A “GAME” changer in plant secondary metabolism

Cholesterol, an essential structural component of membranes and a precursor for steroid hormones, serves as a key metabolite at the interface of primary and secondary metabolism. However, the mechanisms regulating the balance between its diverse downstream metabolic pathways remain poorly understood. One well-known example of cholesterol-derived secondary metabolites is steroidal glycoalkaloids (SGAs). SGAs are potent plant defense compounds but can be self-toxic to plants above a certain threshold and act as antinutritional factors for humans. Understanding the biosynthesis of SGAs is, therefore, critical for balancing plant growth and defense while improving nutritional quality. In tomatoes, the GLYCOALKALOID METABOLISM (GAME) gene cluster has been linked to SGA biosynthesis. Two back-to-back studies, by Jozwiak et al. and Boccia et al., specifically investigated GAME15, which encodes an ER-localized cellulose synthase-like enzyme previously unassociated with SGA biosynthesis. Transient expression of GAME15 in Nicotiana benthamiana resulted in cholesterol glucuronidation and the accumulation of tomatidine, a precursor of SGA biosynthesis. Conversely, silencing GAME15 produced the opposite effect. Interestingly, phylogenetic studies revealed that the ancestral protein of GAME15, CesA, is plasma membrane-localized for cellulose fiber production. This is distinct from the role of GAME15 in cholesterol metabolism and SGA biosynthesis in the ER. These findings not only underscore the unique function of GAME15 as a regulatory hub for cholesterol metabolism but also highlight the evolutionary dynamics driving the emergence of novel metabolic pathways and metabolites. (Summary by Ching Chan @ntnuchanlab) Science 10.1126/science.adq5721; and 10.1126/science.ado3409.