Identification and characterization of the echinocandin B biosynthetic gene cluster from Emericella rugulosa NRRL 11440
-
Altmetric Citations
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...[Show more]
dc.contributor.author | Cacho, Ralph A | |
---|---|---|
dc.contributor.author | Jiang, Wei | |
dc.contributor.author | Chooi, Yit-Heng | |
dc.contributor.author | Walsh, Christopher T | |
dc.contributor.author | Tang, Yi | |
dc.date.accessioned | 2015-12-13T22:49:27Z | |
dc.identifier.issn | 0002-7863 | |
dc.identifier.uri | http://hdl.handle.net/1885/80550 | |
dc.description.abstract | 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-PPi 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. | |
dc.publisher | American Chemical Society | |
dc.source | Journal of the American Chemical Society | |
dc.subject | Keywords: Acetyl-CoA; Amino acid residues; Antifungal agents; Biosynthetic gene cluster; Cyclic hexapeptide; Echinocandin; Gene clusters; Genes encoding; Natural products; Nonribosomal peptide synthetases; Oxygenases; Semi-synthetic derivatives; Thiolation; Encodin | |
dc.title | Identification and characterization of the echinocandin B biosynthetic gene cluster from Emericella rugulosa NRRL 11440 | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.identifier.citationvolume | 134 | |
dc.date.issued | 2012 | |
local.identifier.absfor | 060107 - Enzymes | |
local.identifier.absfor | 060199 - Biochemistry and Cell Biology not elsewhere classified | |
local.identifier.absfor | 060408 - Genomics | |
local.identifier.ariespublication | f5625xPUB8812 | |
local.type.status | Published Version | |
local.contributor.affiliation | Cacho, Ralph A , University of California, | |
local.contributor.affiliation | Jiang, Wei, Harvard Medical School | |
local.contributor.affiliation | Chooi, Yit-Heng, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Walsh, Christopher T, Harvard Medical School | |
local.contributor.affiliation | Tang, Yi, University of California | |
local.description.embargo | 2037-12-31 | |
local.bibliographicCitation.issue | 40 | |
local.bibliographicCitation.startpage | 16781 | |
local.bibliographicCitation.lastpage | 16790 | |
local.identifier.doi | 10.1021/ja307220z | |
local.identifier.absseo | 860803 - Human Pharmaceutical Treatments (e.g. Antibiotics) | |
dc.date.updated | 2016-02-24T09:44:07Z | |
local.identifier.scopusID | 2-s2.0-84867350993 | |
local.identifier.thomsonID | 000309566400053 | |
Collections | ANU Research Publications |
Download
File | Description | Size | Format | Image |
---|---|---|---|---|
01_Cacho_Identification_and_2012.pdf | 1.63 MB | Adobe PDF | Request a copy |
Items in Open Research are protected by copyright, with all rights reserved, unless otherwise indicated.
Updated: 17 November 2022/ Responsible Officer: University Librarian/ Page Contact: Library Systems & Web Coordinator