Department of Chemistry Seminar - Decoding Metabolite-Derived Protein Post-Translational Modifications: Chemical Tools, New Biology, and Therapeutics

Speaker: Prof. Qingfei ZHENG

Institution: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, US

Hosted by: Prof. Dalu CHANG

Abstract

Metabolites are increasingly recognized as signaling molecules that can directly modify proteins and reshape their functions. Our laboratory investigates these metabolite-derived protein post-translational modifications (PTMs) at the interface of metabolism, the gut microbiome, and human disease. By integrating chemical biology, protein engineering, synthetic chemistry, and chemical proteomics, we develop molecular tools to discover new PTMs and define their biological and therapeutic significance. A major focus of our work is protein monoaminylation, an emerging class of PTMs in which monoamine metabolites—including serotonin, dopamine, histamine, and norepinephrine—are covalently incorporated into proteins through transglutaminase (TG)-catalyzed transamidation. We discovered that transglutaminase 2 (TG2) dynamically installs, removes, and replaces monoaminylation and have developed chemical and synthetic biology approaches to map the monoamine-modified proteome. These studies uncovered functionally important modifications in cancer, including histaminylation of histone H2AX and norepinephrinylation of PTPN11/SHP2, revealing new links between metabolite signaling, chromatin regulation, DNA damage responses, and oncogenic signaling. More broadly, clickable chemical probes enabled us to map more than 9,000 TG-reactive glutamine sites across the human proteome that may be modified by host- and microbiome-derived metabolites. Finally, guided by mechanistic insights into TG biochemistry, we are developing first-in-class TG2 inhibitors, providing opportunities to translate metabolite-driven protein chemistry into new therapeutic strategies.