LCSK_PURLI
ID LCSK_PURLI Reviewed; 548 AA.
AC A0A179HJU2;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 07-SEP-2016, sequence version 1.
DT 03-AUG-2022, entry version 21.
DE RecName: Full=Cytochrome P450 monooxygenase lcsK {ECO:0000303|PubMed:27416025};
DE EC=1.-.-.- {ECO:0000305|PubMed:27416025};
DE AltName: Full=Leucinostatins biosynthesis cluster protein K {ECO:0000303|PubMed:27416025};
GN Name=lcsK {ECO:0000303|PubMed:27416025}; ORFNames=VFPBJ_02525, VFPFJ_04697;
OS Purpureocillium lilacinum (Paecilomyces lilacinus).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Ophiocordycipitaceae; Purpureocillium.
OX NCBI_TaxID=33203;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], IDENTIFICATION, FUNCTION,
RP INDUCTION, AND PATHWAY.
RC STRAIN=PLBJ-1;
RX PubMed=27416025; DOI=10.1371/journal.ppat.1005685;
RA Wang G., Liu Z., Lin R., Li E., Mao Z., Ling J., Yang Y., Yin W.B., Xie B.;
RT "Biosynthesis of antibiotic leucinostatins in bio-control fungus
RT Purpureocillium lilacinum and their inhibition on phytophthora revealed by
RT genome mining.";
RL PLoS Pathog. 12:E1005685-E1005685(2016).
CC -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of the lipopeptide antibiotics leucinostatins
CC that show extensive biological activities, including antimalarial,
CC antiviral, antibacterial, antifungal, and antitumor activities, as well
CC as phytotoxic (PubMed:27416025). Leucinostatin A contains nine amino
CC acid residues, including the unusual amino acid 4-methyl-L-proline
CC (MePro), 2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid (AHyMeOA), 3-
CC hydroxyleucine (HyLeu), alpha-aminoisobutyric acid (AIB), beta-Ala, a
CC 4-methylhex-2-enoic acid at the N-terminus as well as a N1,N1-
CC dimethylpropane-1,2-diamine (DPD) at the C-terminus (Probable). The
CC biosynthesis of leucinostatins is probably initiated with the assembly
CC of 4-methylhex-2-enoic acid by a reducing PKS. Two reducing polyketide
CC synthases, lcsB and lcsC, have been identified in the cluster and it is
CC not clear which is the one that assembles 4-methylhex-2-enoic acid
CC since both contain KS, AT, DH, cMT, ER, KR and ACP domains (Probable).
CC The polyketide residue might be transferred to the NRPS lcsA, mediated
CC by two additional enzymes, the acyl-CoA ligase lcsD and the
CC thioesterase lcsE. The linear polyketide carboxylic acid, which is
CC released from PKS, is converted to a CoA thioester by lcsD, and then
CC lcsE hydrolyzes the thiol bond and shuttles the polyketide intermediate
CC to lcsA (Probable). The C domain of the first module catalyzed the
CC condensation of 4-methylhex-2-enoic acid and MePro carried by domain
CC A1, followed by successive condensations of nine amino acids to trigger
CC the elongation of the linear peptide. A5 and A6 domains of lcsA are
CC proposed to incorporate leucine, A2 AHyMeOA, and A3 incorporates HyLeu.
CC A4, A7 and A8 incorporate AIB (Probable). The AHyMeOA in leucinostatin
CC A activated by the A2 might be produced by the second PKS (lcsB or
CC lcsC) present within the cluster (Probable). The MePro is probably
CC produced via leucine cyclization and may originate from a separate
CC pathway, independent of the cluster. Another nonproteinogenic amino
CC acid, beta-Ala, could be produced by an aspartic acid decarboxylase
CC also localized outside of the cluster. Two candidates are VFPBJ_01400
CC and VFPBJ_10476 (Probable). The final peptide scaffold may be released
CC by the NAD(P)H-dependent thioester reductase (TE) at the C-terminal
CC region of lcsA (Probable). Transamination of the lcsA product by the
CC transaminase lcsP may produce DPD at the C-terminus (Probable). Further
CC hydroxylation steps performed alternatively by the cytochrome P450
CC monooxygenases lcsI, lcsK and lcsN then yield the non-methylated
CC leucinostatins precursor. It is also possible that leucines can be
CC hydroxylated prior to their incorporation into the peptide (Probable).
CC Varying extents of methylation then lead to the formation of
CC leucinostatins A and B (Probable). {ECO:0000269|PubMed:27416025,
CC ECO:0000305|PubMed:27416025}.
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000305|PubMed:27416025}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-pass membrane
CC protein {ECO:0000255}.
CC -!- INDUCTION: Expression is positively regulated by the leucinostatins
CC biosynthesis cluster-specific transcription regulator lcsF.
CC {ECO:0000269|PubMed:27416025}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; LSBH01000002; OAQ83757.1; -; Genomic_DNA.
DR EMBL; LSBI01000004; OAQ90537.1; -; Genomic_DNA.
DR RefSeq; XP_018179256.1; XM_018321777.1.
DR AlphaFoldDB; A0A179HJU2; -.
DR SMR; A0A179HJU2; -.
DR EnsemblFungi; OAQ83757; OAQ83757; VFPBJ_02525.
DR EnsemblFungi; OAQ90537; OAQ90537; VFPFJ_04697.
DR GeneID; 28886826; -.
DR KEGG; plj:VFPFJ_04697; -.
DR OrthoDB; 871849at2759; -.
DR Proteomes; UP000078240; Unassembled WGS sequence.
DR Proteomes; UP000078340; Unassembled WGS sequence.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR002403; Cyt_P450_E_grp-IV.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00465; EP450IV.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
PE 2: Evidence at transcript level;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..548
FT /note="Cytochrome P450 monooxygenase lcsK"
FT /id="PRO_0000446605"
FT TRANSMEM 28..48
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 68..88
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 487
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P04798"
FT CARBOHYD 172
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 223
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 242
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 404
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 548 AA; 61528 MW; 6BCB03605B5183DE CRC64;
MPTSLEQAAA LIGGVGTHLL YFKHGERHAY PWRYVALLLA GSLSLWAFKW SREGTTTSIL
AVTSSTSVLL FLYLGGLAGS VLLYRLFFNP LNRFPGPFAA RLSKLYFVYL SSDLRGHRKL
HELHQKYGRY VRVGPNDLSV VDPDGMKIVL GANSKCTKSA WYGQDMPYIS TNTTRDRAAH
DRRRRILAPA FSDKALRGYA SRLQKFHDLL TSQIDASAGK PMNVTKWFGY WGMDMMCDIV
FNGSFNMLAS GETHWALQVV GDGLHLQGFA LPPWLYRVFA TMPKSSSGSR GLAAFAATQL
ENRMQQQGKT AHADMMQPLI EHYDRLSTDT KRAILPLLQG DSRMLIVAGS DTTSTTLVHM
FYRFCKESGL VDRVREEVEP LVSDPNLISY SDIRQAQLLH ACINETLRLH YPGPSGFFRK
TPPEGIHIGE QHVPGDTIIQ MPPYVMGLDE EVYERCSEFV PERWYSKPEM IKHKDAFLPF
LAGSESCIGK NLAYIQLAVV ASQIILQFDV AFAPGEDGNK LVRESKDLGM LHPEDLHVVF
TRRGKTHS
