Principles and Biological Significance of Protein Lactylation Modification

Post-translational modification (PTM) is a core mechanism regulating protein functions, localization, and interactions. Beyond classic modifications such as phosphorylation, acetylation, and ubiquitination, scientists have recently been uncovering a new emerging form of modification—lysine lactylation (Kla). Protein lactylation was first discovered by Zhang et al. in 2019, originating from lactate produced during cellular metabolism. Lactate is not only a terminal product of glycolysis but also an important signaling molecule. The discovery of lysine lactylation challenges the traditional view of lactate as a 'metabolic waste' and provides a new dimension for studying the metabolism-epigenetics interaction network.

 

I. The Molecular Mechanism of Protein Lactylation

1. What is Lysine Lactylation (Kla)?

Lysine lactylation is a modification where a lactyl group (–CO–CH(OH)–CH₃) is covalently attached to the ε-amino group of a protein's lysine residue. This process is similar to acetylation, but its donor molecule is lactyl-CoA or a breakdown product of lactate.

(1) Mechanism of Lactylation: Linking Metabolism and Modification

Current research suggests that the formation of lactylation may be mediated through the following pathways:

• Enzyme-dependent pathway: Certain histone acetyltransferases (such as p300) can catalyze the transfer of lactyl groups from lactyl-CoA to lysine.

• Non-enzymatic pathway: Under high lactate conditions, lactylation may spontaneously chemically modify lysine.

 

2. How to Detect Protein Lactylation?

Lysine lactylation is relatively novel and of low abundance, currently detected usinghigh-resolution mass spectrometry combined with specific anti-lactylation antibody enrichmentmethods, which are the most commonly used. Biotech Company usesthe Orbitrap Exploris™ 480 platformin conjunction with high-specificity Kla antibody enrichment techniques to accurately identify and quantify lactylation sites, suitable for research needs at both histone and whole proteome levels.

 

II. The Biological Significance of Protein Lactylation

1. Regulation at the Epigenetic Level

Lactylation was first discovered onhistone H3 lysine residues (e.g., H3K18)and is associated withpromoting transcriptional activity. Lactylation can regulate chromatin conformation, thereby affecting gene expression programs, particularly prominent in pro-inflammatory factors and key metabolic genes with high glycolytic enzyme expression.

 

2. 'Recorder' of Metabolic Signals

Lactylation can be seen as an 'epigenetic record' of cellular metabolic states—when glycolytic activity is enhanced and lactate accumulates, lactylation levels increase correspondingly, thereby feedback regulating metabolism-related genes. This mechanism is particularly significant inmacrophage M1 polarization、tumor metabolic reprogrammingand other physiological and pathological processes.

 

3. Potential Association with Diseases

(1) Tumor Microenvironment: High glycolysis leads to lactate accumulation, active lactylation modification, promoting the expression of certain oncogenes;

(2) Inflammatory Response: Lactylation regulates the expression of pro-inflammatory factors and participates in immune cell activation;

(3) Neurodegenerative Diseases: Preliminary studies suggest that abnormal expression of lactylation in brain tissues may be associated with disease.

 

With advancements in mass spectrometry sensitivity and data analysis algorithms, research on protein lactylation is rapidly developing. Researchers are systematically exploring the following directions:Mapping the Lactylome: Kla lineages under different cell types and stimuli;Cross-regulation with other Modifications: The 'modification network' between Kla and acetylation, phosphorylation;Functional Validation: Effects of site-specific lactylation on protein activity and cell fate. Biotech Company offers comprehensivepost-translational modification multi-omics solutions, enabling comprehensive omics analysis of Kla modifications, as well as supporting protein interaction network analysis, pathway enrichment, and bioinformatics visualization for advanced research.

 

As an emerging post-translational modification, lysine lactylation is reshaping our understanding of lactate as a 'metabolic byproduct.' From inflammatory response to cancer metabolism, its role in various biological processes is gradually emerging. In this new research direction, omics technologies are becoming the core driving force for revealing its mechanisms. Biotech Company is committed to integratinghigh-resolution mass spectrometry platforms + high-throughput modification enrichment + multi-omics data interpretation capabilities, providing customized protein lactylation modification research services for researchers. We welcome you to contact us to explore the unknown boundaries of post-translational modifications together.

 

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