Identification and Characterization of the Echinocandin B Biosynthetic Gene Cluster from Emericella rugulosa NRRL 11440

Details

• Alternative Title:
  J Am Chem Soc
• Personal Author:
  Cacho, Ralph A. ; Jiang, Wei ; Chooi, Yit-Heng ; Walsh, Christopher T. ; Tang, Yi
• Description:
  Echinocandins are a family of fungal lipidated cyclic hexapeptide natural products. Due to their effectiveness as antifungal agents, three semisynthetic derivatives have been developed and approved for treatment of human invasive candidiasis. All six of the amino acid residues are hydroxylated, including 4R,5R-dihydroxy-L-ornithine, 4R-hydroxyl-L-proline, 3S,4S-dihydroxy-L-homotyrosine, and 3S-hydroxyl-4S-methyl-L-proline. We report here the biosynthetic gene cluster of echinocandin B 1 from Emericella rugulosa NRRL 11440 containing genes encoding for a six-module nonribosomal peptide synthetase EcdA, an acyl-AMP ligase EcdI, and oxygenases EcdG, EcdH, and EcdK. We showed EcdI activates linoleate as linoleyl-AMP and installs it on the first thiolation domain of EcdA. We have also established through ATP-PP(i) exchange assay that EcdA loads L-ornithine in the first module. A separate hty gene cluster encodes four enzymes for de novo generation of L-homotyrosine from acetyl-CoA and 4-hydroxyphenyl-pyruvate is found from the sequenced genome. Deletions in the ecdA, and htyA genes validate their essential roles in echinocandin B production. Five predicted iron-centered oxygenase genes, ecdG, ecdH, ecdK, htyE, and htyF, in the two separate ecd and hty clusters are likely to be the tailoring oxygenases for maturation of the nascent NRPS lipohexapeptidolactam product.
• Keywords:
  Antifungal Echinocandins Emericella Fungal Proteins Genes, Fungal Genome Mining Lipopeptide Multigene Family Nonribosomal Peptide Tyrosine Unnatural Amino Acids

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• Source:
  J Am Chem Soc. 134(40):16781-16790
• Pubmed ID:
  22998630
• Pubmed Central ID:
  PMC3482383
• Document Type:
  Journal Article
• Funding:
  R01 GM092217/GM/NIGMS NIH HHSUnited States/ ; DP1 GM106413/GM/NIGMS NIH HHSUnited States/ ; 1R01GM092217/GM/NIGMS NIH HHSUnited States/ ; 1R01GM49338/GM/NIGMS NIH HHSUnited States/ ; T32 GM008496/GM/NIGMS NIH HHSUnited States/ ; 1DP1GM106413/DP/NCCDPHP CDC HHSUnited States/ ; R01 GM049338/GM/NIGMS NIH HHSUnited States/ ; GM08496/GM/NIGMS NIH HHSUnited States/
• Volume:
  134
• Issue:
  40
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:9cd01f1c4cbdd4be8e8ce82eb392a31f0df093542a707dc1895164768a73c9cf
• Download URL:
  https://stacks.cdc.gov/view/cdc/33455/cdc_33455_DS1.pdf
• File Type:
  [PDF - 1.60 MB ]