A cellulose synthase-like protein governs the biosynthesis of Solanum alkaloids

Decades of research on the infamous antinutritional steroidal glycoalkaloids (SGAs) in Solanaceae plants have provided deep insights into their metabolism and roles. However, engineering SGAs in heterologous hosts has remained a challenge. We discovered that a protein evolved from the machinery involved in building plant cell walls is the crucial link in the biosynthesis of SGAs. We show that cellulose synthase-like M [GLYCOALKALOID METABOLISM15 (GAME15)] functions both as a cholesterol glucuronosyltransferase and a scaffold protein. Silencing GAME15 depletes SGAs, which makes plants more vulnerable to pests. Our findings illuminate plant evolutionary adaptations that balance chemical defense and self-toxicity and open possibilities for producing steroidal compounds in heterologous systems for food, cosmetics, and pharmaceuticals.