Pass-back chain extension expands multimodular assembly line biosynthesis.
Nat Chem Biol
; 16(1): 42-49, 2020 01.
Article
em En
| MEDLINE
| ID: mdl-31636431
ABSTRACT
Modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) enzymatic assembly lines are large and dynamic protein machines that generally effect a linear sequence of catalytic cycles. Here, we report the heterologous reconstitution and comprehensive characterization of two hybrid NRPS-PKS assembly lines that defy many standard rules of assembly line biosynthesis to generate a large combinatorial library of cyclic lipodepsipeptide protease inhibitors called thalassospiramides. We generate a series of precise domain-inactivating mutations in thalassospiramide assembly lines, and present evidence for an unprecedented biosynthetic model that invokes intermodule substrate activation and tailoring, module skipping and pass-back chain extension, whereby the ability to pass the growing chain back to a preceding module is flexible and substrate driven. Expanding bidirectional intermodule domain interactions could represent a viable mechanism for generating chemical diversity without increasing the size of biosynthetic assembly lines and challenges our understanding of the potential elasticity of multimodular megaenzymes.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeo Sintases
/
Peptídeos Cíclicos
/
Família Multigênica
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article