GLOD_GLAL2
ID GLOD_GLAL2 Reviewed; 568 AA.
AC S3DB78;
DT 20-JUN-2018, integrated into UniProtKB/Swiss-Prot.
DT 18-SEP-2013, sequence version 1.
DT 03-AUG-2022, entry version 30.
DE RecName: Full=Acyl-CoA ligase gloD {ECO:0000303|PubMed:25270390};
DE EC=6.2.1.- {ECO:0000305|PubMed:27494047};
DE AltName: Full=Pneumocandin biosynthesis cluster protein D {ECO:0000303|PubMed:25270390};
GN Name=gloD {ECO:0000303|PubMed:25270390};
GN Synonyms=GLligase {ECO:0000303|PubMed:25879325}; ORFNames=GLAREA_10043;
OS Glarea lozoyensis (strain ATCC 20868 / MF5171).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Leotiomycetes;
OC Helotiales; Helotiaceae; Glarea.
OX NCBI_TaxID=1116229;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], IDENTIFICATION, AND
RP FUNCTION.
RC STRAIN=ATCC 20868 / MF5171;
RX PubMed=23688303; DOI=10.1186/1471-2164-14-339;
RA Chen L., Yue Q., Zhang X., Xiang M., Wang C., Li S., Che Y.,
RA Ortiz-Lopez F.J., Bills G.F., Liu X., An Z.;
RT "Genomics-driven discovery of the pneumocandin biosynthetic gene cluster in
RT the fungus Glarea lozoyensis.";
RL BMC Genomics 14:339-339(2013).
RN [2]
RP FUNCTION.
RX PubMed=25270390; DOI=10.1002/cbic.201402175;
RA Houwaart S., Youssar L., Huettel W.;
RT "Pneumocandin biosynthesis: involvement of a trans-selective proline
RT hydroxylase.";
RL ChemBioChem 15:2365-2369(2014).
RN [3]
RP FUNCTION, PATHWAY, AND BIOTECHNOLOGY.
RX PubMed=25879325; DOI=10.1021/acschembio.5b00013;
RA Li Y., Chen L., Yue Q., Liu X., An Z., Bills G.F.;
RT "Genetic manipulation of the pneumocandin biosynthetic pathway for
RT generation of analogues and evaluation of their antifungal activity.";
RL ACS Chem. Biol. 10:1702-1710(2015).
RN [4]
RP FUNCTION, AND BIOTECHNOLOGY.
RX PubMed=25527531; DOI=10.1128/aem.03256-14;
RA Chen L., Yue Q., Li Y., Niu X., Xiang M., Wang W., Bills G.F., Liu X.,
RA An Z.;
RT "Engineering of Glarea lozoyensis for exclusive production of the
RT pneumocandin B0 precursor of the antifungal drug caspofungin acetate.";
RL Appl. Environ. Microbiol. 81:1550-1558(2015).
RN [5]
RP FUNCTION, DISRUPTION PHENOTYPE, PATHWAY, AND BIOTECHNOLOGY.
RX PubMed=27494047; DOI=10.1021/acschembio.6b00604;
RA Chen L., Li Y., Yue Q., Loksztejn A., Yokoyama K., Felix E.A., Liu X.,
RA Zhang N., An Z., Bills G.F.;
RT "Engineering of new pneumocandin side-chain analogues from Glarea
RT lozoyensis by mutasynthesis and evaluation of their antifungal activity.";
RL ACS Chem. Biol. 11:2724-2733(2016).
RN [6]
RP FUNCTION.
RX PubMed=29352089; DOI=10.1128/aem.02370-17;
RA Mattay J., Houwaart S., Huettel W.;
RT "Cryptic production of trans-3-hydroxyproline in echinocandin B
RT biosynthesis.";
RL Appl. Environ. Microbiol. 0:0-0(2018).
RN [7]
RP REVIEW.
RX PubMed=27705900; DOI=10.1515/znc-2016-0156;
RA Huettel W.;
RT "Structural diversity in echinocandin biosynthesis: the impact of oxidation
RT steps and approaches toward an evolutionary explanation.";
RL Z. Naturforsch. C 72:1-20(2017).
CC -!- FUNCTION: Acyl-CoA ligase; part of the gene cluster that mediates the
CC biosynthesis of pneumocandins, lipohexapeptides of the echinocandin
CC family that prevent fungal cell wall formation by non-competitive
CC inhibition of beta-1,3-glucan synthase (PubMed:27705900). The 10,12-
CC dimethylmyristoyl side chain is synthesized by the reducing polyketide
CC synthase gloL/GLPKS4 (PubMed:27494047). The thioesterase gloN/GLHYD
CC exclusively interacts with gloL/GLPKS4 to maintain turnover of the
CC polyketide side chain (PubMed:27494047). The 10R,12S-dimethylmyristic
CC acid is then transferred to the first thiolation domain of the
CC nonribosomal peptide synthetase gloA/GLNRPS4 by the acyl-AMP ligase
CC gloD/GLligase, followed by its acylation to L-ornithine to trigger
CC elongation of the cyclic hexapeptide (PubMed:27494047). L-ornithine,
CC 4R-hydroxyl-L-proline (generated from L-proline by the dioxygenase
CC gloF/GLOXY2), 3S-hydroxyl-L-homotyrosine (generated by gloG/GLHtyB,
CC gloH/GLHtyA, gloI/GLHtyC, gloJ/GLHtyD and hydroxylated at C-3 by the
CC dioxygenase gloM/GLOXY1), 3R-hydroxyl-L-glutamine (generated from L-
CC glutamine probably by the dioxygenase gloE/GLOXY3) and 3S-hydroxyl-L-
CC proline (generated from L-proline by the dioxygenase gloF/GLOXY2 to
CC yield pneumocandin B0), or 3S-hydroxyl-4S-methyl-L-proline (generated
CC from L-leucine by the dioxygenase gloC/GLOXY4 to yield pneumocandin A0)
CC are sequentially added to the growing chain (PubMed:25270390,
CC PubMed:25879325, PubMed:25527531). The last C domain of gloA/GLNRPS4 is
CC proposed to be responsible for cyclization by condensation to form the
CC peptide bond between L-ornithine and 3S-hydroxyl-4S-methyl-L-proline
CC (for pneumocandin A0) or 3S-hydroxyl-L-proline (for pneumocandin B0).
CC Finally, the subsequent C-4 hydroxylation of 3S-hydroxyl-L-homotyrosine
CC and L-ornithine dihydroxylation at C-4 and C-5 are performed by the
CC cytochrome P450 monooxygenases gloP/GLP450-1 and gloO/GLP450-2,
CC respectively (PubMed:25879325). {ECO:0000269|PubMed:25270390,
CC ECO:0000269|PubMed:25527531, ECO:0000269|PubMed:25879325,
CC ECO:0000269|PubMed:27494047, ECO:0000269|PubMed:29352089,
CC ECO:0000303|PubMed:27705900}.
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:27494047,
CC ECO:0000305|PubMed:25879325}.
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: Fails to produce pneumocandins or any new
CC compound that might correspond to a deacylated peptide core or free
CC dimethylmyristic acid (PubMed:27494047). {ECO:0000269|PubMed:27494047}.
CC -!- BIOTECHNOLOGY: Pneumocandin B0 is the starting molecule for the first
CC semisynthetic echinocandin antifungal drug, caspofungin acetate
CC (PubMed:25527531). Pneumocandin B0 is a minor fermentation product, and
CC its industrial production was achieved by a combination of extensive
CC mutation and medium optimization (PubMed:25527531). Inactivation of
CC three of gloP/GLP450-1, gloO/GLP450-2, and gloM/GLOXY1 generates 13
CC different pneumocandin analogs that lack one, two, three, or four
CC hydroxyl groups on 4R,5R-dihydroxy-ornithine and 3S,4S-dihydroxy-
CC homotyrosine of the parent hexapeptide (PubMed:25879325). All of these
CC cyclic lipopeptides show potent antifungal activities, and two new
CC metabolites pneumocandins F and G are more potent in vitro against
CC Candida species and Aspergillus fumigatus than the principal
CC fermentation products, pneumocandins A0 and B0 (PubMed:25879325).
CC Moreover, feeding alternative side chain precursors yields acrophiarin
CC and 4 additional pneumocandin congeners with straight C14, C15, and C16
CC side chains. One of those compounds, pneumocandin I, has elevated
CC antifungal activity and similar hemolytic activity compared to
CC pneumocandin B0, the starting molecule for caspofungin, demonstrating
CC the potential for using gloD/GLligase for future engineering of new
CC echinocandin analogs (PubMed:27494047). {ECO:0000269|PubMed:25527531,
CC ECO:0000269|PubMed:25879325, ECO:0000269|PubMed:27494047}.
CC -!- SIMILARITY: Belongs to the ATP-dependent AMP-binding enzyme family.
CC {ECO:0000305}.
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DR EMBL; KE145356; EPE34349.1; -; Genomic_DNA.
DR RefSeq; XP_008078284.1; XM_008080093.1.
DR AlphaFoldDB; S3DB78; -.
DR SMR; S3DB78; -.
DR STRING; 1116229.S3DB78; -.
DR EnsemblFungi; EPE34349; EPE34349; GLAREA_10043.
DR GeneID; 19469090; -.
DR KEGG; glz:GLAREA_10043; -.
DR eggNOG; KOG1176; Eukaryota.
DR HOGENOM; CLU_000022_59_2_1; -.
DR OrthoDB; 683933at2759; -.
DR Proteomes; UP000016922; 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; IPR020845; AMP-binding_CS.
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.
DR PROSITE; PS00455; AMP_BINDING; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Ligase; Nucleotide-binding; Reference proteome.
FT CHAIN 1..568
FT /note="Acyl-CoA ligase gloD"
FT /id="PRO_0000444485"
FT REGION 282..352
FT /note="SBD1"
FT /evidence="ECO:0000250|UniProtKB:Q42524"
FT REGION 353..415
FT /note="SBD2"
FT /evidence="ECO:0000250|UniProtKB:Q42524"
FT BINDING 211..219
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q08AH3"
FT BINDING 352..357
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q08AH3"
FT BINDING 436
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q08AH3"
FT BINDING 455
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q08AH3"
FT BINDING 553
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q08AH3"
SQ SEQUENCE 568 AA; 62561 MW; E1140E99AF52A6BB CRC64;
MVFTSPSWCQ DILMPIPNNE LVGEFVMRRG HGLNDVSEDS PSSVCAYTGK SYSIRDIRHN
VKSLSKSLSQ ILGWDFNHGN PEDKVVAVCS LNSIDYVPLT WAIHRLGGIC LLLHPTSSAS
ELETLMRKAN CKAVFTCKPL MAQCQAAFTA INGDPSNIFL VELPLPEEQP VKISNTTISQ
LIADGEGLPD LQPLDLQDFD SKERLAYFCP TSGTSGFLKI AKVSHANVMA NILQCTTMDS
YTTASQTDVT LGILPLSHAY GLLVQHFVTF RGDCIILHPK FDMQIALKSV QQYRIVRLYL
VPTIIGALAT NPILFKLFDL SSVKRVITGS ASLPEQVSKA INQLCPEWEI NPGYGLTESF
VCMSWTSPNS QYPGSTGCLL PLVEARLLDA DGSDITAHGQ AGDLLVRSPS VMKEYLDDDL
KRDVTFDSDG WLRTGDVATF KQNPKGDSHL FIVDRKKDIM KVKGIQVPPV EIEGHLVAHP
AVDDAAVVAI SDEDAGERPF AFVVRSQKVM TDIDEKSLKK DISGYIQSTL SEPYWLRQNI
RFIDAIPKSH NGKALKFKLK QQLVTSSA
