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GLOE_GLAL2
ID   GLOE_GLAL2              Reviewed;         328 AA.
AC   S3E7Q2;
DT   20-JUN-2018, integrated into UniProtKB/Swiss-Prot.
DT   18-SEP-2013, sequence version 1.
DT   03-AUG-2022, entry version 35.
DE   RecName: Full=2-oxoglutarate-dependent dioxygenase gloE {ECO:0000303|PubMed:25270390};
DE            EC=1.14.-.- {ECO:0000305|PubMed:25879325};
DE   AltName: Full=Glutamine hydroxylase {ECO:0000303|PubMed:27705900};
DE   AltName: Full=Pneumocandin biosynthesis cluster protein E {ECO:0000303|PubMed:25270390};
GN   Name=gloE {ECO:0000303|PubMed:25270390};
GN   Synonyms=GLOXY3 {ECO:0000303|PubMed:25879325}; ORFNames=GLAREA_10042;
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, 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: 2-oxoglutarate-dependent dioxygenase; part of the gene
CC       cluster that mediates the biosynthesis of pneumocandins,
CC       lipohexapeptides of the echinocandin family that prevent fungal cell
CC       wall formation by non-competitive inhibition of beta-1,3-glucan
CC       synthase (PubMed:27705900). The 10,12-dimethylmyristoyl side chain is
CC       synthesized by the reducing polyketide synthase gloL/GLPKS4
CC       (PubMed:27494047). The thioesterase gloN/GLHYD exclusively interacts
CC       with gloL/GLPKS4 to maintain turnover of the polyketide side chain
CC       (PubMed:27494047). The 10R,12S-dimethylmyristic acid is then
CC       transferred to the first thiolation domain of the nonribosomal peptide
CC       synthetase gloA/GLNRPS4 by the acyl-AMP ligase gloD/GLligase, followed
CC       by its acylation to L-ornithine to trigger elongation of the cyclic
CC       hexapeptide (PubMed:27494047). L-ornithine, 4R-hydroxyl-L-proline
CC       (generated from L-proline by the dioxygenase gloF/GLOXY2), 3S-hydroxyl-
CC       L-homotyrosine (generated by gloG/GLHtyB, gloH/GLHtyA, gloI/GLHtyC,
CC       gloJ/GLHtyD and hydroxylated at C-3 by the dioxygenase gloM/GLOXY1),
CC       3R-hydroxyl-L-glutamine (generated from L-glutamine probably by the
CC       dioxygenase gloE/GLOXY3) and 3S-hydroxyl-L-proline (generated from L-
CC       proline by the dioxygenase gloF/GLOXY2 to yield pneumocandin B0), or
CC       3S-hydroxyl-4S-methyl-L-proline (generated from L-leucine by the
CC       dioxygenase gloC/GLOXY4 to yield pneumocandin A0) are sequentially
CC       added to the growing chain (PubMed:25270390, PubMed:25879325,
CC       PubMed:25527531). The last C domain of gloA/GLNRPS4 is proposed to be
CC       responsible for cyclization by condensation to form the peptide bond
CC       between L-ornithine and 3S-hydroxyl-4S-methyl-L-proline (for
CC       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   -!- COFACTOR:
CC       Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC         Evidence={ECO:0000255|PROSITE-ProRule:PRU00805};
CC       Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000255|PROSITE-
CC       ProRule:PRU00805};
CC   -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000305|PubMed:25879325}.
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 iron/ascorbate-dependent oxidoreductase
CC       family. {ECO:0000305}.
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DR   EMBL; KE145356; EPE34348.1; -; Genomic_DNA.
DR   RefSeq; XP_008078283.1; XM_008080092.1.
DR   AlphaFoldDB; S3E7Q2; -.
DR   SMR; S3E7Q2; -.
DR   STRING; 1116229.S3E7Q2; -.
DR   EnsemblFungi; EPE34348; EPE34348; GLAREA_10042.
DR   GeneID; 19469089; -.
DR   KEGG; glz:GLAREA_10042; -.
DR   eggNOG; KOG0143; Eukaryota.
DR   HOGENOM; CLU_010119_4_0_1; -.
DR   OrthoDB; 622449at2759; -.
DR   Proteomes; UP000016922; Unassembled WGS sequence.
DR   GO; GO:0051213; F:dioxygenase activity; IEA:UniProtKB-KW.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   Gene3D; 2.60.120.330; -; 1.
DR   InterPro; IPR026992; DIOX_N.
DR   InterPro; IPR044861; IPNS-like_FE2OG_OXY.
DR   InterPro; IPR027443; IPNS-like_sf.
DR   InterPro; IPR005123; Oxoglu/Fe-dep_dioxygenase.
DR   Pfam; PF03171; 2OG-FeII_Oxy; 1.
DR   Pfam; PF14226; DIOX_N; 1.
DR   PROSITE; PS51471; FE2OG_OXY; 1.
PE   1: Evidence at protein level;
KW   Dioxygenase; Iron; Metal-binding; Oxidoreductase; Reference proteome.
FT   CHAIN           1..328
FT                   /note="2-oxoglutarate-dependent dioxygenase gloE"
FT                   /id="PRO_0000444482"
FT   DOMAIN          170..271
FT                   /note="Fe2OG dioxygenase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT   BINDING         194
FT                   /ligand="Fe cation"
FT                   /ligand_id="ChEBI:CHEBI:24875"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT   BINDING         196
FT                   /ligand="Fe cation"
FT                   /ligand_id="ChEBI:CHEBI:24875"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT   BINDING         249
FT                   /ligand="Fe cation"
FT                   /ligand_id="ChEBI:CHEBI:24875"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT   BINDING         262
FT                   /ligand="2-oxoglutarate"
FT                   /ligand_id="ChEBI:CHEBI:16810"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
SQ   SEQUENCE   328 AA;  37835 MW;  FD6FFCD93FD85616 CRC64;
     MDYIKQAEST QLSSLSLSRL EGNNAEESKR LLEACAQDGF FYLDLRDHKQ LLVDYEALLE
     IIKQYFNEPL DQKMKDDRKS DTIGYEPVAT SAGVLDGLPD YYESFKVSWN QLRDHVQELP
     TVVETNIEVF DRFAKYVHSI LLMILSRLSQ TMGRNNDNRF ESYHRDSIAT RTNLTFLKYP
     KQDTTEHGVG HNKHTDVGTL TFLLSGQRGL QRLTPEGWCH VEPRSGFAVV NVGDSLRFLS
     DCVLSSVIHR VLPVGAHQTE DRYTLAYFLR PEDDAVFKDI NGNLVSARSW HDRKFDHFRA
     SHNQQKNDTI LMGGMEENQK FLQYKFQA
 
 
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