When, where, and why specialised metabolites are produced: inferring function from expression control.

Although some microbial compounds have been repurposed for human use, microorganisms did not evolve their specialised metabolites with us in mind. Many natural products likely possess hidden activities, while others may be exploited in ways that ignore their most biologically relevant roles. Uncovering the true function of these compounds is essential not only for understanding microbial interactions in native environments but also for unlocking their most appropriate use. To facilitate prioritisation in discovering new natural products, computational tools have been developed to predict the function of compounds hidden in cryptic biosynthetic gene clusters. Yet beyond in silico predictions, understanding when, where, and why metabolites are produced is critical for both fundamental biology and targeted discovery. After all, what nature chooses to activate at a specific time or condition tells us what it is really for. Based on the principle 'function follows regulation', it is no coincidence that expression of metal chelators, phytotoxins, pigments, and antibiotics is controlled by metal availability, plant byproducts, radiations, and competitor sensing, respectively. Likewise, metabolite localisation and production timing also provide clues to function such as intracellular antiproliferative agents coordinating programmed cell death or pigments protecting against oxidative stress. These controlled expression patterns suggest a strategic approach for natural product discovery: focusing on culture conditions that mimic the environmental or developmental contexts under which metabolites are needed for the producer. Integrating expression control information offers a predictive framework to guide experimental design, increases the likelihood of identifying compounds with meaningful ecological roles, and anticipates their applications.