Chemistry of Natural and Unnatural Protein Acylations

Date	30 May 2025
Time	5:00 pm - 6:00 pm (HKT)
Venue	Lecture Theatre P2, Chong Yuet Ming Physics Building
Speaker	Prof. Y. George Zheng
Institution	University of Georgia

Title:

Schedule:

Date: 30^th May, 2025 (Friday)

Time: 5 - 6 pm (HKT)

Venue: Lecture Theatre P2, Chong Yuet Ming Physics Building

Speaker:

Panoz Professor of Pharmacy

Prof. Y. George Zheng

University of Georgia

Abstract

Protein acetylation is widespread post-translational modification in eukaryotic and prokaryotic organisms. This type of PTM greatly diversifies protein functions by changing protein stability, nucleic acid binding, protein-protein interaction, etc. Most markedly, histone acetylation constitutes a leading epigenetic mechanism in the regulation of all DNA-mediated nuclear transactions. The specific acetylation is mediated by lysine acetyltransferases (KATs, also known as histone acetyltransferases, HATs). Many HAT members are found to be dysregulated in human diseases, especially oncological processes. Recent proteomic and biochemical screenings have revealed several types of novel lysine acylations which were previously unknown, including succinylation, malonylation, and fatty acylation (e.g. propionylation, butyrylation, crotonylation). Moreover, evidence has shown that some KATs not only have acetyltransferase activity but also non-acetyltransferase (e.g. propionyl- or butyryl-transferase) activities, implicating even broader functions of KATs. In this seminar, I will discuss two novel lysine acylations we recently discovered in histones in human cells. Both acylations, lysine isobutyrylation and lysine methacrylylation, are protein posttranslational modifications that are derived from key reactive metabolites in the valine metabolism pathway. Valine metabolic chemistry is conserved in all the eukaryotic cells. Dysregulation of valine metabolism is observed in several human pathophysiological conditions. In collaboration, we discovered multiple isobutyrylation and methacrylylation sites in nuclear histones. The gene expression profile is greatly impacted by cellular levels of isobutyrate and methacrylate. We performed detailed biochemical characterization of these new PTMs. The projected work establishes a novel connection of cellular metabolism with biological regulation, and expands current view of regulatory function of post-translational modifications in biology and disease. For the second topic, I will talk about the bioorthogonal profiling of protein acetylation strategy we developed to label and interrogate substrates of KAT enzymes. In this strategy, a suite of Ac-CoA analogs containing either alkynyl or azido functional group were synthesized as potential cofactor surrogate for selective labeling of KAT substrates. Meanwhile, the active site of the KATs was engineered in order to expand the cofactor binding capability of the enzymes to accommodate the bulkier synthetic cofactors. The acylated substrates can be selectively linked through the copper-catalyzed azide-alkyne cycloaddition reaction with fluorescent reporter or biotin affinity tag for optical imaging or protein enrichment on streptavidin-coated resin. We have successfully used this bioorthogonal technology to profile substrates of p300 and GCN5 and HAT1 in the context of complex cellular proteomes. The discovered proteins are extensively involved in various biological events including gene expression, cell cycle, and cellular metabolism. Our chemical biology strategy provides a powerful enabling technology for activity-based KAT substrate profiling on the proteomic scale.

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