Microbes are talented chemists with the ability to generate tremendously
complex and diverse natural products which harbor potent biological
activities. Natural products are produced using sets of specialized
biosynthetic enzymes encoded by secondary metabolism pathways. Here, we
present a two‐step evolutionary model to explain the diversification of
biosynthetic pathways that account for the proliferation of these
molecules. We argue that the appearance of natural product families has
been a slow and infrequent process. The first step led to the original
emergence of bioactive molecules and different classes of natural
products. However, much of the chemical diversity observed today has
resulted from the endless modification of the ancestral biosynthetic
pathways. The second step rapidly modulates the pre‐existing biological
activities to increase their potency and to adapt to changing
environmental conditions. We highlight the importance of enzyme
promiscuity in this process, as it facilitates both the incorporation of
horizontally transferred genes into secondary metabolic pathways and
the functional differentiation of proteins to catalyze novel chemistry.
We provide examples where single point mutations or recombination events
have been sufficient for new enzymatic activities to emerge. A unique
feature in the evolution of microbial secondary metabolism is that gene
duplication is not essential but offers opportunities to synthesize more
complex metabolites. Microbial natural products are highly important
for the pharmaceutical industry due to their unique bioactivities.
Therefore, understanding the natural mechanisms leading to the formation
of diverse metabolic pathways is vital for future attempts to utilize
synthetic biology for the generation of novel molecules.