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Survival strategy of potatoes and tomatoes ― Avoiding self-toxicity while producing protective agents: Discovery of key enzyme by Kobe University group

2025.03.04

A research group led by Professor Masaharu Mizutani, Graduate Student Ayano Yoneda (at the time of the study), and Research Fellow Ryota Akiyama (at the time of the study) of the Graduate School of Agricultural Science at Kobe University, and Drs. Adam Jozwiak and Asaph Aharoni of the Weizmann Institute of Science in Israel, in collaboration with the RIKEN Center for Sustainable Resource Science and the Graduate School of Engineering of Osaka University, have announced their research results showing that "GAME15" involved in the biosynthesis of steroidal glycoalkaloids (SGAs), which are toxic components found in potatoes and tomatoes, serves as a "key enzyme" to efficiently produce SGAs, which also act as protective agents, while preventing the accumulation of harmful intermediates to avoid self-toxicity. The findings are expected to contribute to producing various useful steroid compounds. The results were published in the international journal Science on December 20.

SGAs in Solanum food crops such as tomatoes and potatoes serve as natural protective substances that are toxic to a wide range of organisms. The high steroid synthesis capabilities of these plants have attracted attention for their potential use in creating new physiologically active substances and producing useful ones. SGAs have been known to be biosynthesized from cholesterol, a membrane component, but the mechanism allowing for their efficient biosynthesis without self-toxicity has not been well understood. In metabolite biosynthesis, such as the TCA cycle, multiple enzyme proteins involved in a metabolic pathway form an assembly (metabolon) to increase catalytic efficiency. The formation of metabolons allows for controlling metabolic flux and facilitating local substrate concentrations to reduce substrate outflux to competing pathways. While plant metabolic pathways to synthesize physiologically active substances have been thought to have a similar mechanism, reports on specific examples have been limited.

In this study, the research group focused on "GAME15," a cellulose synthase-like protein with unknown SGA function. Many SGA biosynthesis genes form metabolic enzyme gene clusters in the same genomic region. One of these encodes GAME15/CSLM, a cellulose synthase-like protein of unknown function. GAME15 is co-expressed with the SGA biosynthesis genes and localized in the endoplasmic reticulum along with SGA biosynthesis enzymes. These findings suggest that GAME15 may be involved in SGA biosynthesis.

Therefore, the research group expressed GAME15 in insect and yeast cells. The results confirmed the production of cholesterol glucuronide (CHR-GlcA). Thus, it is clear that GAME15 is a functionally evolved enzyme that transfers glucuronic acid to cholesterol.

The interaction of GAME15 with cholesterol and SGA biosynthesis enzymes was examined, showing that they are in close proximity. Analysis revealed that GAME15 serves as a scaffold protein for the formation of metabolons on the endoplasmic reticulum membrane.

To investigate how this enzyme protein assembly affects metabolite flux, external administration of deuterium-labeled cholesterol to tobacco expressing GAME15 and other proteins resulted in very little deuterium incorporation into the final product SGA. GAME15 links the cholesterol pathway (primary metabolism) and the SGA pathway (secondary metabolism) and facilitates substrate product delivery. GAME15 was found to have functionally evolved to serve a dual function in chemical defense and avoidance of self-toxicity.

In potato individuals in which the GAME15 gene was disrupted by genome editing, they found that α-solanine production was completely lost and a significantly larger area was eaten by cabbage moth larvae in feeding tests. GAME15 was confirmed to be essential for α-solanine biosynthesis in potatoes.

Journal Information
Publication: Science
Title: A cellulose synthase-like protein governs the biosynthesis of Solanum alkaloids
DOI: 10.1126/science.adq5721

This article has been translated by JST with permission from The Science News Ltd. (https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.

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