S3D9F1 · GLOL_GLAL2
- ProteinHighly reducing polyketide synthase gloL
- GenegloL
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids2531 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score4/5
Function
function
Highly reducing polyketide synthase; part of the gene cluster that mediates the biosynthesis of pneumocandins, lipohexapeptides of the echinocandin family that prevent fungal cell wall formation by non-competitive inhibition of beta-1,3-glucan synthase (PubMed:23688303, PubMed:27705900).
The 10,12-dimethylmyristoyl side chain is synthesized by the reducing polyketide synthase gloL/GLPKS4 (PubMed:27494047).
The thioesterase gloN/GLHYD exclusively interacts with gloL/GLPKS4 to maintain turnover of the polyketide side chain (PubMed:27494047).
The 10R,12S-dimethylmyristic acid is then transferred to the first thiolation domain of the nonribosomal peptide synthetase gloA/GLNRPS4 by the acyl-AMP ligase gloD/GLligase, followed by its acylation to L-ornithine to trigger elongation of the cyclic hexapeptide (PubMed:27494047).
L-ornithine, 4R-hydroxyl-L-proline (generated from L-proline by the dioxygenase gloF/GLOXY2), 3S-hydroxyl-L-homotyrosine (generated by gloG/GLHtyB, gloH/GLHtyA, gloI/GLHtyC, gloJ/GLHtyD and hydroxylated at C-3 by the dioxygenase gloM/GLOXY1), 3R-hydroxyl-L-glutamine (generated from L-glutamine probably by the dioxygenase gloE/GLOXY3) and 3S-hydroxyl-L-proline (generated from L-proline by the dioxygenase gloF/GLOXY2 to yield pneumocandin B0), or 3S-hydroxyl-4S-methyl-L-proline (generated from L-leucine by the dioxygenase gloC/GLOXY4 to yield pneumocandin A0) are sequentially added to the growing chain (PubMed:25270390, PubMed:25527531, PubMed:25879325).
The last C domain of gloA/GLNRPS4 is proposed to be responsible for cyclization by condensation to form the peptide bond between L-ornithine and 3S-hydroxyl-4S-methyl-L-proline (for pneumocandin A0) or 3S-hydroxyl-L-proline (for pneumocandin B0). Finally, the subsequent C-4 hydroxylation of 3S-hydroxyl-L-homotyrosine and L-ornithine dihydroxylation at C-4 and C-5 are performed by the cytochrome P450 monooxygenases gloP/GLP450-1 and gloO/GLP450-2, respectively (PubMed:25879325).
The 10,12-dimethylmyristoyl side chain is synthesized by the reducing polyketide synthase gloL/GLPKS4 (PubMed:27494047).
The thioesterase gloN/GLHYD exclusively interacts with gloL/GLPKS4 to maintain turnover of the polyketide side chain (PubMed:27494047).
The 10R,12S-dimethylmyristic acid is then transferred to the first thiolation domain of the nonribosomal peptide synthetase gloA/GLNRPS4 by the acyl-AMP ligase gloD/GLligase, followed by its acylation to L-ornithine to trigger elongation of the cyclic hexapeptide (PubMed:27494047).
L-ornithine, 4R-hydroxyl-L-proline (generated from L-proline by the dioxygenase gloF/GLOXY2), 3S-hydroxyl-L-homotyrosine (generated by gloG/GLHtyB, gloH/GLHtyA, gloI/GLHtyC, gloJ/GLHtyD and hydroxylated at C-3 by the dioxygenase gloM/GLOXY1), 3R-hydroxyl-L-glutamine (generated from L-glutamine probably by the dioxygenase gloE/GLOXY3) and 3S-hydroxyl-L-proline (generated from L-proline by the dioxygenase gloF/GLOXY2 to yield pneumocandin B0), or 3S-hydroxyl-4S-methyl-L-proline (generated from L-leucine by the dioxygenase gloC/GLOXY4 to yield pneumocandin A0) are sequentially added to the growing chain (PubMed:25270390, PubMed:25527531, PubMed:25879325).
The last C domain of gloA/GLNRPS4 is proposed to be responsible for cyclization by condensation to form the peptide bond between L-ornithine and 3S-hydroxyl-4S-methyl-L-proline (for pneumocandin A0) or 3S-hydroxyl-L-proline (for pneumocandin B0). Finally, the subsequent C-4 hydroxylation of 3S-hydroxyl-L-homotyrosine and L-ornithine dihydroxylation at C-4 and C-5 are performed by the cytochrome P450 monooxygenases gloP/GLP450-1 and gloO/GLP450-2, respectively (PubMed:25879325).
Biotechnology
Pneumocandin B0 is the starting molecule for the first semisynthetic echinocandin antifungal drug, caspofungin acetate (PubMed:25527531).
Pneumocandin B0 is a minor fermentation product, and its industrial production was achieved by a combination of extensive mutation and medium optimization (PubMed:25527531).
Inactivation of three of gloP/GLP450-1, gloO/GLP450-2, and gloM/GLOXY1 generates 13 different pneumocandin analogs that lack one, two, three, or four hydroxyl groups on 4R,5R-dihydroxy-ornithine and 3S,4S-dihydroxy-homotyrosine of the parent hexapeptide (PubMed:25879325).
All of these cyclic lipopeptides show potent antifungal activities, and two new metabolites pneumocandins F and G are more potent in vitro against Candida species and Aspergillus fumigatus than the principal fermentation products, pneumocandins A0 and B0 (PubMed:25879325).
Moreover, feeding alternative side chain precursors yields acrophiarin and 4 additional pneumocandin congeners with straight C14, C15, and C16 side chains. One of those compounds, pneumocandin I, has elevated antifungal activity and similar hemolytic activity compared to pneumocandin B0, the starting molecule for caspofungin, demonstrating the potential for using gloD/GLligase for future engineering of new echinocandin analogs (PubMed:27494047).
Pneumocandin B0 is a minor fermentation product, and its industrial production was achieved by a combination of extensive mutation and medium optimization (PubMed:25527531).
Inactivation of three of gloP/GLP450-1, gloO/GLP450-2, and gloM/GLOXY1 generates 13 different pneumocandin analogs that lack one, two, three, or four hydroxyl groups on 4R,5R-dihydroxy-ornithine and 3S,4S-dihydroxy-homotyrosine of the parent hexapeptide (PubMed:25879325).
All of these cyclic lipopeptides show potent antifungal activities, and two new metabolites pneumocandins F and G are more potent in vitro against Candida species and Aspergillus fumigatus than the principal fermentation products, pneumocandins A0 and B0 (PubMed:25879325).
Moreover, feeding alternative side chain precursors yields acrophiarin and 4 additional pneumocandin congeners with straight C14, C15, and C16 side chains. One of those compounds, pneumocandin I, has elevated antifungal activity and similar hemolytic activity compared to pneumocandin B0, the starting molecule for caspofungin, demonstrating the potential for using gloD/GLligase for future engineering of new echinocandin analogs (PubMed:27494047).
Pathway
Mycotoxin biosynthesis.
Features
Showing features for active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Active site | 187 | For beta-ketoacyl synthase activity | ||||
Sequence: C | ||||||
Active site | 322 | For beta-ketoacyl synthase activity | ||||
Sequence: H | ||||||
Active site | 358 | For beta-ketoacyl synthase activity | ||||
Sequence: H | ||||||
Active site | 1003 | Proton acceptor; for dehydratase activity | ||||
Sequence: H | ||||||
Active site | 1169 | Proton donor; for dehydratase activity | ||||
Sequence: D |
GO annotations
Aspect | Term | |
---|---|---|
Molecular Function | 3-oxoacyl-[acyl-carrier-protein] synthase activity | |
Molecular Function | fatty acid synthase activity | |
Molecular Function | methyltransferase activity | |
Molecular Function | oxidoreductase activity | |
Molecular Function | phosphopantetheine binding | |
Biological Process | fatty acid biosynthetic process | |
Biological Process | methylation | |
Biological Process | secondary metabolite biosynthetic process |
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameHighly reducing polyketide synthase gloL
- EC number
- Short namesHR-PKS gloL
- Alternative names
Gene names
Organism names
- Strain
- Taxonomic lineageEukaryota > Fungi > Dikarya > Ascomycota > Pezizomycotina > Leotiomycetes > Helotiales > Helotiaceae > Glarea
Accessions
- Primary accessionS3D9F1
Proteomes
Phenotypes & Variants
Disruption phenotype
Blocks the production of the two major pneumocandins, A0 and B0 (PubMed:23688303).
Leads to the formation of a pneumocandin A0 derivative with a myristic acid side chain as the main pneumocandin product (PubMed:27494047).
Produces also tiny amounts of pneumocandin A0 derivatives with a pentadecanoic or palmitic acid side chain (PubMed:27494047).
Leads to the formation of a pneumocandin A0 derivative with a myristic acid side chain as the main pneumocandin product (PubMed:27494047).
Produces also tiny amounts of pneumocandin A0 derivatives with a pentadecanoic or palmitic acid side chain (PubMed:27494047).
PTM/Processing
Features
Showing features for chain, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000444491 | 1-2531 | Highly reducing polyketide synthase gloL | |||
Sequence: MGDISGSVDPSNMAYEPLAIVGMGMRLPGGIHTAEDFWNLLVEKRSSRCKVPSDRFNIEAFYSPSGRVGTVKMEHGHFLGPTDDLQHFDASFFSMSKKEVEILDPQQRMLLEVVYECMQNAGQSNWRGGNIGCYVGVWGEDWVDIHAKDSQDAGMYRISGGQDFAISNRVSYEYDLKGPSFTIKSGCSSSMIALHEAARAIQAGDCDGAIIAGTNLIISPTMSIAMTEQGVLSPDGACKSFDESADGYARGEAINAIYIKRLSDAIRDGDNIRSVIRATASNCDGKTPGITLPSSESHEAMMRRAYKEACLDPTQTAFVEAHGTGTKIGDPLEATAIARVFSSEKGVYIGSVKPNVGHSEGASGVTSIMKAVLALENRTIPPNINFSTPNPQIPFEASNMKVAVEPIPWPKVQAERASVNSFGIGGANAHVILDSPASMGISSTKRNTTNGLSVNGHSINGNSVNGHSVNGHSTNGHSINGNSVNGHSVNGNSVNGHSTNGHSINGHSANGNSINGHSVNGHSKPRPALLVLSATNTESLRANVVKHQQYIETNPEKLVNIEYNLCNRREHLSNRAFCVTDGLSTLQFSPLTKPKKTPTLVMVFTGQGAQWAEMGKELMADFPSFSQDIDLMNNTLSKLDHPPSWNIKEELLKHESVSCLSKAEFAQPLVTAIQVALVNLLRQFGVKPAAVVGHSSGEIAAAYAANAITANEAIIIAYYRGQVTKGFSRRGGMAAVGLGREDVMSFLNPGVSIACENSSSSVTLSGDEDALNATCEIIKTALPDVFLRPLKVEMAYHSHHMKELGEAYEALLRPHLKSTTPVVPFFSSVSGKVVSKSGTLDAAYWRSNLENPVLFNSAIKLILDTLAQDHLFLEIGPHSALAGPIRQILKANSRKNDTYVTALERGKDCGESILKMIGELYLQHISINFKQVAPNGTVLTDLPLYQWCHDQEYWKESRVSKQWRLRKYPNHEILGSRTVEGNELQPEWRNVLHLDNVPWLRDHQIINDVVFPCAGYLSMACEAIRQISASEDFTFRNIVIQTALVMSDSKSVEMITSLRPVRLTNTLNSVWWDFSISSYNGSLWIKHCGGQIRSGTDNPKFKLPRRIEDHPRSVPSPYPAMKKVGLNYGPTFQGLERLSALPKKMTASATLSKSELSESHYAIHPATIDHCLQLFIVSTCEGTLRNINKLCVPTSIDQLYICGGKSTSGIKAEACGAQTSTGTISGDVVAISGDAIILSLIGGQFSPIEEDSSDEDLDTVAGARLDWKPDLDFVQIDNLIRPRQQSTAATKTLEKFTLLSMIDIGRRISGLVTKSEYLEKFRSWINAQVERASEDRYNLVEDAQALTVLNAGERQMLIAELSKEISNSEVATSGELISRVVKNCEDIMVGKIDGIEVLLPENGLTHFYDSLEHRTDCIDFFTAAGHSKPNLRVLEIGSGTGGTSAVVLKGLTSTAQRMYSTYTYTDISSGFFVEAQERFKDYHGLEYKVLDISKDPTEQGFQEGSYDLIIAANVLHATPSLNTTLGHARKLLAEDGRLFLQELSPQVQFANLIMGVLPGWWLGEADGRANEPYISPERWAVELRKAGFSGCDATVYDAEQPYQFNANIISRPAKVDRIARRITLLYEPNLNIQQIKFSLENKGYSVDLCTIQEEPPAGQDIVSLLELETPMFEKISGTDLALFQRLVKNLGTNHLLWVTRSAQIESYDPRFGMVLGLARTLRSELSLSIATLEIDTVDEVAYNAITNVFDKLKNSSSVSDMNPDYEFVLSKGVVNIGRYHPVSVEQELAVSASQSQAVKLEIGRFGLLQTLRWVPDLQNKVGHDQVIVEPRCAGLNFKDVLVSMGIVSGDGLGLEGSGTVVGVGSEVTDFQVGDRVLYIDQNCFSTRTAIPALRCAKIPSTLSWEEAATMPCVYATVIHSLLNLGRIQKGQSVLIHSACGGIGLAAIQICQNIVGAQIYVTVGNEEKVHYLMDTFGISRDHIFNSRDTSFLPAIKAATNGRGVDVVLNSLSGELLHASWECVAEYGSMVEIGKRDFIGKAQLNMDLFESNRSFFGVDLAKFDAARCQLLLVQMMEFYEKGLIKPIAPMKVFEGAKVEDSFRYMQKGSHIGKIVVTIPEQNTDLPLASIVPKLKLNPDAGYLLVGGLGGLGRAVSTWMVERGARHLIFLSRSAGKSDQDQSFFRELESQDCTVQAFTGSVATFQDVQNAVQRASKPIKGVFQMSMVLNDKPFLEMSCSDWETSVLPKVEGTWHLHHALPKDLDFFVATSSLSGSFGNAGQANYAAANTFLDAFVQYRHSLGLPASVVDIGVMGDIGYVSRNAAIQESLRGAGTYFLQEQDFLDSLNWAVAKSAVKPSLPGQNQLLIGVRSSKSLSDPSNRVSFKRDARMGAYLNTGSSTSANTTNATDQLKSFMSSVETDSSILNVPASLDLVTNEIGVRIYTFMLQPIEDLDVSQTLAALGVDSLVTIEIRNWMKRSFGGLEFSTLEILNAGTIEALGLLTIEGLKRKYEMKDGEAKFSEREDTYLLMKAP | ||||||
Modified residue | 2464 | O-(pantetheine 4'-phosphoryl)serine | ||||
Sequence: S |
Keywords
- PTM
Interaction
Protein-protein interaction databases
Structure
Family & Domains
Features
Showing features for domain, compositional bias, region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 15-435 | Ketosynthase family 3 (KS3) | ||||
Sequence: YEPLAIVGMGMRLPGGIHTAEDFWNLLVEKRSSRCKVPSDRFNIEAFYSPSGRVGTVKMEHGHFLGPTDDLQHFDASFFSMSKKEVEILDPQQRMLLEVVYECMQNAGQSNWRGGNIGCYVGVWGEDWVDIHAKDSQDAGMYRISGGQDFAISNRVSYEYDLKGPSFTIKSGCSSSMIALHEAARAIQAGDCDGAIIAGTNLIISPTMSIAMTEQGVLSPDGACKSFDESADGYARGEAINAIYIKRLSDAIRDGDNIRSVIRATASNCDGKTPGITLPSSESHEAMMRRAYKEACLDPTQTAFVEAHGTGTKIGDPLEATAIARVFSSEKGVYIGSVKPNVGHSEGASGVTSIMKAVLALENRTIPPNINFSTPNPQIPFEASNMKVAVEPIPWPKVQAERASVNSFGIGGANAHVILDS | ||||||
Compositional bias | 449-520 | Polar residues | ||||
Sequence: TNGLSVNGHSINGNSVNGHSVNGHSTNGHSINGNSVNGHSVNGNSVNGHSTNGHSINGHSANGNSINGHSVN | ||||||
Region | 449-525 | Disordered | ||||
Sequence: TNGLSVNGHSINGNSVNGHSVNGHSTNGHSINGNSVNGHSVNGNSVNGHSTNGHSINGHSANGNSINGHSVNGHSKP | ||||||
Region | 602-909 | Malonyl-CoA:ACP transacylase (MAT) domain | ||||
Sequence: MVFTGQGAQWAEMGKELMADFPSFSQDIDLMNNTLSKLDHPPSWNIKEELLKHESVSCLSKAEFAQPLVTAIQVALVNLLRQFGVKPAAVVGHSSGEIAAAYAANAITANEAIIIAYYRGQVTKGFSRRGGMAAVGLGREDVMSFLNPGVSIACENSSSSVTLSGDEDALNATCEIIKTALPDVFLRPLKVEMAYHSHHMKELGEAYEALLRPHLKSTTPVVPFFSSVSGKVVSKSGTLDAAYWRSNLENPVLFNSAIKLILDTLAQDHLFLEIGPHSALAGPIRQILKANSRKNDTYVTALERGKDC | ||||||
Region | 971-1099 | N-terminal hotdog fold | ||||
Sequence: HEILGSRTVEGNELQPEWRNVLHLDNVPWLRDHQIINDVVFPCAGYLSMACEAIRQISASEDFTFRNIVIQTALVMSDSKSVEMITSLRPVRLTNTLNSVWWDFSISSYNGSLWIKHCGGQIRSGTDNP | ||||||
Region | 971-1251 | Dehydratase (DH) domain | ||||
Sequence: HEILGSRTVEGNELQPEWRNVLHLDNVPWLRDHQIINDVVFPCAGYLSMACEAIRQISASEDFTFRNIVIQTALVMSDSKSVEMITSLRPVRLTNTLNSVWWDFSISSYNGSLWIKHCGGQIRSGTDNPKFKLPRRIEDHPRSVPSPYPAMKKVGLNYGPTFQGLERLSALPKKMTASATLSKSELSESHYAIHPATIDHCLQLFIVSTCEGTLRNINKLCVPTSIDQLYICGGKSTSGIKAEACGAQTSTGTISGDVVAISGDAIILSLIGGQFSPIEED | ||||||
Domain | 971-1254 | PKS/mFAS DH | ||||
Sequence: HEILGSRTVEGNELQPEWRNVLHLDNVPWLRDHQIINDVVFPCAGYLSMACEAIRQISASEDFTFRNIVIQTALVMSDSKSVEMITSLRPVRLTNTLNSVWWDFSISSYNGSLWIKHCGGQIRSGTDNPKFKLPRRIEDHPRSVPSPYPAMKKVGLNYGPTFQGLERLSALPKKMTASATLSKSELSESHYAIHPATIDHCLQLFIVSTCEGTLRNINKLCVPTSIDQLYICGGKSTSGIKAEACGAQTSTGTISGDVVAISGDAIILSLIGGQFSPIEEDSSD | ||||||
Region | 1109-1254 | C-terminal hotdog fold | ||||
Sequence: DHPRSVPSPYPAMKKVGLNYGPTFQGLERLSALPKKMTASATLSKSELSESHYAIHPATIDHCLQLFIVSTCEGTLRNINKLCVPTSIDQLYICGGKSTSGIKAEACGAQTSTGTISGDVVAISGDAIILSLIGGQFSPIEEDSSD | ||||||
Region | 1419-1597 | Methyltransferase (CMet) domain | ||||
Sequence: DFFTAAGHSKPNLRVLEIGSGTGGTSAVVLKGLTSTAQRMYSTYTYTDISSGFFVEAQERFKDYHGLEYKVLDISKDPTEQGFQEGSYDLIIAANVLHATPSLNTTLGHARKLLAEDGRLFLQELSPQVQFANLIMGVLPGWWLGEADGRANEPYISPERWAVELRKAGFSGCDATVYD | ||||||
Region | 1806-2114 | Enoyl reductase (ER) (ER) domain | ||||
Sequence: GLLQTLRWVPDLQNKVGHDQVIVEPRCAGLNFKDVLVSMGIVSGDGLGLEGSGTVVGVGSEVTDFQVGDRVLYIDQNCFSTRTAIPALRCAKIPSTLSWEEAATMPCVYATVIHSLLNLGRIQKGQSVLIHSACGGIGLAAIQICQNIVGAQIYVTVGNEEKVHYLMDTFGISRDHIFNSRDTSFLPAIKAATNGRGVDVVLNSLSGELLHASWECVAEYGSMVEIGKRDFIGKAQLNMDLFESNRSFFGVDLAKFDAARCQLLLVQMMEFYEKGLIKPIAPMKVFEGAKVEDSFRYMQKGSHIGKIVV | ||||||
Region | 2139-2312 | Ketoreductase (KR) domain | ||||
Sequence: GYLLVGGLGGLGRAVSTWMVERGARHLIFLSRSAGKSDQDQSFFRELESQDCTVQAFTGSVATFQDVQNAVQRASKPIKGVFQMSMVLNDKPFLEMSCSDWETSVLPKVEGTWHLHHALPKDLDFFVATSSLSGSFGNAGQANYAAANTFLDAFVQYRHSLGLPASVVDIGVMG | ||||||
Domain | 2413-2505 | Carrier | ||||
Sequence: MSSVETDSSILNVPASLDLVTNEIGVRIYTFMLQPIEDLDVSQTLAALGVDSLVTIEIRNWMKRSFGGLEFSTLEILNAGTIEALGLLTIEGL |
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length2,531
- Mass (Da)276,382
- Last updated2013-09-18 v1
- ChecksumE4875D3AFDC6A774
Features
Showing features for compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 449-520 | Polar residues | ||||
Sequence: TNGLSVNGHSINGNSVNGHSVNGHSTNGHSINGNSVNGHSVNGNSVNGHSTNGHSINGHSANGNSINGHSVN |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
KE145356 EMBL· GenBank· DDBJ | EPE34340.1 EMBL· GenBank· DDBJ | Genomic DNA |