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Biomolecules
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Advances and Novel Strategies for Studying Underexplored Post-Translational Modifications (PTMs)
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Advances and Novel Strategies for Studying Underexplored Post-Translational Modifications (PTMs)

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 31 January 2026 | Viewed by 4103

Special Issue Editor

Dr. Yue Chen

E-Mail Website
Guest Editor
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota at Twin Cities, Minneapolis, MN 55455, USA
Interests: posttranslational modifications; epigenetics; oxygen sensing; chemical proteomics; quantitative proteomics; metabolism; lysine acylation; hydroxylation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

To date, over 600 types of protein post-translational modifications (PTMs) have been documented. However, only a limited number have been thoroughly characterized to understand their regulatory pathways and functional significance in physiology, while the vast majority remain underexplored. Emerging evidence suggests that these lesser-known PTMs play critical roles in diverse metabolic and signaling pathways. Yet, the systematic and functional characterization of underexplored PTMs remains challenging due to several factors.

First, there is often a lack of efficient methods to enrich and confidently identify PTM sites and proteins from complex biological samples. Second, quantitative strategies to assess modification dynamics, prevalence, or crosstalk with other PTMs are frequently lacking. Third, effective approaches to investigate the site-specific roles of PTMs in regulating substrate activity and physiological outcomes remain underdeveloped. Finally, there is a significant knowledge gap regarding the regulatory pathways that control these modifications.

Advances in both technological development and functional studies are urgently needed to close these gaps. Such efforts will deepen our understanding of the biological pathways and networks governed by underexplored PTMs, as well as their dynamics and responses to cellular metabolic changes. Ultimately, this may lay the foundation for the discovery of novel disease markers and therapeutic targets. This Special Issue invites the latest research and reviews on the discovery and functional characterization of underexplored protein modification targets and regulatory enzymes in cellular metabolism, development, aging and various disease phenotypes, including cancer and metabolic diseases.

Dr. Yue Chen
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • post-translational modifications proteomics
  • chemical biology
  • cell signaling
  • epigenetics
  • metabolic regulation
  • cancer
  • diabetes
  • microbiome
  • aging

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Published Papers (3 papers)

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13 pages, 1636 KB  
Article
The Identification of a Sub-Micromolar Peptide-Based Protein Arginine Methyltransferase 1 (PRMT1) Inhibitor from a Plate-Based Screening Assay
by Tina M. Sawatzky, Sarah A. Mann, Jordan Shauna Tucker, Aida A. Bibart, Corey P. Causey and Bryan Knuckley
Biomolecules 2025, 15(11), 1494; https://doi.org/10.3390/biom15111494 - 23 Oct 2025
Viewed by 1096
Abstract
Post-translational modifications (PTMs) expand the structural diversity of proteins beyond the standard amino acids, influencing protein-protein interactions. Protein methylation, a prevalent PTM, involves the transfer of methyl groups from S-adenosylmethionine (SAM) to lysine and arginine residues. Arginine methylation is catalyzed by the Protein [...] Read more.
Post-translational modifications (PTMs) expand the structural diversity of proteins beyond the standard amino acids, influencing protein-protein interactions. Protein methylation, a prevalent PTM, involves the transfer of methyl groups from S-adenosylmethionine (SAM) to lysine and arginine residues. Arginine methylation is catalyzed by the Protein Arginine Methyltransferase (PRMT) family to yield mono- and dimethylarginine forms. PRMT1, the isozyme responsible for the majority of asymmetric dimethylation (ADMA) is implicated in various diseases, including cancer. Here, we report the synthesis and screening of a second-generation peptide library to identify novel PRMT1 substrates. The library, based on histone peptides, incorporated varying sequences of amino acids, facilitating substrate specificity studies. Screening identified 7 peptide sequences as exceptional PRMT1 substrates, which were confirmed by kinetic analysis. Consensus sequences revealed key recognition elements for PRMT1 catalysis, suggesting roles for small non-polar side chains and specific residues near the substrate arginine. Furthermore, we developed a peptide-based PRMT1 inhibitor by substituting the substrate arginine with a chloroacetamidine warhead. The inhibitor exhibited sub-micromolar inhibitory potency against PRMT1, surpassing previous peptide-based inhibitors. Our findings contribute to understanding PRMT1 substrate specificity and provide a scaffold for developing potent inhibitors targeting PRMT1 in diseases, including cancer. Full article
(This article belongs to the Special Issue Advances and Novel Strategies for Studying Underexplored Post-Translational Modifications (PTMs))
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Review

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27 pages, 3010 KB  
Review
Targeting the Reactive Proteome: Recent Advances in Activity-Based Protein Profiling and Probe Design
by Yuan-Fei Zhou, Ling Zhang, Zhuoyi L. Niu and Zhipeng A. Wang
Biomolecules 2025, 15(12), 1699; https://doi.org/10.3390/biom15121699 - 5 Dec 2025
Viewed by 548
Abstract
Activity-based protein profiling (ABPP) has emerged as a powerful chemical proteomics approach for profiling active amino acid residues, mapping functional proteins, and guiding covalent drug development in complex biological systems. Recent methodological advances have produced several novel formats, including tandem orthogonal proteolysis-ABPP (TOP-ABPP), [...] Read more.
Activity-based protein profiling (ABPP) has emerged as a powerful chemical proteomics approach for profiling active amino acid residues, mapping functional proteins, and guiding covalent drug development in complex biological systems. Recent methodological advances have produced several novel formats, including tandem orthogonal proteolysis-ABPP (TOP-ABPP), isotopic tandem orthogonal proteolysis-ABPP (IsoTOP-ABPP), and competitive IsoTOP-ABPP, enabling broader target identification and quantitative analysis for varied experimental purposes. In parallel, chemical probe design has evolved to selectively target specific amino acid residues, such as cysteine (Cys), lysine (Lys), and histidine (His), and to incorporate photoaffinity labeling (PAL) functionalities for capturing transient or weak protein-ligand interactions. Additionally, the integration of cleavable linkers with diverse cleavage mechanisms, including acid/base-mediated, redox-mediated, and photo irradiation mechanisms, has enhanced probe versatility and downstream analytical workflows. This review summarizes recent advances in ABPP methodologies and the design of activity-based probes and PAL probes, emphasizing their implications for future work in chemical biology. Full article
(This article belongs to the Special Issue Advances and Novel Strategies for Studying Underexplored Post-Translational Modifications (PTMs))
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20 pages, 1902 KB  
Review
Pyruvate Kinase M2 Links Metabolism and Epigenetics: A New Target for Liver Disease Treatment
by Xiaoya Zhang, Danmei Zhang, Jin Guo, Chunxia Shi and Zuojiong Gong
Biomolecules 2025, 15(9), 1327; https://doi.org/10.3390/biom15091327 - 17 Sep 2025
Viewed by 2179
Abstract
The aberrant activation of glycolysis plays a pivotal role in the progression of liver diseases. Pyruvate kinase M2 (PKM2), one of the rate-limiting enzymes of glycolysis, not only regulates cellular metabolism but also translocates to the nucleus in its dimeric form, acting as [...] Read more.
The aberrant activation of glycolysis plays a pivotal role in the progression of liver diseases. Pyruvate kinase M2 (PKM2), one of the rate-limiting enzymes of glycolysis, not only regulates cellular metabolism but also translocates to the nucleus in its dimeric form, acting as a co-factor to modulate gene transcription. To further explore the regulatory mechanisms of PKM2, this review outlines the effects of post-translational modifications on PKM2’s structure, activity, and localization, and discusses the integrative role of PKM2 in epigenetics and metabolism, providing a foundation for the development of PKM2 regulators. Due to PKM2’s distinct biochemical properties, targeting PKM2 with specific regulators may offer a promising therapeutic strategy for the treatment of liver diseases. Full article
(This article belongs to the Special Issue Advances and Novel Strategies for Studying Underexplored Post-Translational Modifications (PTMs))
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