Protein lysine lactylation machinery (Kla machinery)

Protein lysine lactylation (Kla) is a post-translational modification where a lactyl group is added to lysine residues, primarily on histone proteins, using lactyl-CoA as a substrate (Zhang et al., 2019, Nature). The machinery responsible for this process includes 'writer' enzymes, most notably the acetyltransferase p300 (EP300), and 'eraser' enzymes such as histone deacetylases (HDAC1, HDAC2, HDAC3) and sirtuins (SIRT1, SIRT2, SIRT3) (Moreno-Yruela et al., 2022, Science Advances). This modification serves as a critical metabolic-epigenetic link, where lactate produced during glycolysis acts as a signaling molecule to stimulate gene expression involved in macrophage polarization and tissue repair (Zhang et al., 2019, Nature). In disease states, particularly cancer, aberrant lactylation is associated with poor prognosis as it promotes oncogene expression and metabolic reprogramming (Wan et al., 2022, Cell Death & Disease). Therapeutic strategies involve using small molecule inhibitors of p300 or HDACs to modulate the lactylation landscape and restore normal cellular function. As a relatively recent discovery, targeting the lactylation machinery offers a novel approach for treating metabolic and inflammatory conditions, though achieving specificity among various acyl modifications remains a significant challenge (Yang et al., 2023, Frontiers in Cell and Developmental Biology).

Other names

Lysine lactylationKlaHistone lactylationLactyl-lysine modificationLactyl-CoA-dependent lysine modification

Modulation of lysine lactylation levels through the inhibition of 'writer' enzymes such as p300 (EP300) or 'eraser' enzymes such as Histone Deacetylases (HDAC1-3) and Sirtuins (SIRT1-3) to alter gene expression and metabolic pathways (Moreno-Yruela et al., 2022, Science Advances).