Functional and evolutionary genomics of the Streptomyces metabolism

TL;DR

This thesis develops EvoMining, a bioinformatic pipeline that uncovers novel natural product biosynthetic pathways in Streptomyces and related actinobacteria, revealing evolutionary mechanisms and metabolic expansions linked to natural product biosynthesis.

Contribution

Introduces EvoMining, a new bioinformatic method for discovering biosynthetic pathways, and provides insights into the evolution of metabolism and natural product production in Streptomyces.

Findings

EvoMining predicted new biosynthetic pathways in Actinobacteria.

Discovery of an unprecedented peptide bond formation system.

Identification of metabolic expansions linked to natural product biosynthesis.

Abstract

This thesis is focused in the study of the evolution of the metabolic repertoire of Streptomyces, which are renowned as proficient producers of bioactive Natural Products (NPs). The main goal of my work was to contribute into the understanding of the evolutionary mechanisms behind the evolution of NP biosynthetic pathways. Specifically, the development of a bioinformatic method that helps into the discovery of new NP biosynthetic pathways from actinobacterial genome sequences with emphasis on members of the genus Streptomyces. I developed this method using a comparative and functional genomics perspective. My studies indicate that central metabolic enzymes were expanded in a genus-specific manner in Actinobacteria, and that they have been extensively recruited for the biosynthesis of NPs. Based in these observations, I developed EvoMining, a bioinformatic pipeline for the identificatoon of novel biosynthetic pathways in microbial genomes. Using EvoMining several new NP biosynthetic pathways have been predicted in different members of the phylum Actinobacteria, including the model organism S. lividans 66. To test this approach, the genome sequence of this model strain was obtained, and its analysis led to the discovery of an unprecedented system for peptide bond formation, as well as a biosynthetic pathway for an arsenic-containing metabolite. Moreover, this work also led to the identification of expansions on a conserved metabolic node in the glycolytic pathway of Streptomyces. These expansions occurred before the radiation of Streptomyces and are concomitant with the evolution of their capability to produce NPs. Experimental analyses indicate that this node evolved to mediate the interplay between central an NP metabolism.