Metabolic enzymes moonlighting as protein kinases and phosphatases

Protein phosphorylation is a central and reversible mechanism regulating virtually all cellular processes and is classically mediated by the canonical protein kinome and phosphatome. However, beyond their traditional roles as metabolic catalysts, a subset of metabolic enzymes also exhibits noncanonical 'moonlighting' activities as protein kinases or phosphatases, directly linking metabolic states to phosphorylation-dependent signaling. These unexpected functions of enzymes involved in glucose, fructose, lipid, nucleotide, and creatine metabolism influence a broad spectrum of cellular processes, including chromatin remodeling, transcription, cell cycle progression, metabolism, autophagy, cell survival and death, and immune responses. As a result, metabolic enzymes are increasingly recognized as key regulators that bridge cellular metabolism and signaling networks, with important implications for both normal physiology and disease.