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This report is written by MaltSci based on the latest literature and research findings

What is the role of protein post-translational modifications? ​

Abstract ​

Post-translational modifications (PTMs) are critical biochemical processes that significantly influence protein function and activity, playing essential roles in cellular regulation and signaling. These modifications, which occur after protein synthesis, encompass a diverse array of chemical alterations including phosphorylation, glycosylation, ubiquitination, acetylation, and more. PTMs are integral to modulating protein stability, localization, interactions with other biomolecules, and overall cellular signaling pathways. The understanding of PTMs has advanced significantly, revealing their multifaceted roles in cellular homeostasis and disease mechanisms. For instance, phosphorylation is pivotal in signal transduction pathways, while acetylation and ubiquitination are crucial regulators of protein function. Despite significant advancements, the landscape of PTMs remains complex and not fully understood, necessitating a comprehensive approach to study their functional consequences. Aberrant PTMs have been implicated in a range of diseases, including cancer, neurodegenerative disorders, and metabolic syndromes, highlighting the urgent need for continued research in this field. This review aims to provide a comprehensive overview of the different types of PTMs, their enzymatic mechanisms, and the biological implications of these modifications in health and disease. By synthesizing current knowledge and recent findings, we underscore the importance of PTMs in the context of cellular regulation and their potential as therapeutic targets in various diseases.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Overview of Post-Translational Modifications
    • 2.1 Types of PTMs
    • 2.2 Enzymatic Mechanisms of PTMs
  • 3 Functional Consequences of PTMs
    • 3.1 Impact on Protein Stability
    • 3.2 Effects on Protein-Protein Interactions
  • 4 PTMs in Cellular Signaling Pathways
    • 4.1 Role in Signal Transduction
    • 4.2 PTMs in Hormonal Regulation
  • 5 PTMs in Disease Mechanisms
    • 5.1 Cancer
    • 5.2 Neurodegenerative Diseases
    • 5.3 Metabolic Disorders
  • 6 Therapeutic Implications of Targeting PTMs
    • 6.1 PTMs as Drug Targets
    • 6.2 Therapeutic Strategies Involving PTMs
  • 7 Conclusion

1 Introduction ​

Post-translational modifications (PTMs) are critical biochemical processes that profoundly influence protein function and activity, thereby playing essential roles in cellular regulation and signaling. These modifications, which occur after protein synthesis, encompass a diverse array of chemical alterations including phosphorylation, glycosylation, ubiquitination, acetylation, and more. The significance of PTMs extends beyond mere structural changes; they are integral to modulating protein stability, localization, interactions with other biomolecules, and overall cellular signaling pathways. The ability of PTMs to fine-tune protein functionality underlines their importance in a variety of biological processes, such as cell signaling, immune responses, and the pathogenesis of numerous diseases [1][2].

The understanding of PTMs has advanced significantly over the past few decades, revealing their multifaceted roles in cellular homeostasis and disease mechanisms. For instance, phosphorylation, one of the most extensively studied PTMs, is pivotal in signal transduction pathways, influencing cellular responses to external stimuli [3]. Similarly, modifications such as acetylation and ubiquitination have emerged as crucial regulators of protein function, affecting processes from transcriptional regulation to protein degradation [4][5]. Recent advancements in proteomic technologies have facilitated the identification and characterization of various PTMs, leading to the discovery of novel modifications and their implications in health and disease [2][6].

Despite the growing body of knowledge, the landscape of PTMs remains complex and not fully understood. The dynamic nature of these modifications, influenced by cellular context and environmental factors, poses challenges in elucidating their precise roles. For example, the diverse effects of PTMs on protein interactions and signaling pathways necessitate a comprehensive approach to study their functional consequences [3][7]. Furthermore, aberrant PTMs have been implicated in a range of diseases, including cancer, neurodegenerative disorders, and metabolic syndromes, highlighting the urgent need for continued research in this field [1][8].

This review aims to provide a comprehensive overview of the different types of protein post-translational modifications, their enzymatic mechanisms, and the biological implications of these modifications in health and disease. The organization of this review is as follows: Section 2 will present an overview of PTMs, detailing the various types and their enzymatic mechanisms. Section 3 will discuss the functional consequences of PTMs, focusing on their impact on protein stability and protein-protein interactions. In Section 4, we will explore the role of PTMs in cellular signaling pathways, including their significance in signal transduction and hormonal regulation. Section 5 will examine the implications of PTMs in disease mechanisms, specifically in cancer, neurodegenerative diseases, and metabolic disorders. Finally, Section 6 will discuss the therapeutic implications of targeting PTMs, highlighting potential strategies for drug development aimed at modulating these critical modifications. By synthesizing current knowledge and recent findings, we hope to underscore the importance of PTMs in the context of cellular regulation and their potential as therapeutic targets in various diseases.

2 Overview of Post-Translational Modifications ​

2.1 Types of PTMs ​

Post-translational modifications (PTMs) are critical biochemical alterations that occur on proteins following their synthesis. These modifications play essential roles in regulating protein function, stability, localization, and interactions with other cellular molecules. PTMs are pivotal in various biological processes, including signaling pathways, metabolic regulation, and the modulation of immune responses.

PTMs can be broadly classified into several types, each contributing uniquely to protein functionality:

  1. Phosphorylation: This is one of the most studied PTMs, involving the addition of a phosphate group to specific amino acids, typically serine, threonine, or tyrosine. Phosphorylation can activate or deactivate enzymes and receptors, thereby influencing signal transduction pathways and cellular responses to stimuli [9].

  2. Acetylation: This modification typically occurs on lysine residues and can affect protein interactions and stability. Acetylation is known to regulate various cellular processes, including gene expression and metabolism [10].

  3. Ubiquitination: The attachment of ubiquitin, a small protein, to a target protein often marks it for degradation via the proteasome. This process is crucial for regulating protein turnover and maintaining cellular homeostasis [9].

  4. Methylation: This modification involves the addition of methyl groups, primarily to lysine or arginine residues. Methylation can influence protein interactions and functions, playing significant roles in gene regulation and chromatin dynamics [1].

  5. Glycosylation: The addition of carbohydrate moieties to proteins affects their folding, stability, and recognition by other molecules. Glycosylation is essential for proper protein function and is involved in cell-cell communication and immune responses [11].

  6. SUMOylation: This involves the attachment of Small Ubiquitin-like Modifier (SUMO) proteins to target proteins, influencing their localization, stability, and interactions. SUMOylation is important in various cellular processes, including gene regulation and response to stress [8].

  7. Nitrosylation: The addition of a nitric oxide group to cysteine residues can alter protein function and is involved in signaling pathways related to oxidative stress and inflammation [9].

  8. Lipidation: This modification involves the attachment of lipid groups, which can affect protein membrane localization and function, playing crucial roles in signaling and cellular communication [11].

The diversity of PTMs and their regulatory mechanisms enable cells to respond rapidly to environmental changes and internal signals, thereby maintaining homeostasis and facilitating complex biological processes. Advances in proteomics have enhanced our understanding of the extensive landscape of PTMs, revealing their critical roles in health and disease, including cancer, cardiovascular diseases, and metabolic disorders [9][12][13]. Understanding the dynamics and functional implications of these modifications is essential for developing targeted therapies and interventions in various diseases.

2.2 Enzymatic Mechanisms of PTMs ​

Protein post-translational modifications (PTMs) are critical biochemical processes that significantly influence various cellular functions. These modifications occur after the synthesis of proteins and involve the covalent alteration of amino acid side chains, which can affect protein activity, stability, localization, and interactions. The role of PTMs is multifaceted, impacting a range of biological processes, from cellular signaling to the regulation of gene expression.

The diversity of PTMs includes phosphorylation, acetylation, methylation, glycosylation, and ubiquitination, among others. Each type of modification is mediated by specific enzymes that catalyze the addition or removal of functional groups. For instance, phosphorylation, a well-studied PTM, is primarily facilitated by kinases that add phosphate groups to serine, threonine, or tyrosine residues, thereby altering the protein's conformation and function. This modification plays a vital role in signal transduction pathways, regulating processes such as cell division, metabolism, and apoptosis [14].

Acetylation is another significant PTM, often associated with the regulation of gene expression through modifications of histones. Acetyltransferases catalyze the addition of acetyl groups, which can relax chromatin structure, promoting transcription [4]. Recent studies have also highlighted the importance of non-histone protein acetylation, indicating that this modification is not limited to chromatin but extends to various cellular proteins, influencing their activity and interactions [3].

The enzymatic mechanisms underlying PTMs are diverse and complex. For example, SUMOylation involves the attachment of small ubiquitin-like modifiers (SUMOs) to target proteins, which can regulate their stability, localization, and interaction with other proteins [15]. The enzymes involved in these processes, such as SUMO ligases, play a crucial role in determining the specificity and outcome of the modification.

Moreover, the impact of PTMs extends beyond individual proteins; they can influence entire signaling networks and cellular pathways. For instance, post-translational modifications are essential for the integration of signals from the cellular microenvironment, enabling cells to adapt to changing conditions [3]. This dynamic regulation is vital for maintaining cellular homeostasis and responding to stressors, pathogens, and developmental cues.

In summary, protein post-translational modifications serve as a sophisticated regulatory mechanism that modulates protein function and cellular processes. The enzymatic mechanisms that govern these modifications are integral to their specificity and biological outcomes, highlighting the importance of PTMs in cellular physiology and their potential implications in disease mechanisms and therapeutic strategies [2]. Further research into PTMs will enhance our understanding of their roles in health and disease, paving the way for novel therapeutic interventions.

3 Functional Consequences of PTMs ​

3.1 Impact on Protein Stability ​

Post-translational modifications (PTMs) are critical biochemical processes that involve the covalent modification of proteins after their synthesis. These modifications play a pivotal role in regulating various aspects of protein functionality, including stability, localization, interactions, and activity. The impact of PTMs on protein stability is particularly significant, as they can induce conformational changes that influence a protein's structural integrity and functional capabilities.

PTMs can alter the physicochemical properties of amino acids, thereby affecting enzymatic activity and protein-protein interactions. For instance, phosphorylation and acetylation are well-studied PTMs that have been shown to modulate protein stability. In a study focusing on O-linked N-acetylglucosamine (O-GlcNAc), it was found that this modification can stabilize certain proteins; however, it can also destabilize others, indicating a bidirectional regulatory role on protein stability [16].

The prevalence of PTMs in various cellular contexts highlights their importance in maintaining cellular homeostasis. For example, tissue factor (TF), a crucial initiator of the blood coagulation cascade, undergoes multiple PTMs such as glycosylation and phosphorylation, which modulate its stability and functional roles in signaling pathways [17]. Moreover, studies have demonstrated that the modification of proteins by PTMs can significantly influence their structural dynamics. For example, it has been shown that glycosylation and phosphorylation lead to conformational changes that can stabilize proteins by reducing global conformational heterogeneity [18].

Furthermore, the structural impact of PTMs is not limited to global changes; they can also induce localized conformational adjustments that are essential for protein function. For instance, certain PTMs may facilitate or hinder the binding of proteins to their targets, thereby influencing cellular signaling pathways [3]. The subtlety of these changes emphasizes the complex regulatory mechanisms that PTMs impart on protein function.

In the context of disease, particularly cancer, the dysregulation of PTMs can lead to aberrant protein stability and activity, contributing to disease progression. For example, in prostate cancer, specific PTMs such as phosphorylation and ubiquitination are implicated in the regulation of proteins that drive cancer phenotypes [19]. Understanding these modifications provides insight into potential therapeutic strategies that could target these pathways to restore normal protein function and stability.

In summary, PTMs serve as essential regulatory mechanisms that modulate protein stability and functionality. They enable proteins to respond dynamically to cellular signals and environmental changes, thereby influencing a wide range of biological processes. The ability of PTMs to induce both local and global structural changes underscores their critical role in maintaining protein homeostasis and their potential implications in various diseases.

3.2 Effects on Protein-Protein Interactions ​

Post-translational modifications (PTMs) are crucial regulatory mechanisms that significantly alter the properties of proteins, impacting their functions, interactions, and overall cellular dynamics. These modifications can include a wide range of chemical alterations such as phosphorylation, glycosylation, acetylation, and ubiquitination, each playing distinct roles in modulating protein characteristics.

PTMs influence protein-protein interactions (PPIs) in various ways. For instance, glycosylation generally facilitates binding by modifying the surface properties of proteins, thereby enhancing their interaction capabilities. Conversely, phosphorylation can have a more context-dependent effect, either promoting or disrupting interactions depending on the specific protein and the nature of the modification. This dual role amplifies the biological impact of proteins, allowing for a nuanced regulation of cellular functions in response to environmental changes [20].

Research indicates that the effects of PTMs on PPIs are complex and cannot be merely summed up as local changes. For example, in a study involving Saccharomyces cerevisiae, it was observed that acetylations tend to have locally stabilizing effects on protein interactions, whereas phosphorylations may destabilize these interactions [21]. This interplay highlights the intricate network of PTM cross-talk that can significantly influence cellular signaling and response mechanisms.

Furthermore, PTMs contribute to the dynamic nature of protein interactions, facilitating a highly adaptable regulatory network. This adaptability is essential for various biological processes, including signal transduction, metabolic pathways, and responses to stress [1]. For instance, modifications such as methylation and acetylation have been shown to affect protein stability and localization, thereby influencing their interaction with other cellular components [22].

In the context of disease, particularly cancer, the implications of PTMs on PPIs become even more critical. Aberrant PTMs can disrupt normal protein interactions, leading to altered signaling pathways that contribute to tumorigenesis [1]. The understanding of how PTMs affect PPIs not only provides insights into fundamental biological processes but also opens avenues for therapeutic interventions targeting these modifications.

In summary, protein post-translational modifications serve as vital regulators of protein properties and interactions, profoundly affecting cellular behavior and functionality. The complex interplay of PTMs shapes the dynamics of protein-protein interactions, underscoring their significance in both health and disease contexts.

4 PTMs in Cellular Signaling Pathways ​

4.1 Role in Signal Transduction ​

Protein post-translational modifications (PTMs) play a critical role in cellular signaling pathways and are essential for the regulation of signal transduction. These modifications, which occur after protein synthesis, include processes such as phosphorylation, ubiquitination, methylation, acetylation, and lactylation, among others. Each type of PTM can significantly alter the function, localization, stability, and interaction of proteins, thus modulating their activity within signaling pathways.

Phosphorylation, in particular, is recognized as the most common and significant type of PTM involved in signal transduction. It serves as a reversible modification that can activate or deactivate proteins, thereby controlling a myriad of cellular processes, including cell growth, differentiation, and apoptosis. The balance of phosphorylation and dephosphorylation, regulated by protein kinases and phosphatases, is crucial for maintaining cellular homeostasis and responding to external stimuli [23].

In addition to phosphorylation, other PTMs have garnered attention for their roles in modulating protein function within signaling pathways. For example, the methylation of lysine and arginine residues, as well as acetylation and nitrosylation of thiol groups and tyrosine residues, contribute to the complexity of cellular signaling networks [24]. These modifications can affect protein interactions and the assembly of signaling complexes, thereby influencing the outcome of signaling cascades.

Moreover, PTMs are integral to the dynamic remodeling of cellular responses. RNA-binding proteins (RBPs), for instance, undergo PTMs that regulate their interactions with mRNAs in response to internal and external stimuli, highlighting the integration of signaling events with gene expression [25]. This interplay between PTMs and signal transduction is vital for the rapid adaptation of cells to environmental changes.

Ubiquitination, another significant PTM, regulates various cellular functions, including the DNA damage response and apoptosis. The ubiquitin-proteasome system has been shown to modulate key signaling pathways, impacting the pathophysiology of diseases such as cancer and cardiac conditions [26]. The mechanisms by which ubiquitination affects signaling pathways further exemplify the complexity and importance of PTMs in cellular signaling.

In summary, PTMs are fundamental to the regulation of cellular signaling pathways. They enable the modulation of protein function and interactions, facilitating the conversion of external signals into appropriate biological responses. Understanding the mechanisms and implications of PTMs in signal transduction is essential for advancing therapeutic strategies aimed at various diseases. As research continues to uncover the roles of different PTMs, their potential as targets for drug discovery and disease intervention becomes increasingly apparent [[pmid:15539140],[pmid:18837465]].

4.2 PTMs in Hormonal Regulation ​

Post-translational modifications (PTMs) of proteins are critical regulatory mechanisms that significantly influence various cellular processes, including signal transduction and hormonal regulation. These modifications occur after protein synthesis and can involve the covalent attachment of chemical groups to specific amino acid residues, thereby altering the protein's properties, such as activity, localization, and stability.

PTMs play a pivotal role in cellular signaling pathways by modulating protein interactions and functions in response to environmental cues. For instance, phosphorylation, one of the most studied PTMs, is crucial in the signaling cascades that mediate responses to hormones and growth factors. It allows cells to quickly respond to external signals, facilitating processes such as cell growth, differentiation, and apoptosis. The dynamic nature of PTMs enables a rapid and reversible mechanism to regulate protein activity, which is essential for maintaining cellular homeostasis and adapting to changing conditions (Dutta & Jain, 2023) [1].

In the context of hormonal regulation, PTMs can significantly influence how hormones exert their effects on target cells. For example, the ubiquitin-proteasome system, a key mechanism of PTM, regulates the degradation of proteins involved in hormone signaling pathways. This regulation can impact the availability and activity of hormone receptors, thereby influencing the cellular response to hormonal stimuli. In particular, the ubiquitination of proteins can modulate their stability and interactions, affecting downstream signaling events (Portbury et al., 2012) [26].

Additionally, other PTMs such as acetylation and methylation have been shown to play significant roles in the modulation of hormone signaling. Acetylation can influence transcription factors' ability to activate or repress gene expression in response to hormonal signals, while methylation can alter protein-protein interactions essential for signal transduction (Friedmann & Marmorstein, 2013) [4]. These modifications contribute to the fine-tuning of hormonal responses, allowing for precise control over physiological processes.

Moreover, the integration of various PTMs provides a complex regulatory network that ensures the proper functioning of hormonal signaling pathways. This integration allows for the coordination of multiple signals, facilitating a comprehensive cellular response to hormonal changes (Deribe et al., 2010) [3].

In summary, protein post-translational modifications are essential for the regulation of cellular signaling pathways and hormonal responses. They enable cells to adapt to various stimuli by altering protein function, stability, and interactions, thus playing a fundamental role in maintaining physiological balance and facilitating appropriate cellular responses to hormonal signals. The ongoing research into PTMs continues to unveil their intricate roles and potential therapeutic implications in various diseases.

5 PTMs in Disease Mechanisms ​

5.1 Cancer ​

Post-translational modifications (PTMs) of proteins play a critical role in various cellular processes, particularly in the context of cancer. These modifications involve the covalent attachment of chemical groups to proteins, which can significantly alter their structure, function, and interactions with other molecules. PTMs are essential for regulating numerous biological processes, including signal transduction, protein localization, stability, and interactions with other proteins.

In cancer biology, PTMs are implicated in several hallmark functions associated with tumorigenesis, such as cellular proliferation, apoptosis, angiogenesis, and metastatic dissemination. For instance, the dysregulation of PTMs can contribute to oncogenic transformations, leading to enhanced cancer cell survival and growth. Various types of PTMs, including phosphorylation, glycosylation, acetylation, ubiquitination, and palmitoylation, have been shown to influence critical signaling pathways involved in cancer progression [27][28][29].

Phosphorylation is one of the most well-studied PTMs and is known to regulate many signaling pathways. For example, it can activate or deactivate enzymes and receptors, thus affecting cell cycle progression and apoptosis. Similarly, glycosylation is crucial for cell-cell interactions and can modulate immune responses, impacting tumor immunity and metastasis [30][31].

Palmitoylation, a reversible lipid-based modification, has been identified as a significant regulator of protein stability and localization, affecting signaling pathways associated with cancer [32]. Furthermore, lactylation, a newer type of PTM linked to metabolic processes, has been associated with tumor progression and poor clinical outcomes [31][33]. This modification illustrates the intricate relationship between cancer metabolism and epigenetic regulation, suggesting that metabolic reprogramming in tumors can influence gene expression and protein function.

Moreover, the interplay between various PTMs can create a complex regulatory network that governs tumor behavior. For instance, the crosstalk between phosphorylation and ubiquitination can dictate protein degradation and activity, thereby influencing cancer cell fate [1][34]. Understanding these modifications is crucial for identifying potential biomarkers and therapeutic targets, as aberrant PTMs can serve as hallmarks of cancer [29][35].

Overall, the study of PTMs in cancer is essential for uncovering the molecular mechanisms underlying tumorigenesis and for developing novel therapeutic strategies. By targeting specific PTMs or the enzymes responsible for these modifications, researchers aim to enhance the efficacy of cancer treatments and improve patient outcomes [33][36].

5.2 Neurodegenerative Diseases ​

Post-translational modifications (PTMs) of proteins play a critical role in the pathogenesis of neurodegenerative diseases (NDDs) by influencing protein structure, function, stability, and interactions. These modifications occur after protein synthesis and include a variety of chemical alterations such as phosphorylation, acetylation, ubiquitination, glycosylation, and oxidation, among others. Each type of PTM can significantly impact the biological activity of proteins, particularly in the context of neurodegeneration.

One of the hallmark features of neurodegenerative disorders is the accumulation of aggregated and non-functional proteins within cells. PTMs are essential regulators of this protein aggregation process. For instance, alterations in the post-translational mechanisms and protein quality control systems, including molecular chaperones and the ubiquitin-proteasome system, can enhance the accumulation of misfolded proteins, leading to neuronal dysfunction [37]. Specifically, in diseases like Alzheimer's and Parkinson's, abnormal PTMs, such as hyperphosphorylation of tau protein and abnormal ubiquitination of α-synuclein, have been linked to the aggregation of these proteins, which is a critical aspect of disease pathology [38].

Different PTMs can regulate protein homeostasis, influencing protein turnover rates and the propensity for aggregation. For example, phosphorylation can alter protein interactions and stability, while ubiquitination typically marks proteins for degradation, thereby preventing the accumulation of toxic aggregates [39]. In neurodegenerative diseases, the dysregulation of these PTMs can lead to the pathological aggregation of proteins, contributing to neuronal cell death and disease progression [40].

Emerging research indicates that targeting specific PTMs may offer therapeutic avenues for neurodegenerative diseases. For example, small molecules that modulate PTMs could reverse misfolded protein accumulation and enhance neuroprotection [37]. Additionally, modifications such as O-GlcNAcylation have shown protective effects against protein misfolding and aggregation in conditions like Alzheimer's and Parkinson's diseases [41].

Moreover, oxidative modifications of proteins, which can result from cellular stress, have also been implicated in neurodegeneration. These modifications can affect protein function and contribute to the pathophysiology of diseases like Alzheimer's and Parkinson's [42]. The interplay between various PTMs further complicates the landscape, as these modifications can affect one another, influencing overall protein behavior and cellular responses [40].

In summary, PTMs are pivotal in the mechanisms underlying neurodegenerative diseases, as they regulate protein aggregation, stability, and interactions. Understanding these modifications offers potential pathways for therapeutic interventions aimed at mitigating the effects of neurodegeneration. The ongoing exploration of PTMs and their roles in protein homeostasis continues to be a vital area of research in the quest to develop effective treatments for these debilitating conditions.

5.3 Metabolic Disorders ​

Protein post-translational modifications (PTMs) play a crucial role in the regulation of various biological processes and are integral to the pathophysiology of metabolic disorders. PTMs are biochemical modifications that occur on specific amino acid residues of proteins after their synthesis, significantly increasing the functional diversity of the proteome. The range of PTMs includes phosphorylation, acetylation, methylation, ubiquitination, glycosylation, and several novel modifications such as lactylation and succinylation [43][44][45].

In the context of metabolic disorders, PTMs are implicated in the regulation of metabolic pathways, cellular signaling, and protein interactions. For instance, the modification of proteins through phosphorylation and acetylation has been shown to influence the activity of key metabolic enzymes, thereby affecting glucose and lipid metabolism. Dysregulation of these PTMs can lead to metabolic dysfunctions, contributing to diseases such as diabetes, obesity, and nonalcoholic fatty liver disease (NAFLD) [46][47].

Research indicates that specific PTMs are associated with the progression of various metabolic conditions. For example, the succinylation of proteins can modulate metabolic enzyme activity, impacting cellular processes related to energy production and storage [6]. Furthermore, modifications such as lactylation have emerged as significant regulators in cardiometabolic disorders, influencing the interplay between metabolism and pathological tissue remodeling [48][49].

Moreover, PTMs can also affect the structural conformation of proteins, leading to alterations in their functional capabilities. This structural modulation can have profound implications for cellular signaling pathways and metabolic homeostasis. For example, aberrant PTMs may disrupt normal signaling cascades, contributing to the development of insulin resistance and other metabolic syndromes [47][50].

In summary, PTMs serve as critical regulatory mechanisms that not only diversify protein functions but also play significant roles in the onset and progression of metabolic disorders. Understanding the intricate relationships between PTMs and metabolic pathways is essential for identifying novel therapeutic targets and developing effective interventions for metabolic diseases. Continued research in this area promises to unveil new insights into the molecular mechanisms underlying these conditions, potentially leading to improved strategies for diagnosis and treatment [44][45][46].

6 Therapeutic Implications of Targeting PTMs ​

6.1 PTMs as Drug Targets ​

Protein post-translational modifications (PTMs) are crucial biochemical alterations that occur after protein synthesis, fundamentally influencing protein structure, function, localization, and interactions with other cellular molecules. These modifications can significantly impact various biological processes, including signal transduction, metabolic regulation, and immune responses. Common forms of PTMs include phosphorylation, acetylation, ubiquitination, glycosylation, and emerging types such as lactylation and succinylation [9][51].

The therapeutic implications of targeting PTMs have gained substantial attention in recent years, particularly in the context of cancer immunotherapy and other diseases. PTMs play a vital role in modulating immune cell activity within the tumor microenvironment (TME), influencing the proliferation, activation, and metabolic reprogramming of immune cells. For instance, modifications can regulate the functional states of T cells, macrophages, and dendritic cells, thereby determining the nature and intensity of immune responses [51][52]. Furthermore, PTMs can affect the stability and function of immune checkpoint molecules, which are critical in tumor immune evasion [51].

In addition to cancer, PTMs are implicated in various pathological conditions, including ischemic heart disease and autoimmune disorders. For example, the dysregulation of PTMs can lead to abnormal signaling pathways that contribute to disease progression [52][53]. As such, PTMs are emerging as potential drug targets, offering new avenues for therapeutic interventions. Strategies targeting PTM-modifying enzymes, such as kinases and deacetylases, are being explored to enhance the efficacy of existing therapies and develop novel treatment approaches [1][51].

Moreover, the dynamic nature of PTMs, which can exhibit spatiotemporal specificity during disease progression, suggests that a deeper understanding of these modifications could lead to the identification of novel biomarkers and therapeutic targets. For instance, targeting specific PTMs involved in tumor metabolism and immune regulation could enhance the effectiveness of cancer therapies [1][11].

The exploration of combinatorial approaches that simultaneously target multiple PTM pathways may also yield synergistic effects, thereby improving treatment outcomes [51]. Overall, the role of PTMs in regulating critical biological processes and their potential as therapeutic targets underscore their significance in advancing precision medicine and developing innovative therapeutic strategies.

6.2 Therapeutic Strategies Involving PTMs ​

Protein post-translational modifications (PTMs) are critical biochemical alterations that occur on specific amino acid residues of proteins after their synthesis. These modifications can profoundly influence protein structure, function, stability, localization, and interactions with other molecules, thus playing pivotal roles in numerous biological processes and disease mechanisms. The common types of PTMs include phosphorylation, acetylation, glycosylation, and ubiquitination, among others, which can either activate or inactivate proteins, modulate their activity, or alter their cellular localization.

In the context of cancer and other diseases, PTMs have been identified as key regulators of various metabolic processes and immune responses. For instance, in tumor biology, PTMs can regulate immune checkpoint molecules, which are crucial for tumor immune evasion and recognition by immune cells. This regulation is essential in determining the intensity and nature of immune responses within the tumor microenvironment (TME) (Zhang et al., 2025) [51]. Additionally, PTMs are involved in the proliferation, activation, and metabolic reprogramming of immune cells, thereby influencing the effectiveness of tumor immunotherapy (Li et al., 2023) [9].

Given their significant roles, targeting PTMs presents promising therapeutic opportunities. Emerging immunotherapeutic strategies are increasingly focusing on key PTM-modifying enzymes, such as kinases, deacetylases, and deubiquitinases. These strategies aim to overcome challenges like drug specificity, resistance, and off-target effects. For example, the combinational targeting of distinct PTM pathways may enhance therapeutic efficacy and improve patient outcomes (Zhang et al., 2025) [51].

Moreover, advancements in understanding the interplay between different PTMs and their regulatory networks open new avenues for precision immunotherapies. For instance, the exploration of PTMs in the context of metabolic diseases has revealed their potential as therapeutic targets, highlighting the need for a deeper understanding of how these modifications influence disease progression (Wu et al., 2023) [43].

In addition to cancer, PTMs have implications in various other diseases, including chronic kidney disease, cardiovascular diseases, and autoimmune disorders. In these contexts, PTMs can serve as biomarkers for disease progression and therapeutic targets. For instance, in rheumatoid arthritis, PTMs such as citrullination are linked to the disease's pathogenesis, providing insights into potential diagnostic and therapeutic strategies (Carubbi et al., 2019) [53].

In conclusion, the multifaceted roles of PTMs in regulating protein function and their implications in various diseases underscore their potential as therapeutic targets. The development of novel strategies to manipulate PTMs could lead to innovative treatments for a range of conditions, emphasizing the need for continued research in this dynamic field. As the understanding of PTMs deepens, it is anticipated that new therapeutic approaches will emerge, providing more effective and targeted interventions for patients.

7 Conclusion ​

This review has highlighted the multifaceted roles of post-translational modifications (PTMs) in regulating protein function and cellular processes. Key findings include the diverse types of PTMs, such as phosphorylation, acetylation, and ubiquitination, which are crucial for modulating protein stability, interactions, and signaling pathways. The complexity of PTMs underscores their significance in various biological processes and their implications in disease mechanisms, particularly in cancer, neurodegenerative diseases, and metabolic disorders. Current research emphasizes the need for a deeper understanding of PTMs to uncover their roles in health and disease, as well as their potential as therapeutic targets. Future research should focus on elucidating the dynamic interplay between different PTMs, developing targeted therapies that modulate these modifications, and exploring their applications in precision medicine. By advancing our knowledge of PTMs, we can pave the way for innovative therapeutic strategies that improve patient outcomes across a range of diseases.

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