Protein‐Metabolite Interactions: Discovery and Significance

Abstract

Metabolites orchestrate cellular processes as either substrates, co-enzymes, inhibitors, or activators of cellular proteins such as enzymes and receptors. Although traditional biochemical and structural biology-based approaches have been successfully employed for the discovery of protein-metabolite interactions, they often fail to detect transient and low-affinity biomolecular relationships. Another limitation of these approaches is that they are performed under in vitro conditions lacking the physiological context. Recently developed mass spectrometrybased methodologies overcome both these shortcomings, and have resulted in the discovery of global protein-metabolite cellular interaction networks. Herein, we describe traditional and modern approaches for the discovery of protein-metabolite interactions, and discuss the impact of these discoveries on our understanding of cellular physiology and on drug development.

Arachidonic acid released by PIK3CA mutant tumor cells triggers malignant transformation of colonic epithelium by inducing chromatin remodeling

“…Protein-metabolite interactions (PMIs) are specific interactions that play a crucial role in various cellular processes and modulate signal transduction by affecting the conformation, stability, and function of target proteins through allosteric modulation. 35 , 36 , 37 However, PMIs often exhibit low affinity and are challenging to systematically identify. In the present study, we developed an immunoprecipitation integrated with an LC-MS/MS approach to quantify trace-level ligand-based metabolites and characterize PMIs by enriching proteins with metabolites.…”

Decoding the molecular interplay in the central dogma: An overview of mass spectrometry‐based methods to investigate protein‐metabolite interactions

“…With the rapid development and use of ‐omics technologies, it is increasingly apparent that key metabolites influence cellular pathways which have facilitated the development of small molecule therapeutics [45, 46]. Despite significant advances in genetic and proteomic techniques such as photoaffinity labeling‐based chemoproteomic methods [see 11, 47–49 for comprehensive reviews], a complete portrait of the proteome and its dynamic interactions and modifications still remains elusive [50]. The protein folding equilibrium can be influenced by the preferential binding of ligands to either the native or unfolded state of the protein, leading to a change in the target protein's susceptibility to thermal or chemical (enzymatic or solvent) denaturation.…”

“…In this review, we aim to summarize information on protein‐metabolite interactions that play a significant role in drug (target) discovery. Complementary to other recent reviews [11, 12], we provide an overview of the evolving tools and methods utilized for metabolite‐protein interaction in the field of mass spectrometry. We start with methods to probe single protein‐metabolite interaction and progress through the hierarchy of complexity concluding with large‐scale proteome‐metabolome methods and computational tools.…”