Principles and Biological Significance of Protein Lactylation Modification
-
Enzyme-dependent mechanism: certain histone acetyltransferases, such as p300, have been shown to catalyze the transfer of lactyl groups from lactyl-CoA to lysine residues.
-
Non-enzymatic mechanism: under elevated lactate concentrations, lactylation may occur via spontaneous chemical reactions independent of enzymatic catalysts.
-
Lactylation atlas mapping under diverse cell types and stimulation conditions.
-
Crosstalk analysis between Kla and other PTMs such as acetylation and phosphorylation.
-
Functional assays assessing how site-specific lactylation influences protein activity and cell fate.
Post-translational modification (PTM) is a core regulatory mechanism governing protein function, subcellular localization, and molecular interactions. In addition to classical modifications such as phosphorylation, acetylation, and ubiquitination, an emerging modification - lysine lactylation (Kla) - has been recently uncovered. First reported by Zhang et al. in 2019, lactylation is derived from lactate generated during cellular metabolism, a metabolite traditionally viewed as a terminal product of glycolysis but increasingly recognized as a signaling molecule. The identification of lysine lactylation has challenged the conventional perception of lactate as “metabolic waste” and expanded the conceptual framework of metabolic-epigenetic crosstalk.
Molecular Mechanisms Underlying Protein Lactylation
1. Definition of Lysine Lactylation (Kla)
Lysine lactylation refers to the covalent attachment of a lactyl group (-CO-CH(OH)-CH₃) to the ε-amino group of lysine residues on proteins. Although analogous to lysine acetylation, the donor molecules for lactylation are lactyl-CoA or intermediates derived from lactate metabolism.
(1) Mechanistic Basis: Coupling Metabolism to Modification
Current evidence suggests that lactylation formation can proceed through multiple routes:
2. Strategies for Detecting Protein Lactylation
Given its novelty and low abundance, the detection of lysine lactylation commonly relies on high-resolution mass spectrometry combined with affinity enrichment using modification-specific anti-Kla antibodies. Utilizing the Orbitrap Exploris™ 480 platform together with high-specificity Kla antibody enrichment workflows, MtoZ Biolabs enables site-resolved identification and quantitative analysis of lactylation events at both histone-focused and whole-proteome scales.
Biological Significance of Protein Lactylation
1. Epigenetic Regulation
Lactylation was initially observed on lysine residues of histone H3 (e.g., H3K18) and was linked to transcriptionally active chromatin. By modulating chromatin architecture, lactylation influences gene expression programs, particularly affecting metabolic genes such as inflammatory cytokines and glycolytic enzymes.
2. A Metabolic “Recorder”
Lactylation functions as an epigenetic readout of cellular metabolic status. Enhanced glycolytic flux and lactate accumulation are accompanied by elevated lactylation levels, which in turn provide feedback regulation over metabolism-related gene networks. This mechanism has been highlighted in biological contexts such as macrophage M1 polarization and tumor metabolic reprogramming.
3. Potential Links to Disease Pathogenesis
(1) Tumor microenvironment: elevated glycolysis drives lactate accumulation and promotes active lactylation, facilitating the expression of oncogenic programs.
(2) Inflammatory responses: lactylation modulates the expression of pro-inflammatory mediators and contributes to immune cell activation.
(3) Neurodegenerative disorders: early evidence suggests aberrant lactylation patterns in brain tissues may be associated with disease progression.
Advances in mass spectrometry sensitivity and data analysis algorithms have accelerated research in lactylation biology. Ongoing efforts include:
MtoZ Biolabs offers comprehensive multi-omics solutions for PTM analysis, supporting Kla-focused proteomics, protein interaction network reconstruction, pathway enrichment, and bioinformatics visualization.
As an emerging PTM, lysine lactylation is reshaping our understanding of lactate beyond its role as a metabolic by-product. From inflammatory regulation to cancer metabolism, its biological relevance continues to expand. With omics-based technologies becoming central to mechanistic dissection, MtoZ Biolabs integrates high-resolution mass spectrometry platforms, high-throughput enrichment strategies, and multi-omics data interpretation to support customized investigations into protein lactylation. Researchers are welcome to contact us to jointly explore the expanding landscape of post-translational modifications.
MtoZ Biolabs, an integrated chromatography and mass spectrometry (MS) services provider.
Related Services
How to order?
