Entabolons: how metabolites modify the biochemical function of proteins and cause the correlated behavior of proteins in pathways.

Skolnick, Jeffrey; Srinivasan, Bharath; Skolnick, Samuel; Edelman, Brice; Zhou, Hongyi

Abstract

Although there are over 100,000 distinct human metabolites, their biological significance is often not fully appreciated. Metabolites can reshape the protein pockets to which they bind by COLIG formation, thereby influencing enzyme kinetics and altering the monomer-multimer equilibrium in protein complexes. Binding a common metabolite to a set of protein monomers or multimers results in metabolic entanglements that couple the conformational states and functions of nonhomologous, nonphysically interacting proteins that bind the same metabolite. These shared metabolites might provide the collective behavior responsible for protein pathway formation. Proteins whose binding and functional behavior is modified by a set of metabolites are termed an "entabolon"─a portmanteau of metabolic entanglement and metabolon. 55%-60% (22%-24%) of pairs of nonenzymatic proteins that likely bind the same metabolite have a p-value that they are in the same pathway, which is <0.05 (0.0005). Interestingly, the most populated pairs of proteins common to multiple pathways bind ancient metabolites. Similarly, we suggest how metabolites can possibly activate, terminate, or preclude transcription and other nucleic acid functions and may facilitate or inhibit the binding of nucleic acids to proteins, thereby influencing transcription and translation processes. Consequently, metabolites likely play a critical role in the organization and function of biological systems.

Citation

SKOLNICK, J., SRINIVASAN, B., SKOLNICK, S., EDELMAN, B. and ZHOU, H. 2025. Entabolons: how metabolites modify the biochemical function of proteins and cause the correlated behavior of proteins in pathways. Journal of chemical information and modeling [online], ASAP articles. Available from: https://doi.org/10.1021/acs.jcim.5c00462

• Journal Article Type: Article
• Acceptance Date: May 7, 2025
• Online Publication Date: May 16, 2025
• Deposit Date: May 29, 2025
• Publicly Available Date: May 29, 2025
• Journal: Journal of chemical information and modeling
• Print ISSN: 1549-9596
• Electronic ISSN: 1549-960X
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1021/acs.jcim.5c00462
• Keywords: Ligands; Metabolism; Monomers; Oligomers; Peptides and proteins
• Public URL: https://rgu-repository.worktribe.com/output/2849091
• Related Public URLs: https://rgu-repository.worktribe.com/output/2849119 (Journal article output)