A scalable platform to identify fungal secondary metabolites and their gene clusters.
Nat Chem Biol
; 13(8): 895-901, 2017 Aug.
Article
em En
| MEDLINE
| ID: mdl-28604695
ABSTRACT
The genomes of filamentous fungi contain up to 90 biosynthetic gene clusters (BGCs) encoding diverse secondary metabolites-an enormous reservoir of untapped chemical potential. However, the recalcitrant genetics, cryptic expression, and unculturability of these fungi prevent scientists from systematically exploiting these gene clusters and harvesting their products. As heterologous expression of fungal BGCs is largely limited to the expression of single or partial clusters, we established a scalable process for the expression of large numbers of full-length gene clusters, called FAC-MS. Using fungal artificial chromosomes (FACs) and metabolomic scoring (MS), we screened 56 secondary metabolite BGCs from diverse fungal species for expression in Aspergillus nidulans. We discovered 15 new metabolites and assigned them with confidence to their BGCs. Using the FAC-MS platform, we extensively characterized a new macrolactone, valactamide A, and its hybrid nonribosomal peptide synthetase-polyketide synthase (NRPS-PKS). The ability to regularize access to fungal secondary metabolites at an unprecedented scale stands to revitalize drug discovery platforms with renewable sources of natural products.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Aspergillus
/
Família Multigênica
/
Sesterterpenos
/
Metabolismo Secundário
/
Genes Fúngicos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Nat Chem Biol
Assunto da revista:
BIOLOGIA
/
QUIMICA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos