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

被引:109
作者
Cacho, Ralph A. [1 ]
Jiang, Wei [3 ]
Chooi, Yit-Heng [1 ]
Walsh, Christopher T. [3 ]
Tang, Yi [1 ,2 ]
机构
[1] Univ Calif Los Angeles, Dept Chem & Biomol Engn, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA
[3] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
关键词
BIOCHEMICAL-CHARACTERIZATION; ZALERION-ARBORICOLA; INVASIVE CANDIDIASIS; ASPERGILLUS-NIDULANS; ADENYLATION DOMAIN; PEPTIDE; LIPOPEPTIDE; ACID; CLONING; PNEUMOCANDINS;
D O I
10.1021/ja307220z
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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-omithine 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.
引用
收藏
页码:16781 / 16790
页数:10
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