Translation as a regulatory hub for secondary metabolism in Streptomyces spp

Streptomycetes are known for their production of diverse secondary metabolites, many of which have medicinal applications. The enzymes facilitating the production of these metabolites are encoded in biosynthetic gene clusters (BGCs) with regulatory and transport proteins. Regulation of secondary metabolite biosynthesis is tightly controlled in laboratory conditions, and many natural products have low yields or are not expressed in laboratory cultures. Although transcriptional regulation has been a major focus in the past, translational control has recently emerged as a critical determinant of BGC activity. Due to the energy requirement for translation, evidence suggests a greater degree of translational regulation than transcriptional regulation. Many translation factors impact protein synthesis rates, such as regulatory RNAs, ribonucleases, transcript quality control, ribosome rescue systems, tRNA pools, and antibiotic-induced ribosome mutations. These convergent components respond to environmental cues and metabolic states to coordinate secondary metabolism with demands for growth and development of streptomycetes. A deeper understanding of translational control will not only reveal key functions that control and coordinate specialized metabolism but will also highlight new strategies for activating silent gene clusters and enhancing natural product yields. The present review explores how translation serves as a central regulatory hub for BGC activity and discusses emerging tools to manipulate protein synthesis for natural product discovery and biotechnological advancement.