Emerging PTMs

Lactylation is a recently identified lysine post-translational modification (PTM) driven by cellular lactate metabolism. By modifying lysine residues, lactylation serves as a molecular link between cellular metabolism and protein regulation. Lactylation has been implicated in diverse biological processes, including gene expression, chromatin remodeling, immune regulation, and inflammatory responses. Emerging evidence suggests that dysregulated lactylation contributes to the development of various diseases, including cancer, cardiovascular disorders, and neurological diseases.

Crotonylation is a recently identified lysine acylation modification that was first recognized as a histone modification in 2011. This modification is characterized by the addition of a crotonyl group to lysine residues. Enriched in transcriptionally active chromatin, histone crotonylation regulates chromatin organization and gene expression. Growing evidence indicates that crotonylation participates in diverse biological processes, including cell differentiation, reproductive development, and cellular regulation. The identification of crotonylation provides new insights into the epigenetic mechanisms underlying gene expression and biological functions.

Succinylation is an acylation modification involving the covalent attachment of a succinyl group to lysine residues. Compared with other lysine acylations, succinylation markedly alters the physicochemical properties of proteins, thereby influencing protein structure and function. Widely distributed in both histone and non-histone proteins, succinylation plays important roles in cellular metabolism, epigenetic regulation, and signal transduction.

Lysine β-hydroxybutyrylation (Kbhb) is a novel post-translational modification mediated by the ketone body β-hydroxybutyrate (BHB). Kbhb levels are dynamically regulated under ketogenic metabolic conditions, including fasting, ketogenic diets, and prolonged physical exercise. Emerging evidence has highlighted Kbhb as an important metabolic-epigenetic interface that connects cellular energy status with chromatin regulation and protein function. Kbhb has demonstrated regulatory roles across diverse biological contexts, including oncology, immunomodulation, metabolic homeostasis, circadian remodeling, and developmental processes.

Lysine butyrylation (Kbu) is a lysine acylation modification driven by butyrate, a short-chain fatty acid produced by microbial fermentation in the gut. The identification of Kbu has provided new insights into how gut microbial-driven metabolites regulate host protein function and epigenetic process. Kbu has been detected on histone and non-histone proteins, where it contributes to the regulation of gene expression, cellular metabolism, and physiological functions. Growing evidence has linked Kbu to biological processes including cancer progression, inflammation, metabolic disorders, and host-microbiome interactions.

Lysine 2-hydroxyisobutyrylation (Khib) is a widespread lysine acylation modification conserved across prokaryotic and eukaryotic organisms. Khib is predominantly enriched on histone proteins located at transcriptionally active genomic regions, highlighting its involvement in chromatin regulation and gene expression. Increasing evidence indicates that Khib participates in gene expression regulation, cellular differentiation, and metabolic processes.

Lysine propionylation (Kpr) is a propionyl-CoA-dependent lysine acylation modification. It covalently links propionyl groups to lysine residues of target proteins. Regulated by cellular metabolism, Kpr mirrors intracellular metabolic status and modulates functions of histones and non-histone proteins. A growing body of evidence shows that Kpr regulates chromatin dynamics, transcription and core metabolic processes.

Lysine malonylation (Kmal) is a reversible post-translational modification mediated by malonyl-CoA. The introduction of malonyl groups converts lysine residues from a positive to a negative charge, potentially reshaping protein conformation and molecular interactions. Kmal is widely involved in metabolic regulation, particularly in fatty acid metabolism, mitochondrial function, and glycolysis.

Lysine glutarylation (Kglu) is a reversible lysine acylation modification derived from glutaryl-CoA. By introducing glutaryl groups onto lysine residues, Kglu alters protein physicochemical properties and influences protein interactions and functions. Kglu is enriched in mitochondrial proteins and has been implicated in mitochondrial function and metabolic regulation.

Lysine pyruvylation (Kpy) is a metabolite-associated modification derived from pyruvate, a central intermediate of glycolysis. The transfer of pyruvoyl groups to lysine residues is mediated by acyltransferases such as p300 and HAT1, while SIRT3 contributes to the removal of this modification. Kpy has been implicated in the regulation of protein function and cellular processes associated with metabolic adaptation.

Lysine leucylation (KLeu) represents a unique connection between amino acid metabolism and protein modification. By using leucyl-tRNA as the donor, KLeu introduces leucine residues onto lysine sites, creating an amino acid-based regulatory mechanism distinct from conventional acylations. KLeu has been implicated in the regulation of protein function and cellular adaptation to nutrient conditions.

Lysine fumarylation (Kfu) is a recently identified PTM first characterized in Escherichia coli. The fumaryl group are installed onto lysine residues by SpeG and removed by CobB. Derived from fumarate, a key metabolite of the TCA cycle, Kfu participates in cellular stress adaptation, including temperature and oxidative stress responses.

Lysine methacrylation (Kmea) is a new type of posttranslational modification and a structural isomer of crotonyllysine (Kcr). Kmea is a reversible PTM, which is related by HAT1 as a methacryltransferase and SIRT2 as a demethacrylase. The discovery of Kmea provides new insights into the interplay between metabolism and epigenetic regulation.

Lysine benzoylation (Kbz) is a reversible aromatic lysine acylation modification. Using benzoyl-CoA as its acyl donor, this marker accumulates mainly on histone tails within gene promoters to remodel chromatin and mediate transcriptional regulation.

Itaconate is an immunometabolite that drives two distinct protein modifications: cysteine itaconation (S-itaconation) and lysine itaconylation (K-itaconylation). S-itaconation was first characterized in 2018 as an electrophilic cysteine modification involved in inflammatory regulation. In 2023, K-itaconylation was identified as a novel lysine acylation modification. Despite sharing the same metabolic origin, these modifications are mediated through distinct chemical mechanisms and contribute to different biological processes.

Serotonylation is a recently characterized PTM, wherein serotonin is covalently conjugated to glutamine residues of substrate proteins. This reaction is catalyzed by transglutaminases, and target substrates include small GTPases, fibronectin, cytoskeletal proteins, and histones. Serotonylation remodels the molecular functions of these proteins, thereby modulating diverse cellular signaling pathways and biological regulatory processes.

Carboxyethylation includes two distinct types of protein modifications with different mechanisms and biological functions. Cysteine carboxyethylation is an emerging enzyme-dependent PTM linked to gut microbiota-mediated immune regulation and autoimmune disease. In contrast, lysine carboxyethylation (Kce) is a non-enzymatic glycation-derived modification associated with diabetes and aging research.

Protein tyrosine nitration is a non-enzymatic PTM triggered by reactive nitrogen species (RNS) under oxidative and inflammatory conditions. This modification results in the formation of 3-nitrotyrosine through the addition of a nitro group (-NO2) to tyrosine residues, altering protein structure and function. Tyrosine nitration is recognized as a marker of nitrosative stress and has been implicated in inflammation, aging, and chronic diseases.

4-Hydroxynonenal (4-HNE) is a reactive aldehyde generated during lipid peroxidation under oxidative stress conditions. It forms covalent adducts with cysteine, histidine, and lysine residues through Michael addition, affecting cellular signaling and stress responses. Accumulation of 4-HNE-protein adducts reflects lipid peroxidation and oxidative damage, which is frequently observed in aging, neurodegenerative diseases and cancer.