Novel mechanisms of protein post-translational modifications regulated by multiple metabolites and strategies for drug screening

<p indent="0mm">Metabolites are the primary donors for the modification of biomacromolecules, and changes in metabolites caused by environmental or cellular stress signals are also integrated into life signal networks. Classical post-translational modifications (PTMs), such as protein phosphorylation, acetylation, and methylation use energy or substance-indicating metabolites like ATP, acetyl-CoA, and <italic>S</italic>-adenosyl methionine (SAM) as substrates to convey common metabolic signals. Our research has found that metabolites can regulate other PTMs through different mechanisms outside of their role as donors: Crotonyl-CoA can act as an acyl donor to promote the crotonylation of cell cycle-dependent EB1 protein, maintaining genomic stability; α-KIV and α-KG can respectively regulate protein phosphorylation and hydroxylation modifications, mediating TCR signaling pathways and Hedgehog signaling pathway. In addition, natural metabolites can also promote the ubiquitination and degradation of AD-related proteins. Based on the new mechanisms of metabolite regulation of post-translational modifications, we have high-throughput screened small molecule inhibitors of the transient receptor potential vanilloid channel 3 protein (TRPV3) and dipeptidyl peptidase-4 (DPP4), using key proteins in pathological processes as examples, providing new ideas for the development of innovative drugs and the intervention of diseases.