MoonlightingEnzyme

MoonlightingEnzyme is a term used to describe a class of proteins that act as enzymes in metabolism yet perform one or more additional, distinct biological functions that are unrelated to their primary catalytic activity. Unlike enzymes with multiple catalytic activities, moonlighting enzymes carry out a non-enzymatic role, such as structural support, signaling, adhesion, or regulation, in the same or a different cellular compartment. The phenomenon is known as protein moonlighting and is thought to arise from properties such as catalytic promiscuity, alternative localization, protein–protein interactions, and post-translational modifications that reveal new functions without changes to the amino acid sequence.

Examples commonly cited include enolase, which functions as a glycolytic enzyme in the cytosol but can be displayed on the cell surface acting as a receptor for plasminogen, facilitating tissue remodeling. GAPDH, a glycolytic enzyme, also participates in RNA binding, nuclear transcriptional regulation, and DNA repair. Pyruvate kinase M2 (PKM2) can function in glycolysis or translocate to the nucleus to influence gene expression and cell cycle control. Aldolase is another example, with roles in cytoskeletal organization in addition to metabolism. In bacteria, moonlighting proteins can contribute to host interaction and virulence, complicating the interpretation of pathogenesis.

Research on moonlighting enzymes combines biochemistry, cell biology, and proteomics to identify secondary functions, map their regulatory cues, and assess physiological relevance. Understanding these proteins expands views of metabolism, cellular organization, and the complexity of protein function.