GLOB_GLAL2
ID GLOB_GLAL2 Reviewed; 682 AA.
AC S3DQQ3;
DT 20-JUN-2018, integrated into UniProtKB/Swiss-Prot.
DT 18-SEP-2013, sequence version 1.
DT 25-MAY-2022, entry version 20.
DE RecName: Full=Pneumocandin biosynthesis cluster protein B {ECO:0000303|PubMed:25270390};
GN Name=gloB {ECO:0000303|PubMed:25270390};
GN Synonyms=GLHYP {ECO:0000303|PubMed:25879325}; ORFNames=GLAREA_10045;
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, 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: Part of the gene cluster that mediates the biosynthesis of
CC pneumocandins, lipohexapeptides of the echinocandin family that prevent
CC fungal cell wall formation by non-competitive inhibition of beta-1,3-
CC glucan synthase (PubMed:27705900). The 10,12-dimethylmyristoyl side
CC chain is 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 -!- 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}.
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DR EMBL; KE145356; EPE34351.1; -; Genomic_DNA.
DR RefSeq; XP_008078286.1; XM_008080095.1.
DR AlphaFoldDB; S3DQQ3; -.
DR EnsemblFungi; EPE34351; EPE34351; GLAREA_10045.
DR GeneID; 19469092; -.
DR KEGG; glz:GLAREA_10045; -.
DR eggNOG; ENOG502T008; Eukaryota.
DR HOGENOM; CLU_403347_0_0_1; -.
DR OrthoDB; 1596001at2759; -.
DR Proteomes; UP000016922; Unassembled WGS sequence.
PE 1: Evidence at protein level;
KW Reference proteome.
FT CHAIN 1..682
FT /note="Pneumocandin biosynthesis cluster protein B"
FT /id="PRO_0000444487"
FT REGION 63..86
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 107..129
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 251..358
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 63..80
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 251..293
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 311..335
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ SEQUENCE 682 AA; 76217 MW; 4E5C740FA6A8BA37 CRC64;
MDLFQSPGGD LIQDEDSVEV IEMLCIDFRD RLLVALSTTC QSDFREAKKV VEERLRDILE
TASSLSSTEV TSSPNASPLY NTDAPEDVVP TVGLDVGLDE PMADYSQNTP SITGGTASAE
YQNSGDTNQM TLEDPACVDM FAAESQNTGH IPDSCLRDWS FEGVSMKSPS LFDWSSRNSN
FPLTQEHENQ FAEFLTLFEG EPNFDNWLST MTWSSLESHS SPINGHSAGA TPQLDQMHTV
SNSRVARSVV SESTVTNTGS ANSLNSGLLA NTPSSSHSSV FERACSSVQE PTPEPTPVRG
LQRKLRKQGP RQTTEATPCD QQIGPRASRA TSQLPERRSM KMVRKEARDT PLTTSPANST
QINIEANTIP SDLSVEYAFG CFSDAKEVFE TFYKRLSDDR KHLSSLLMRL FYAVGSPDAL
RQLRDALDLS RKNSMIASYH DSNDLAATVS VLDQLDATTT LSHILRRYHL VRLLDHRSKL
ESNHKAAKLA VKGTKRRLKY DCERIELMRR GENADCDANT RSAKERLKYR SKTRALTDLM
QTLYPDLSPD SEGITTAGGC EYTRKLTKLR NRLACARNWY QFEETFPGAI LALIPCATGD
LSISIDHVEK LPSDVLKIFL DYLKERRGVF LSKMSRILSK DLYDVLMRRN VTKRYKLEQT
NENSLTDGLH DDDRLLELCE TV
