Noncanonical Functions of Enzyme Cofactors as Building Blocks in Natural Product Biosynthesis

[Image: see text] Enzymes involved in secondary metabolite biosynthetic pathways have typically evolutionarily diverged from their counterparts functioning in primary metabolism. They often catalyze diverse and complex chemical transformations and are thus a treasure trove for the discovery of unique enzyme-mediated chemistries. Besides major natural product classes, such as terpenoids, polyketides, and ribosomally or nonribosomally synthesized peptides, biosynthetic investigations of noncanonical natural product biosynthetic pathways often reveal functionally distinct enzyme chemistries. In this Perspective, we aim to highlight challenges and opportunities of biosynthetic investigations on noncanonical natural product pathways that utilize primary metabolites as building blocks, otherwise generally considered as enzyme cofactors. A focus is made on the discovered chemical and enzymological novelties.