The unconventional RNA-binding activity of metabolic enzymes

Metabolism involves a wide range of pathways and chemical reactions catalysed by specialized enzymes whose activity is fundamental for living cells. In the past three decades, metabolic enzymes have emerged as critical regulators of gene expression, thus revealing unexpected functions beyond their canonical metabolic roles. In this Review, we discuss the evidences that these enzymes, with a particular focus on enzymes participating in the glucose metabolism, can directly bind RNA. This binding has been recurrently shown to be involved in the post-trasncriptional gene regulation, by influencing processes such as RNA stability, localization, translation, and degradation. Although the mechanisms underlying RNA-enzyme interactions and their regulation are still not fully elucidated, several reports suggest that some of these interactions can be influenced by substrates, metabolites, and cellular metabolic states. In contrast, direct and specific binding of RNAs was also shown to regulate the activity, stability, interaction and localization of the enzymes. The discovery of the non-canonical RNA-binding activity of metabolic enzymes not only expands our understanding of these seemingly well-characterized proteins, but also provides new perspectives on the integration of metabolic and gene regulatory networks, besides revealing potential therapeutic vulnerabilities.