S3D9F1 · GLOL_GLAL2

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).

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).

Pathway

Mycotoxin biosynthesis.

Features

Showing features for active site.

TypeIDPosition(s)Description
Active site187For beta-ketoacyl synthase activity
Active site322For beta-ketoacyl synthase activity
Active site358For beta-ketoacyl synthase activity
Active site1003Proton acceptor; for dehydratase activity
Active site1169Proton donor; for dehydratase activity

GO annotations

AspectTerm
Molecular Function3-oxoacyl-[acyl-carrier-protein] synthase activity
Molecular Functionfatty acid synthase activity
Molecular Functionmethyltransferase activity
Molecular Functionoxidoreductase activity
Molecular Functionphosphopantetheine binding
Biological Processfatty acid biosynthetic process
Biological Processmethylation
Biological Processsecondary metabolite biosynthetic process

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Highly reducing polyketide synthase gloL
  • EC number
  • Short names
    HR-PKS gloL
  • Alternative names
    • Pneumocandin acyl side chain synthase
    • Pneumocandin biosynthesis cluster protein L

Gene names

    • Name
      gloL
    • Synonyms
      GLPKS4
    • ORF names
      GLAREA_10034

Organism names

Accessions

  • Primary accession
    S3D9F1

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).

PTM/Processing

Features

Showing features for chain, modified residue.

TypeIDPosition(s)Description
ChainPRO_00004444911-2531Highly reducing polyketide synthase gloL
Modified residue2464O-(pantetheine 4'-phosphoryl)serine

Keywords

Interaction

Protein-protein interaction databases

Structure

Family & Domains

Features

Showing features for domain, compositional bias, region.

TypeIDPosition(s)Description
Domain15-435Ketosynthase family 3 (KS3)
Compositional bias449-520Polar residues
Region449-525Disordered
Region602-909Malonyl-CoA:ACP transacylase (MAT) domain
Region971-1099N-terminal hotdog fold
Region971-1251Dehydratase (DH) domain
Domain971-1254PKS/mFAS DH
Region1109-1254C-terminal hotdog fold
Region1419-1597Methyltransferase (CMet) domain
Region1806-2114Enoyl reductase (ER) (ER) domain
Region2139-2312Ketoreductase (KR) domain
Domain2413-2505Carrier

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    2,531
  • Mass (Da)
    276,382
  • Last updated
    2013-09-18 v1
  • Checksum
    E4875D3AFDC6A774
MGDISGSVDPSNMAYEPLAIVGMGMRLPGGIHTAEDFWNLLVEKRSSRCKVPSDRFNIEAFYSPSGRVGTVKMEHGHFLGPTDDLQHFDASFFSMSKKEVEILDPQQRMLLEVVYECMQNAGQSNWRGGNIGCYVGVWGEDWVDIHAKDSQDAGMYRISGGQDFAISNRVSYEYDLKGPSFTIKSGCSSSMIALHEAARAIQAGDCDGAIIAGTNLIISPTMSIAMTEQGVLSPDGACKSFDESADGYARGEAINAIYIKRLSDAIRDGDNIRSVIRATASNCDGKTPGITLPSSESHEAMMRRAYKEACLDPTQTAFVEAHGTGTKIGDPLEATAIARVFSSEKGVYIGSVKPNVGHSEGASGVTSIMKAVLALENRTIPPNINFSTPNPQIPFEASNMKVAVEPIPWPKVQAERASVNSFGIGGANAHVILDSPASMGISSTKRNTTNGLSVNGHSINGNSVNGHSVNGHSTNGHSINGNSVNGHSVNGNSVNGHSTNGHSINGHSANGNSINGHSVNGHSKPRPALLVLSATNTESLRANVVKHQQYIETNPEKLVNIEYNLCNRREHLSNRAFCVTDGLSTLQFSPLTKPKKTPTLVMVFTGQGAQWAEMGKELMADFPSFSQDIDLMNNTLSKLDHPPSWNIKEELLKHESVSCLSKAEFAQPLVTAIQVALVNLLRQFGVKPAAVVGHSSGEIAAAYAANAITANEAIIIAYYRGQVTKGFSRRGGMAAVGLGREDVMSFLNPGVSIACENSSSSVTLSGDEDALNATCEIIKTALPDVFLRPLKVEMAYHSHHMKELGEAYEALLRPHLKSTTPVVPFFSSVSGKVVSKSGTLDAAYWRSNLENPVLFNSAIKLILDTLAQDHLFLEIGPHSALAGPIRQILKANSRKNDTYVTALERGKDCGESILKMIGELYLQHISINFKQVAPNGTVLTDLPLYQWCHDQEYWKESRVSKQWRLRKYPNHEILGSRTVEGNELQPEWRNVLHLDNVPWLRDHQIINDVVFPCAGYLSMACEAIRQISASEDFTFRNIVIQTALVMSDSKSVEMITSLRPVRLTNTLNSVWWDFSISSYNGSLWIKHCGGQIRSGTDNPKFKLPRRIEDHPRSVPSPYPAMKKVGLNYGPTFQGLERLSALPKKMTASATLSKSELSESHYAIHPATIDHCLQLFIVSTCEGTLRNINKLCVPTSIDQLYICGGKSTSGIKAEACGAQTSTGTISGDVVAISGDAIILSLIGGQFSPIEEDSSDEDLDTVAGARLDWKPDLDFVQIDNLIRPRQQSTAATKTLEKFTLLSMIDIGRRISGLVTKSEYLEKFRSWINAQVERASEDRYNLVEDAQALTVLNAGERQMLIAELSKEISNSEVATSGELISRVVKNCEDIMVGKIDGIEVLLPENGLTHFYDSLEHRTDCIDFFTAAGHSKPNLRVLEIGSGTGGTSAVVLKGLTSTAQRMYSTYTYTDISSGFFVEAQERFKDYHGLEYKVLDISKDPTEQGFQEGSYDLIIAANVLHATPSLNTTLGHARKLLAEDGRLFLQELSPQVQFANLIMGVLPGWWLGEADGRANEPYISPERWAVELRKAGFSGCDATVYDAEQPYQFNANIISRPAKVDRIARRITLLYEPNLNIQQIKFSLENKGYSVDLCTIQEEPPAGQDIVSLLELETPMFEKISGTDLALFQRLVKNLGTNHLLWVTRSAQIESYDPRFGMVLGLARTLRSELSLSIATLEIDTVDEVAYNAITNVFDKLKNSSSVSDMNPDYEFVLSKGVVNIGRYHPVSVEQELAVSASQSQAVKLEIGRFGLLQTLRWVPDLQNKVGHDQVIVEPRCAGLNFKDVLVSMGIVSGDGLGLEGSGTVVGVGSEVTDFQVGDRVLYIDQNCFSTRTAIPALRCAKIPSTLSWEEAATMPCVYATVIHSLLNLGRIQKGQSVLIHSACGGIGLAAIQICQNIVGAQIYVTVGNEEKVHYLMDTFGISRDHIFNSRDTSFLPAIKAATNGRGVDVVLNSLSGELLHASWECVAEYGSMVEIGKRDFIGKAQLNMDLFESNRSFFGVDLAKFDAARCQLLLVQMMEFYEKGLIKPIAPMKVFEGAKVEDSFRYMQKGSHIGKIVVTIPEQNTDLPLASIVPKLKLNPDAGYLLVGGLGGLGRAVSTWMVERGARHLIFLSRSAGKSDQDQSFFRELESQDCTVQAFTGSVATFQDVQNAVQRASKPIKGVFQMSMVLNDKPFLEMSCSDWETSVLPKVEGTWHLHHALPKDLDFFVATSSLSGSFGNAGQANYAAANTFLDAFVQYRHSLGLPASVVDIGVMGDIGYVSRNAAIQESLRGAGTYFLQEQDFLDSLNWAVAKSAVKPSLPGQNQLLIGVRSSKSLSDPSNRVSFKRDARMGAYLNTGSSTSANTTNATDQLKSFMSSVETDSSILNVPASLDLVTNEIGVRIYTFMLQPIEDLDVSQTLAALGVDSLVTIEIRNWMKRSFGGLEFSTLEILNAGTIEALGLLTIEGLKRKYEMKDGEAKFSEREDTYLLMKAP

Features

Showing features for compositional bias.

TypeIDPosition(s)Description
Compositional bias449-520Polar residues

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
KE145356
EMBL· GenBank· DDBJ
EPE34340.1
EMBL· GenBank· DDBJ
Genomic DNA

Genome annotation databases

Similar Proteins

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. Our staff consists of biologists and biochemists that are not trained to give medical advice.
We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.
FeedbackHelp