LCSD_PURLI
ID LCSD_PURLI Reviewed; 386 AA.
AC A0A179HJB8;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 07-SEP-2016, sequence version 1.
DT 03-AUG-2022, entry version 22.
DE RecName: Full=Acyl-CoA ligase lcsD {ECO:0000303|PubMed:27416025};
DE EC=6.2.1.- {ECO:0000305|PubMed:27416025};
DE AltName: Full=Leucinostatins biosynthesis cluster protein D {ECO:0000303|PubMed:27416025};
GN Name=lcsD {ECO:0000303|PubMed:27416025}; ORFNames=VFPBJ_02533, VFPFJ_04705;
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 DISRUPTION PHENOTYPE, 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: Acyl-CoA ligase; part of the gene cluster that mediates the
CC biosynthesis of the lipopeptide antibiotics leucinostatins that show
CC extensive biological activities, including antimalarial, antiviral,
CC antibacterial, antifungal, and antitumor activities, as well as
CC phytotoxic (PubMed:27416025). Leucinostatin A contains nine amino acid
CC residues, including the unusual amino acid 4-methyl-L-proline (MePro),
CC 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 -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000305|PubMed:27416025}.
CC -!- INDUCTION: Expression is positively regulated by the leucinostatins
CC biosynthesis cluster-specific transcription regulator lcsF.
CC {ECO:0000269|PubMed:27416025}.
CC -!- DOMAIN: Both substrate-binding domains (SBD1 and SBD2) are involved in
CC the substrate recognition, and are sufficient to confer the substrate
CC specificity. {ECO:0000250|UniProtKB:Q42524}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of leucinostatins A and
CC B. {ECO:0000269|PubMed:27416025}.
CC -!- SIMILARITY: Belongs to the ATP-dependent AMP-binding enzyme family.
CC {ECO:0000305}.
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DR EMBL; LSBH01000002; OAQ83766.1; -; Genomic_DNA.
DR EMBL; LSBI01000004; OAQ90546.1; -; Genomic_DNA.
DR RefSeq; XP_018179265.1; XM_018321785.1.
DR AlphaFoldDB; A0A179HJB8; -.
DR SMR; A0A179HJB8; -.
DR STRING; 33203.A0A179HJB8; -.
DR EnsemblFungi; OAQ83766; OAQ83766; VFPBJ_02533.
DR EnsemblFungi; OAQ90546; OAQ90546; VFPFJ_04705.
DR GeneID; 28886834; -.
DR KEGG; plj:VFPFJ_04705; -.
DR OrthoDB; 683933at2759; -.
DR Proteomes; UP000078240; Unassembled WGS sequence.
DR Proteomes; UP000078340; Unassembled WGS sequence.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR Gene3D; 3.30.300.30; -; 1.
DR Gene3D; 3.40.50.12780; -; 1.
DR InterPro; IPR025110; AMP-bd_C.
DR InterPro; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR042099; ANL_N_sf.
DR Pfam; PF00501; AMP-binding; 1.
DR Pfam; PF13193; AMP-binding_C; 1.
PE 2: Evidence at transcript level;
KW ATP-binding; Ligase; Nucleotide-binding; Reference proteome.
FT CHAIN 1..386
FT /note="Acyl-CoA ligase lcsD"
FT /id="PRO_0000446602"
FT REGION 62..132
FT /note="SBD1"
FT /evidence="ECO:0000250|UniProtKB:Q42524"
FT REGION 133..195
FT /note="SBD2"
FT /evidence="ECO:0000250|UniProtKB:Q42524"
FT REGION 352..386
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 352..376
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 107..115
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q08AH3"
FT BINDING 137
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q08AH3"
FT BINDING 216
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q08AH3"
FT BINDING 235
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q08AH3"
FT BINDING 243..245
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000250|UniProtKB:Q08AH3"
FT BINDING 313..316
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000250|UniProtKB:Q08AH3"
FT BINDING 331
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q08AH3"
SQ SEQUENCE 386 AA; 42272 MW; 916BD897A6ACC2B2 CRC64;
MISHRNAIAN IMQIVTYEST YQSDEPELCL GVLPQSHIYS LVVVSQASIW RGDGVVVLQG
FELEQTLLAI QTNGIKRLWL VPPMLVAITK APRIVESYDL SSVSVAAVGA SGISKDVMAT
FGELLPACKI IQGYGMTETT GVVCFGNVED SMDGSCGHLY PGYEARLIDG EGKDVESHNT
PGELVLRSPS VVIGYYNDES ATSEAMMDGG WLRTGDLVEI RQSEKGHEHV FVVDRVKELI
KVRGLQVAPA ELESHLILHP AVAEVAVIPV PDDRAGELPK AYIVRASGAE LDEQVLRKEL
SQYVEGQFAR HKHLDGGIEF LDSLPKTASG KMQRKTLKEK ARTDAEARRQ AREKAANGVH
KVHVNGVKRP EKMEVFDLSS DDEDDD
