Lactate as a Chemical Modification on Proteins and Metabolites

Lactate's role in biochemistry and physiology has attracted considerable biochemical interest for over a century. Beyond its classical description as a glycolytic byproduct, lactate is now recognized as a central energy metabolite, a redox shuttle, and a signaling molecule. Modern advances in mass spectrometry have uncovered yet another dimension of lactate biology: lactate as a chemical modification on proteins and metabolites. Covalent conjugation of lactate to the ε-amine of a protein lysine side chain generates a posttranslational modification (lysine lactylation); in a related reaction on metabolites, conjugation of lactate to the α-amine of free amino acids produces a class of bioactive lactate-modified amino acids (the N -lactoyl amino acids). These lactate modifications represent a fundamental mechanism by which transient increases in glycolytic flux are translated into durable downstream effectors. Here, we review the detection, regulation, and function of these lactate-derived modifications in cellular and organismal homeostasis.