Echinocandins are a family of N-acylated cyclic hexapeptides that are fungicidal for candida strains and fungistatic for aspergilli by targeting cell wall 1,3-�-glucan synthases. Due to their effectiveness as antifungal agents, three semisynthetic derivatives have been developed and approved for treatment of human invasive candidiasis. In addition to its utility as an antifungal agent, echinocandins B also contains a variety of hydroxylated amino acids 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 from Emericella rugulosa NRRL 11440 containing genes for a six-module nonribosomal peptide synthetase (NRPS) EcdA, an acyl-AMP ligase EcdI, and oxygenases EcdG, EcdH, and EcdK. Using a combination of genetic and enzymatic methods, we have elucidated the function of NRPS EcdA and interrogated the mechanism of lipoinitiation of EcdA by EcdI. In addition, we have uncovered the mechanism by which the nonproteinogenic amino acids L-homotyrosine and L-methylproline are synthesized by E.rugulosa. Finally, we report the function of the iron-centered oxygenases EcdG and EcdH in the maturation of the hexapeptidolactam core of echinocandin B.

Elucidation of the biosynthesis of the antifungal lipopeptide Echinocandin B

247th National Meeting (2014)

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