GLOP_GLAL2
ID GLOP_GLAL2 Reviewed; 546 AA.
AC S3DQN8;
DT 20-JUN-2018, integrated into UniProtKB/Swiss-Prot.
DT 18-SEP-2013, sequence version 1.
DT 03-AUG-2022, entry version 32.
DE RecName: Full=Cytochrome P450 monooxygenase gloP {ECO:0000303|PubMed:25270390};
DE EC=1.-.-.- {ECO:0000305|PubMed:25879325};
DE AltName: Full=Homotyrosine 4-hydroxylase {ECO:0000303|PubMed:27705900};
DE AltName: Full=Pneumocandin biosynthesis cluster protein P {ECO:0000303|PubMed:25270390};
GN Name=gloP {ECO:0000303|PubMed:25270390};
GN Synonyms=GLP450-1 {ECO:0000303|PubMed:25879325}; ORFNames=GLAREA_10030;
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, DISRUPTION PHENOTYPE, 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: Cytochrome P450 monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of pneumocandins, lipohexapeptides of the
CC echinocandin family that prevent fungal cell wall formation by non-
CC competitive inhibition of beta-1,3-glucan synthase (PubMed:27705900).
CC The 10,12-dimethylmyristoyl side chain is synthesized by the reducing
CC polyketide synthase gloL/GLPKS4 (PubMed:27494047). The thioesterase
CC gloN/GLHYD exclusively interacts with gloL/GLPKS4 to maintain turnover
CC of the polyketide side chain (PubMed:27494047). The 10R,12S-
CC dimethylmyristic acid is then transferred to the first thiolation
CC domain of the nonribosomal peptide synthetase gloA/GLNRPS4 by the acyl-
CC AMP ligase gloD/GLligase, followed by its acylation to L-ornithine to
CC trigger elongation of the cyclic hexapeptide (PubMed:27494047). L-
CC ornithine, 4R-hydroxyl-L-proline (generated from L-proline by the
CC dioxygenase gloF/GLOXY2), 3S-hydroxyl-L-homotyrosine (generated by
CC gloG/GLHtyB, gloH/GLHtyA, gloI/GLHtyC, gloJ/GLHtyD and hydroxylated at
CC C-3 by the dioxygenase gloM/GLOXY1), 3R-hydroxyl-L-glutamine (generated
CC from L-glutamine probably by the dioxygenase gloE/GLOXY3) and 3S-
CC hydroxyl-L-proline (generated from L-proline by the dioxygenase
CC gloF/GLOXY2 to yield pneumocandin B0), or 3S-hydroxyl-4S-methyl-L-
CC proline (generated from L-leucine by the dioxygenase gloC/GLOXY4 to
CC yield pneumocandin A0) are sequentially added to the growing chain
CC (PubMed:25270390, PubMed:25879325, PubMed:25527531). The last C domain
CC of gloA/GLNRPS4 is proposed to be responsible for cyclization by
CC condensation to form the peptide bond between L-ornithine and 3S-
CC hydroxyl-4S-methyl-L-proline (for pneumocandin A0) or 3S-hydroxyl-L-
CC proline (for pneumocandin B0). Finally, the subsequent C-4
CC hydroxylation of 3S-hydroxyl-L-homotyrosine and L-ornithine
CC dihydroxylation at C-4 and C-5 are performed by the cytochrome P450
CC monooxygenases gloP/GLP450-1 and gloO/GLP450-2, respectively
CC (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=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:25879325}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- DISRUPTION PHENOTYPE: Leads to the production of pneumocandin analogs
CC with 3S-hydroxyl-L-homotyrosine (PubMed:25879325).
CC {ECO:0000269|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 cytochrome P450 family. {ECO:0000305}.
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DR EMBL; KE145356; EPE34336.1; -; Genomic_DNA.
DR RefSeq; XP_008078271.1; XM_008080080.1.
DR AlphaFoldDB; S3DQN8; -.
DR SMR; S3DQN8; -.
DR STRING; 101852.XP_008078271.1; -.
DR EnsemblFungi; EPE34336; EPE34336; GLAREA_10030.
DR GeneID; 19469077; -.
DR KEGG; glz:GLAREA_10030; -.
DR eggNOG; KOG0684; Eukaryota.
DR HOGENOM; CLU_022195_9_2_1; -.
DR OrthoDB; 595327at2759; -.
DR Proteomes; UP000016922; 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; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002403; Cyt_P450_E_grp-IV.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00465; EP450IV.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..546
FT /note="Cytochrome P450 monooxygenase gloP"
FT /id="PRO_0000444490"
FT TRANSMEM 17..37
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 492
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 189
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 413
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 416
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 546 AA; 62378 MW; 57DD8F1EC262B7AA CRC64;
MLSEVIARVE LLIGEQTLSG GILTFLFIVV IAHFVLTRFT VHSRFWNSQA WTGVREEWFP
KMRAKVRTIG NIRQMLSDGY EGFSKQNKAF ALPVIAEKPW LVLPHSCIPE LLAKSDSEID
MKIIHEEQLM HEYTTGSLGR HVVDVPIQYD ILLRQVNRKL PLLISAFNEE LDKSFCHYWG
TDTSYSEVNL SETCEKIVTQ ALNRIFAGKE ICRDEGFLEH SRLYSEGVGR NAIMVRMLPP
LLRPLLAPFI TYSNRKHRDI CLRVCLPVIR ERVQHTAAKR ADAEHKWEPP LDVLQWIIEE
SFARNDPKEL DPRMITQRLL ALNFVAIDTT HMSMAHTILD LYRSPNSDDF LVGLREECER
VLQANGGQWT KSGLDDLVCV DSTIRESMRY SDLGYISLTR MVVDPKGTQF NANGTNSSSP
LSVPPGIRIC VPAHAIHRDA ALYPSPYEFQ AFRFSKAREK YRGTQTELSE PKVSIVTTTD
KFLPFGHGRH ACPGRFFAAQ QMKLMLAYLV QNYDVEKLST KIQNKIMVGT TKPDASLKIK
VKRRKV
