyclic decalin
CC containing polyketide and a linear 12 carbon dioic acid structure
CC (PubMed:30598828). The polyketide synthase calA is probably responsible
CC for forming the decalin moiety. Because calA lacks a designated
CC enoylreductase (ER) domain, the required activity is provided by the
CC trans-enoyl reductase calK (PubMed:30598828). Following release from
CC the PKS, calF then probably catalyzes the oxidation and the subsequent
CC Diels Alder cycloisomerization that lead to the formation of the
CC decalin moiety (Probable). The decalin polyketide backbone includes two
CC C-methyl groups, at C7 and C11 in backbone, of which the C7 position is
CC probably methylated by the methyltransferase domain of calA. A
CC candidate for adding the methyl group at C11, if not done by CalA, is
CC the cluster methyltransferase calH (Probable). Several additional
CC tailoring enzymes within the cluster could be involved in the
CC modification of the decalin polyketide product. Those include the 3
CC cytochrome P450 monooxygenases CalE, CalG and CalL, of which one might
CC be responsible for the introduction of the extra hydroxyl group
CC attached to the backbone of the decalin moiety, at position C9 in the
CC backbone, that allows for attachment of the linear moiety (Probable).
CC One tailoring enzyme activity that is expected to be involved in
CC biosynthesis of calbistrin is an acyltransferase for connecting the two
CC polyketide synthase products, and which could be performed by the
CC cluster acyltransferase calJ (Probable). The enzyme responsible for the
CC biosynthesis of the linear moiety, probably a second PKS, has not been
CC identified yet (Probable). {ECO:0000269|PubMed:30598828,
CC ECO:0000305|PubMed:30598828}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:30598828}.
CC -!- INDUCTION: Expression is induced in complex medium (Czapek yeast
CC autolysate medium) supporting calbistrin production (PubMed:30598828).
CC Expression is positively regulated by the calbistrin biosynthesis
CC cluster-specific transcription factor calC (PubMed:30598828).
CC {ECO:0000269|PubMed:30598828}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of calbistrin and of the
CC related metabolites decumbenones, whereas production of unrelated
CC compounds, such as andrastin C, remains unaffected.
CC {ECO:0000269|PubMed:30598828}.
CC -!- BIOTECHNOLOGY: Calbistrin A has been reported to possess a number of
CC interesting bioactivities including antifungal active against Candida
CC albicans and cytotoxic toward both healthy and leukemic human cells.
CC {ECO:0000269|PubMed:24287995, ECO:0000269|PubMed:8436557}.
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DR EMBL; MDYL01000013; OQD73955.1; -; Genomic_DNA.
DR SMR; A0A1V6PAF7; -.
DR OMA; IHLDRIF; -.
DR OrthoDB; 19161at2759; -.
DR Proteomes; UP000191522; 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; 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; IPR013120; Far_NAD-bd.
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; 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; PF07993; NAD_binding_4; 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; 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..2910
FT /note="Highly reducing polyketide synthase calA"
FT /id="PRO_0000446473"
FT DOMAIN 2406..2488
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:30598828"
FT REGION 11..447
FT /note="Ketoacyl synthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30598828"
FT REGION 559..875
FT /note="Acyl transferase (AT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30598828"
FT REGION 949..1242
FT /note="Dehydratase (DH) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30598828"
FT REGION 1399..1586
FT /note="Methyltransferase (MT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30598828"
FT REGION 2125..2298
FT /note="Ketoreductase (KR)domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30598828"
FT REGION 2492..2565
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2597..2826
FT /note="Reductase (R) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30598828"
FT COMPBIAS 2507..2560
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 181
FT /note="For ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2448
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2910 AA; 317354 MW; AABD082662F29E88 CRC64;
MAEDMPINEP LAIVGSACRF AGGVSSPSKL WDLLSNPRDV RSEILKSRFN AENYYHPDSA
YHGHSNIQHS YLLEEDVAAF DSQFFGIKPV EAKAIDPQQR LLMETVYEGL ESAGLTIDSL
RDSDTAVYVG LMCGDYEASL LRDLSTAPVY AATGIGRSIL SNRVSYFFNW HGPSMTIDTA
CSSSLVAVHL AAQALRSGES RVALACGSNL LLGPENYIME SKLKMLSPDG RSKMWDKDAN
GYARGDGVAA CVLKTLSAAI EDGDDIECII RETGVNQDGA TTGITMPSAT AQQALIRSTY
KKAGLDLSKV NDRPQFFEAH GTGTPAGDPI EAEAISKAFF DEQYGTMVAA EPLYVGSIKT
ILGHTEGTAG LAALLKASLA LQHSVVPPNM LLNNLSDKVA PFTKNLEILK APKAWPSVEA
GQPRRASVNS FGFGGTNAHA ILESYEPRRH LQNGVTNSEA IVQFTPFVFS ALSHQSLRAT
LSAYADHIQS NPAVNLRDMA YTLQERRSAF PYRVSFAALS ADELATKIRA EVEGTKAEEL
GVRVSAPQTD GKRRKVLGVF TGQGAQYARM GAELLETSAT ARKIIQELQT CLEQLPEDLR
PDFSLEEELR AAADSSRVLT GAFSFLSTVV QLLLVDLLKL AGVQFDAIVA HSSGEMAAAY
AAGRLSARDA MCVAYFRGRF ASKMESPNGA DKKGAMLAAG MSEEDAATLC ADEIFAGRVC
VAAVNSSSSV TISGDEDAID EFKLILDDEN KFNRKLRVDR AYHSNHVSRR LADYVTLIQS
AGVQALEPGK DAPLWISSVY GREVTTDMNL DDEYWGASVA RSVQFYQALK LVLEADDYQV
ALEVGPHPAL KGPASQTIQE LGKSIPYYGV LSRGTDATVS LASSLGSLWC HLGGEQLDLT
GFEKEVNDNK SSLRVVKGLP RYQWNHEASY WHESRASKKH KAQTQPFNQL LGTMMPDSAA
HHLSWGHLLR ASEIEWASGH QVQSQTVFPA AGYICTAFEG ARVLAANRDV RLFELKDFVI
HQALTFSHDD AGIEVQASIA DIQRPSNDRI KAKFTYSASL GGEDLDLVAE AELHIVFGPS
SERTLPHRAA RPPHMISVDN ERFYTFLATL GYGFEGPFKS LHTLRRKLGS SVCAVNSVPR
ENTFGRPLLV HPAELDGGIQ SLILAYSYPD DDQLLNMHLP TSMSSIRVNP ALCQSMTDIS
VDSRLGRNKS AGFSGDVSLY TSNSECAAIQ MQGVELKPLG ALTAKDDRKV FSKYQWVKNR
LDGDLAACDT TVTKHHQDVL EGLERISTYY LNKLDAEVPV DSPLRKEGPH SNYLNYAHHI
VELIQKGEHK VAKKEWLSDS PEDLHQATAH LSDLIDYRMM HLVGQQMPRV LRGETNMLEE
MRVSNILDDY YKGAFGSREA GLWIGKIISQ LAERYPHLNI LEVGAGTGGA TTRVLQGLSN
KFLSYTFTDV SSGFFEGAAE MFSEHKDRMV FKTFDCGQDP VTQGYAEGTC DVVVAFLVIH
ATPDLELTMR NIRKLLKPGG LLVVGEGTNN GQPYGSAGFI FGSLPGWWLG ADTGRPLSPF
VSYSEWERLL KASAFSGIDS TAPQAFQDIL GMTVFAAQAV DDRVNFLREP LNPDVLSQSS
AAIEYPIKNL VVVGGSTERT RPLVASVTDT LKNHSAQVHT FETLSAVDFS LVDEDATVVS
LSELDKPVFQ DLTPDEWMAF KTLFSCPTRL FWVTSGRLSE EPFSNMTVGF ARTAVFETPA
LRFQNVDISN LETLTPQDLA EKVLRFHAST SPVPADLKQF AWPLEPEIVI DAQGEELVPR
LRHIAERNDR YNSARRPITN ETDITKTPAT LHNDREGWKL KELPGCASPA EHPGDRLSLE
VTHSVLSALR TPYGHQFLVF GIERQSQTRF MALVPTLISV VDVSKGSAIP LPTSTLADSE
LLTSLAATLV SMAVVDPLME GDTLVVQNAT ELFASTIATL ATSKKIRIVF VADFARPNVP
ESWVKLEPYV TQSEIAEILP ANTACFVDLS IEASENASVI PSSLPLHHRK ENVSTLYSPL
GWESGSSSAG TALGQLLHRA WFYAQQEAFA HRQNNATSQV VGITDLLEGL NPGNPATVID
WTLSKTHPVH VSRLDSVVFF KGDKTYWLCG LSGALGVSLV DWMIERGAKY LVLTSRNPNI
SPDWIAGHKR NGVTVTIVPC DVTNEPAIRA AHQFICETLP PIVGVLNGAM VLRDVSIRNM
SYELMSDVFR PKVHGSIHLD RIFRDEPLDF FILFSSINCV IGNLGQANYA AANTFMCSLA
AQRRKRGLAA TALNVGAIIG AGYMERESSK ALDLTVSKMA LMHLSEQDYH QLFAEGIDSG
RPGSGDEAEL TTGLLDIPAA TDTENTPKWH SNPAFLDFIV HQVEKNGADS GNEVVASVQD
QLAACQSRSE VLAVVKGRFA MQLRNVLQMT TADEDLMALR SRDIGLDSLI SVDIRSWFLK
NFEVSVPVLK IMGNDTMAEL AELAAEQAPA SLLPGLGGEA PAPTEEAQAN NAASQPVPLT
VVPQSDETGS SSADSNHDGS PGESRGGSTG YTTPTTPDPH STKGPIRIDW DAEIALPNAA
NIAIEIVPVA RPQKIVLTGV SGLLGRSLLL RLLEDASVKK IFCIAVRRLE ERLQSEELLL
DDRVQYFSGN LEQPRLGLSE EDAIAIFSQA DAVIHNGADT SHLKFYPEIK AANAGSTKEL
ISLCMARKVP IHYISTVGVA LFGNYESFPQ VSIAAHHPPI DGSHGYVAAK WVSERLLEEL
QRQHGVNVWI HRPSTIVREG ADNENAAAQT DWMNALMAYM RKMQAVPVMK NLRGALDFVY
VKNAADSILT AVLENKPVGA SYTHQVGDIV IPLDNLKEFI EDTGALNVEE LPIEKWSARA
VTVGLNRGVA ALIDSMDDPG QPHYPRLLRQ
