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Protein Methyltransferases in Human Health and Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 March 2026 | Viewed by 6679

Special Issue Editor


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Guest Editor
Centre for Molecular Medicine and Biobanking, University of Malta, MSD2080 Msida, Malta
Interests: proteomics; functional biochemistry; post-translational modifications; lysine methylation; mass spectrometry; cancer diagnostics

Special Issue Information

Dear Colleagues,

A wide variety of methyltransferases add methylations to proteins in key regulatory pathways, which are spatially, temporally, and chemically dynamic. Despite the abundance of these post-translational modifications (PTM) in the human proteome, our understanding of the role of most of these methyltransferase enzymes in cellular biology and disease is still limited. This has a particularly significant impact on cancer and neurodegenerative diseases, where novel treatment strategies are being sought.

Moreover, in relation to the different methyltrasnsferase enzyme families, the degree of methylation adds an extra layer of complexity, since lysine can undergo mono- (Kme1), di- (Kme2), or tri- (Kme3) methylation, while arginine can undergo mono- (Rme1), di-symetrical (sRme2), and di-asymmetrical (aRme2) methylation, and these are sometimes performed by different enzymes at one specific residue. The addition of this PTM leads to some sort of change in protein properties, which consequently, either directly or indirectly, impacts the function via domain activity, interaction strength to target proteins or DNA, localization, and protein stability or half-life. Moreover, methylation can crosstalk or compete with other PTMs, adding another layer of regulation. For this reason, protein methylation is gaining interest for diagnostic and prognostic applications, particularly on lysines and arginines in non-histone proteins. The dysregulation of protein methyltransferases has also been implicated in disease, making such enzymes potential therapeutic targets, for which there are only few inhibiting small molecules that are in clinical trials. However, despite recognizing the importance of methyltransferase enzymes in both cellular biology and human disease, much is still unknown regarding their full complement of target proteins, modified residue positions, degree, and function. The main reasons for this are a lack of reliable tools and methods for studying these modifications.

This Special Issue aims to gather any advances in relation to the protein methyltransferase enzymes. Topics include, but are not limited to:

  • Identification of protein methyltransferases as biomarkers in diagnostics or therapeutics;
  • Identification of pathways or contexts in which protein methyltransferases are involved;
  • Testing of novel protein methyltransferase inhibitors for controlling disease progression.

Dr. Byron Baron
Guest Editor

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Keywords

  • lysine and arginine methylation
  • mass spectrometry
  • PTM cross talk
  • functional proteomics
  • cancer
  • neurological disorders

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Published Papers (3 papers)

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Review

31 pages, 2887 KB  
Review
Mechanistic Insights into SAM-Dependent Methyltransferases: A Review of Computational Approaches
by Mateusz Jędrzejewski, Łukasz Szeleszczuk and Dariusz Maciej Pisklak
Int. J. Mol. Sci. 2025, 26(18), 9204; https://doi.org/10.3390/ijms26189204 - 20 Sep 2025
Viewed by 761
Abstract
Methylation reactions catalyzed by S-adenosylmethionine (SAM)-dependent methyltransferases are essential to numerous biological functions, including gene expression regulation, epigenetic modifications, and biosynthesis of natural products. Dysregulation of these enzymes is associated with diseases, including cancer and neurodevelopmental disorders, making them attractive drug targets. This [...] Read more.
Methylation reactions catalyzed by S-adenosylmethionine (SAM)-dependent methyltransferases are essential to numerous biological functions, including gene expression regulation, epigenetic modifications, and biosynthesis of natural products. Dysregulation of these enzymes is associated with diseases, including cancer and neurodevelopmental disorders, making them attractive drug targets. This review explores the contribution of computational methods, particularly quantum chemical calculations and molecular dynamics (MD) simulations, in elucidating the mechanisms of SAM-dependent methyltransferases. These techniques enable detailed characterization of transition states and reaction pathways, often inaccessible by experimental methods. The review discusses molecular modeling approaches such as the quantum chemical cluster approach (QM-cluster) and hybrid QM/MM methods, emphasizing their applications in studying methyl group transfer, substrate specificity, and the roles of water molecules and metal ions in catalysis. Additionally, dynamic aspects of enzyme function are addressed using classical MD and QM/MM MD simulations. Case studies demonstrate how computational predictions align with experimental data and enable rational design of selective inhibitors and engineered enzymes with altered specificity. Overall, computational chemistry offers a powerful, atomistic view of SAM-dependent methyltransferases, not only complementing experimental studies but also providing a foundation for the design of future experiments in this field. Full article
(This article belongs to the Special Issue Protein Methyltransferases in Human Health and Diseases)
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26 pages, 644 KB  
Review
Therapeutic Targeting of Protein Lysine and Arginine Methyltransferases: Principles and Strategies for Inhibitor Design
by Isaac Micallef and Byron Baron
Int. J. Mol. Sci. 2025, 26(18), 9038; https://doi.org/10.3390/ijms26189038 - 17 Sep 2025
Cited by 1 | Viewed by 784
Abstract
Standard cancer chemotherapy is increasingly being supplemented with novel therapeutics to overcome known chemoresistance pathways. Resistance to treatment is common across various tumour types, driven by multiple mechanisms. One emerging contributor is protein methylation, a post-translational modification mediated by protein methyltransferases (PMTs), which [...] Read more.
Standard cancer chemotherapy is increasingly being supplemented with novel therapeutics to overcome known chemoresistance pathways. Resistance to treatment is common across various tumour types, driven by multiple mechanisms. One emerging contributor is protein methylation, a post-translational modification mediated by protein methyltransferases (PMTs), which regulate protein function by adding methyl groups, mainly on lysine and arginine residues. Dysregulation of protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs) has been linked to cancer progression and drug resistance, making them attractive therapeutic targets. Consequently, several small-molecule PMT inhibitors have been developed, with some progressing to clinical trials. However, many candidates showing promise in preclinical studies fail to demonstrate efficacy or safety in later stages, limiting clinical success. This gap highlights the need to rethink current approaches to PMT inhibitor design. A deeper understanding of PMT mechanisms, catalytic domains, and their roles in chemoresistance is essential for creating more selective, potent, and clinically viable inhibitors. This review will summarise major chemoresistance pathways and PMTs implicated in cancer, then explore current and prospective PMT inhibitor classes. Building on mechanistic insights, we propose strategies to develop next-generation inhibitors with improved therapeutic potential against chemoresistant cancers. Full article
(This article belongs to the Special Issue Protein Methyltransferases in Human Health and Diseases)
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25 pages, 2435 KB  
Review
Role of PRMT1 and PRMT5 in Breast Cancer
by Sébastien Martinez, Stéphanie Sentis, Coralie Poulard, Olivier Trédan and Muriel Le Romancer
Int. J. Mol. Sci. 2024, 25(16), 8854; https://doi.org/10.3390/ijms25168854 - 14 Aug 2024
Cited by 9 | Viewed by 4235
Abstract
Breast cancer is the most common cancer diagnosed in women worldwide. Early-stage breast cancer is curable in ~70–80% of patients, while advanced metastatic breast cancer is considered incurable with current therapies. Breast cancer is a highly heterogeneous disease categorized into three main subtypes [...] Read more.
Breast cancer is the most common cancer diagnosed in women worldwide. Early-stage breast cancer is curable in ~70–80% of patients, while advanced metastatic breast cancer is considered incurable with current therapies. Breast cancer is a highly heterogeneous disease categorized into three main subtypes based on key markers orientating specific treatment strategies for each subtype. The complexity of breast carcinogenesis is often associated with epigenetic modification regulating different signaling pathways, involved in breast tumor initiation and progression, particularly by the methylation of arginine residues. Protein arginine methyltransferases (PRMT1-9) have emerged, through their ability to methylate histones and non-histone substrates, as essential regulators of cancers. Here, we present an updated overview of the mechanisms by which PRMT1 and PRMT5, two major members of the PRMT family, control important signaling pathways impacting breast tumorigenesis, highlighting them as putative therapeutic targets. Full article
(This article belongs to the Special Issue Protein Methyltransferases in Human Health and Diseases)
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