Combinatorial biosynthesis in plants: A (p)review on its potential and future exploitation

Combinatorial biochemistry, also called combinatorial biosynthesis, comprises a series of methods that establish novel enzyme–substrate combinations in vivo and, in turn, lead to the biosynthesis of new, natural product-derived compounds that can be used in drug discovery programs. Plants are an extremely rich source of bioactive natural products and continue to possess a huge potential for drug discovery. In this review, we discuss the state-of-the-art in combinatorial biosynthesis methods to generate novel molecules from plants. We debate on the progress and potential in biotransformation, mutasynthesis, combinatorial metabolism in hybrids, activation of silent plant metabolism and synthetic biology in plants to create opportunities for the combinatorial biosynthesis of plant-derived natural products, and, ultimately, for drug discovery. The therapeutic value of two classes of natural products, the terpenoid indole alkaloids and the triterpene saponins, is particularly highlighted.