Protecting Group Strategies in Natural Product Biosynthesis

The utilization of protecting groups is a well-established strategy in the organic synthesis of natural products. Protecting groups are introduced as temporary masks for reactive functional groups in synthetic intermediates to prevent side reactions and enhance chemoselectivity under synthetic conditions. In contrast, it has long been believed that biosynthetic systems do not require protecting groups because enzymes catalyze reactions with remarkable regioselectivity and chemoselectivity. However, recent studies have revealed that certain biosynthetic systems in microorganisms and plants employ protection-deprotection strategies in natural product biosynthesis. These biosynthetic systems use temporary protecting group modifications to regulate the reactivity of biosynthetic intermediates, thereby preventing undesired side reactions that would otherwise derail pathway fidelity. After fulfilling their protective roles, these protecting groups are enzymatically removed to produce the final bioactive metabolites. Understanding these natural protection-deprotection mechanisms deepens our knowledge of enzymatic chemistry and provides valuable inspiration for pathway engineering and the development of chemoenzymatic synthetic methodologies. This review summarizes the current understanding of protection-deprotection mechanisms in natural product biosynthesis.