Plant isopropylmalate synthases: in and beyond leucine biosynthesis

Primary metabolic enzymes in amino acid biosynthesis pathways are involved in amino acid synthesis and maintenance of metabolic homeostasis through feedback regulatory mechanisms. The genes encoding these enzymes are also known to undergo functional diversification through evolutionary processes to encode specific secondary metabolic enzymes. One such enzyme is α-isopropylmalate synthase (α-IPMS), which catalyzes and regulates leucine (Leu) biosynthesis in eubacteria, archaebacteria, fungi, and plants, and has served as an evolutionary progenitor for specialized enzymes in distinct secondary metabolic pathways. However, most information on IPMS comes from the bacterial research community, particularly in the context of Leu overproduction or as a target for developing drugs against tuberculosis. In plants, only a few studies have reported on IPMS, focusing primarily on its role in regulating Leu homeostasis. Herein, we review the complex regulatory network that exists in Leu metabolism, focusing on the regulation of its biosynthesis and its key regulatory enzyme, IPMS. This review also highlights how evolution has independently recruited IPMS for specialized metabolism in several plant lineages. Finally, we describe the emerging roles of IPMS as a candidate for engineering amino acid and yield-related traits in crop plants. We also identify important open questions in this area that remain to be addressed.