Work

Natural diversifying evolution of nonribosomal peptide synthetases in a defensive symbiont reveals nonmodular functional constraints

Year: 2024

Type: article

Abstract: The modular architecture of nonribosomal peptide synthetases (NRPSs) has inspired efforts to study their evolution and engineering. In this study, we analyze in detail a unique family of NRPSs from the defensive intracellular bacterial symbiont, Candidatus Endobryopsis kahalalidifaciens (Ca. E. kahalalidifaciens). We show that intensive and indiscriminate recombination events erase trivial sequence covariations induced by phylogenetic relatedness, revealing nonmodular functional constraints and clear recombination units. Moreover, we reveal unique substrate specificity determinants for multiple enzymatic domains, allowing us to accurately predict and experimentally discover the products of an orphan NRPS in Ca. E. kahalalidifaciens directly from environmental samples of its algal host. Finally, we expanded our analysis to 1,531 diverse NRPS pathways and revealed similar functional constraints to those observed in Ca. E. kahalalidifaciens’ NRPSs. Our findings reveal the sequence bases of genetic exchange, functional constraints, and substrate specificity in Ca. E. kahalalidifaciens’ NRPSs, and highlight them as a uniquely primed system for diversifying evolution.

Source: PNAS Nexus

DOI: 10.1093/pnasnexus/pgae384

Authors: Zhiyuan Li, Laura P Ióca, Ruolin He, Mohamed S Donia

Institutions: Princeton University, Peking University, Center for Life Sciences

Language: English

Topic: Microbial Natural Products and Biosynthesis

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

Open Access status: gold

Estimated APC paid: $4,202

Funders: Gordon and Betty Moore Foundation, National Natural Science Foundation of China