GLOL_GLAL2
ID GLOL_GLAL2 Reviewed; 2531 AA.
AC S3D9F1;
DT 20-JUN-2018, integrated into UniProtKB/Swiss-Prot.
DT 18-SEP-2013, sequence version 1.
DT 03-AUG-2022, entry version 51.
DE RecName: Full=Highly reducing polyketide synthase gloL {ECO:0000303|PubMed:23688303};
DE Short=HR-PKS gloL {ECO:0000305};
DE EC=2.3.1.- {ECO:0000305|PubMed:23688303};
DE AltName: Full=Pneumocandin acyl side chain synthase {ECO:0000303|PubMed:27494047};
DE AltName: Full=Pneumocandin biosynthesis cluster protein L {ECO:0000303|PubMed:25270390};
GN Name=gloL {ECO:0000303|PubMed:25270390};
GN Synonyms=GLPKS4 {ECO:0000303|PubMed:23688303}; ORFNames=GLAREA_10034;
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, FUNCTION,
RP DISRUPTION PHENOTYPE, AND PATHWAY.
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, DOMAIN, 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: Highly reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of pneumocandins, lipohexapeptides of
CC the echinocandin family that prevent fungal cell wall formation by non-
CC competitive inhibition of beta-1,3-glucan synthase (PubMed:23688303.
CC PubMed:27705900). The 10,12-dimethylmyristoyl side chain is synthesized
CC by the reducing polyketide synthase gloL/GLPKS4 (PubMed:27494047). The
CC thioesterase gloN/GLHYD exclusively interacts with gloL/GLPKS4 to
CC maintain turnover of the polyketide side chain (PubMed:27494047). The
CC 10R,12S-dimethylmyristic acid is then transferred to the first
CC thiolation domain of the nonribosomal peptide synthetase gloA/GLNRPS4
CC by the acyl-AMP ligase gloD/GLligase, followed by its acylation to L-
CC ornithine to trigger elongation of the cyclic hexapeptide
CC (PubMed:27494047). L-ornithine, 4R-hydroxyl-L-proline (generated from
CC L-proline by the dioxygenase gloF/GLOXY2), 3S-hydroxyl-L-homotyrosine
CC (generated by gloG/GLHtyB, gloH/GLHtyA, gloI/GLHtyC, gloJ/GLHtyD and
CC hydroxylated at C-3 by the dioxygenase gloM/GLOXY1), 3R-hydroxyl-L-
CC glutamine (generated from L-glutamine probably by the dioxygenase
CC gloE/GLOXY3) and 3S-hydroxyl-L-proline (generated from L-proline by the
CC dioxygenase gloF/GLOXY2 to yield pneumocandin B0), or 3S-hydroxyl-4S-
CC methyl-L-proline (generated from L-leucine by the dioxygenase
CC gloC/GLOXY4 to yield pneumocandin A0) are sequentially added to the
CC growing chain (PubMed:25270390, PubMed:25879325, PubMed:25527531). The
CC last C domain of gloA/GLNRPS4 is proposed to be responsible for
CC cyclization by condensation to form the peptide bond between L-
CC ornithine and 3S-hydroxyl-4S-methyl-L-proline (for pneumocandin A0) or
CC 3S-hydroxyl-L-proline (for pneumocandin B0). Finally, the subsequent C-
CC 4 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:23688303,
CC ECO:0000269|PubMed:25270390, ECO:0000269|PubMed:25527531,
CC ECO:0000269|PubMed:25879325, ECO:0000269|PubMed:27494047,
CC ECO:0000269|PubMed:29352089, ECO:0000303|PubMed:27705900}.
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:23688303,
CC ECO:0000269|PubMed:27494047, ECO:0000305|PubMed:25879325}.
CC -!- DISRUPTION PHENOTYPE: Blocks the production of the two major
CC pneumocandins, A0 and B0 (PubMed:23688303). Leads to the formation of a
CC pneumocandin A0 derivative with a myristic acid side chain as the main
CC pneumocandin product (PubMed:27494047). Produces also tiny amounts of
CC pneumocandin A0 derivatives with a pentadecanoic or palmitic acid side
CC chain (PubMed:27494047). {ECO:0000269|PubMed:23688303,
CC 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}.
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DR EMBL; KE145356; EPE34340.1; -; Genomic_DNA.
DR RefSeq; XP_008078275.1; XM_008080084.1.
DR AlphaFoldDB; S3D9F1; -.
DR SMR; S3D9F1; -.
DR STRING; 1116229.S3D9F1; -.
DR EnsemblFungi; EPE34340; EPE34340; GLAREA_10034.
DR GeneID; 19469081; -.
DR KEGG; glz:GLAREA_10034; -.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_000022_31_1_1; -.
DR OrthoDB; 19161at2759; -.
DR Proteomes; UP000016922; Unassembled WGS sequence.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR001227; Ac_transferase_dom_sf.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR014043; Acyl_transferase.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR013149; ADH-like_C.
DR InterPro; IPR011032; GroES-like_sf.
DR InterPro; IPR018201; Ketoacyl_synth_AS.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR013217; Methyltransf_12.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR032821; PKS_assoc.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR020843; PKS_ER.
DR InterPro; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00107; ADH_zinc_N; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF08242; Methyltransf_12; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00829; PKS_ER; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF50129; SSF50129; 1.
DR SUPFAM; SSF51735; SSF51735; 2.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme; NADP;
KW Oxidoreductase; Phosphopantetheine; Phosphoprotein; Reference proteome;
KW Transferase.
FT CHAIN 1..2531
FT /note="Highly reducing polyketide synthase gloL"
FT /id="PRO_0000444491"
FT DOMAIN 2413..2505
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:25879325"
FT REGION 18..438
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 449..525
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 602..909
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 971..1251
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 1419..1597
FT /note="Methyltransferase (CMet) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 1806..2114
FT /note="Enoyl reductase (ER) (ER) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 2139..2312
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT COMPBIAS 449..520
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 187
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2464
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2531 AA; 276382 MW; E4875D3AFDC6A774 CRC64;
MGDISGSVDP SNMAYEPLAI VGMGMRLPGG IHTAEDFWNL LVEKRSSRCK VPSDRFNIEA
FYSPSGRVGT VKMEHGHFLG PTDDLQHFDA SFFSMSKKEV EILDPQQRML LEVVYECMQN
AGQSNWRGGN IGCYVGVWGE DWVDIHAKDS QDAGMYRISG GQDFAISNRV SYEYDLKGPS
FTIKSGCSSS MIALHEAARA IQAGDCDGAI IAGTNLIISP TMSIAMTEQG VLSPDGACKS
FDESADGYAR GEAINAIYIK RLSDAIRDGD NIRSVIRATA SNCDGKTPGI TLPSSESHEA
MMRRAYKEAC LDPTQTAFVE AHGTGTKIGD PLEATAIARV FSSEKGVYIG SVKPNVGHSE
GASGVTSIMK AVLALENRTI PPNINFSTPN PQIPFEASNM KVAVEPIPWP KVQAERASVN
SFGIGGANAH VILDSPASMG ISSTKRNTTN GLSVNGHSIN GNSVNGHSVN GHSTNGHSIN
GNSVNGHSVN GNSVNGHSTN GHSINGHSAN GNSINGHSVN GHSKPRPALL VLSATNTESL
RANVVKHQQY IETNPEKLVN IEYNLCNRRE HLSNRAFCVT DGLSTLQFSP LTKPKKTPTL
VMVFTGQGAQ WAEMGKELMA DFPSFSQDID LMNNTLSKLD HPPSWNIKEE LLKHESVSCL
SKAEFAQPLV TAIQVALVNL LRQFGVKPAA VVGHSSGEIA AAYAANAITA NEAIIIAYYR
GQVTKGFSRR GGMAAVGLGR EDVMSFLNPG VSIACENSSS SVTLSGDEDA LNATCEIIKT
ALPDVFLRPL KVEMAYHSHH MKELGEAYEA LLRPHLKSTT PVVPFFSSVS GKVVSKSGTL
DAAYWRSNLE NPVLFNSAIK LILDTLAQDH LFLEIGPHSA LAGPIRQILK ANSRKNDTYV
TALERGKDCG ESILKMIGEL YLQHISINFK QVAPNGTVLT DLPLYQWCHD QEYWKESRVS
KQWRLRKYPN HEILGSRTVE GNELQPEWRN VLHLDNVPWL RDHQIINDVV FPCAGYLSMA
CEAIRQISAS EDFTFRNIVI QTALVMSDSK SVEMITSLRP VRLTNTLNSV WWDFSISSYN
GSLWIKHCGG QIRSGTDNPK FKLPRRIEDH PRSVPSPYPA MKKVGLNYGP TFQGLERLSA
LPKKMTASAT LSKSELSESH YAIHPATIDH CLQLFIVSTC EGTLRNINKL CVPTSIDQLY
ICGGKSTSGI KAEACGAQTS TGTISGDVVA ISGDAIILSL IGGQFSPIEE DSSDEDLDTV
AGARLDWKPD LDFVQIDNLI RPRQQSTAAT KTLEKFTLLS MIDIGRRISG LVTKSEYLEK
FRSWINAQVE RASEDRYNLV EDAQALTVLN AGERQMLIAE LSKEISNSEV ATSGELISRV
VKNCEDIMVG KIDGIEVLLP ENGLTHFYDS LEHRTDCIDF FTAAGHSKPN LRVLEIGSGT
GGTSAVVLKG LTSTAQRMYS TYTYTDISSG FFVEAQERFK DYHGLEYKVL DISKDPTEQG
FQEGSYDLII AANVLHATPS LNTTLGHARK LLAEDGRLFL QELSPQVQFA NLIMGVLPGW
WLGEADGRAN EPYISPERWA VELRKAGFSG CDATVYDAEQ PYQFNANIIS RPAKVDRIAR
RITLLYEPNL NIQQIKFSLE NKGYSVDLCT IQEEPPAGQD IVSLLELETP MFEKISGTDL
ALFQRLVKNL GTNHLLWVTR SAQIESYDPR FGMVLGLART LRSELSLSIA TLEIDTVDEV
AYNAITNVFD KLKNSSSVSD MNPDYEFVLS KGVVNIGRYH PVSVEQELAV SASQSQAVKL
EIGRFGLLQT LRWVPDLQNK VGHDQVIVEP RCAGLNFKDV LVSMGIVSGD GLGLEGSGTV
VGVGSEVTDF QVGDRVLYID QNCFSTRTAI PALRCAKIPS TLSWEEAATM PCVYATVIHS
LLNLGRIQKG QSVLIHSACG GIGLAAIQIC QNIVGAQIYV TVGNEEKVHY LMDTFGISRD
HIFNSRDTSF LPAIKAATNG RGVDVVLNSL SGELLHASWE CVAEYGSMVE IGKRDFIGKA
QLNMDLFESN RSFFGVDLAK FDAARCQLLL VQMMEFYEKG LIKPIAPMKV FEGAKVEDSF
RYMQKGSHIG KIVVTIPEQN TDLPLASIVP KLKLNPDAGY LLVGGLGGLG RAVSTWMVER
GARHLIFLSR SAGKSDQDQS FFRELESQDC TVQAFTGSVA TFQDVQNAVQ RASKPIKGVF
QMSMVLNDKP FLEMSCSDWE TSVLPKVEGT WHLHHALPKD LDFFVATSSL SGSFGNAGQA
NYAAANTFLD AFVQYRHSLG LPASVVDIGV MGDIGYVSRN AAIQESLRGA GTYFLQEQDF
LDSLNWAVAK SAVKPSLPGQ NQLLIGVRSS KSLSDPSNRV SFKRDARMGA YLNTGSSTSA
NTTNATDQLK SFMSSVETDS SILNVPASLD LVTNEIGVRI YTFMLQPIED LDVSQTLAAL
GVDSLVTIEI RNWMKRSFGG LEFSTLEILN AGTIEALGLL TIEGLKRKYE MKDGEAKFSE
REDTYLLMKA P
