Protein Post-translational Modifications (PTMs): Small Changes, Big Impact

Dr. Sushabhan Sadhukhan
Thu, 12th Jul, 2018 11:00 amAdd to Calendar 2018-07-12 11:00:00 2018-07-12 11:00:00 Title Description Location IIT Palakkad UTC public
Thu, 12th Jul, 2018 12:00 pm

Protein post-translational modifications (PTMs) refer to the covalent addition of functional groups onto a protein. They offer another dimension to the functional diversity of the proteins and allow them to do chemistry that is otherwise difficult. Thus, a deeper understanding on the regulatory mechanism of different PTMs can provide critical insights into various underlying cellular processes. In this talk, I will share two PTM-related stories from a chemical biology standpoint. The first one deals with the fate of a lipid-derived electrophile, 4-hydroxy-2-(E)-nonenal (4-HNE) that can lead to several PTMs. Herein, I will describe how we figured out the tactic that cell uses to eliminate 4- HNE and protects biomacromolecules (e.g., protein, DNA, etc.) from getting modified by 4-HNE. This uncovered a novel parallel catabolic pathway of 4-HNE using a combination of strategic synthesis of a number of stable isotopically (2H, 13C) labeled 4-HNE and their metabolomics. In the second case, the comprehensive metabolomics and proteomics studies will be presented that led us to identify the major physiological function of a recently recognized PTM, protein lysine succinylation by succinyl-CoA. This PTM can only be reversed by Sirtuin 5 or SIRT5, an NAD+ -dependent deacylase. Although numerous proteins undergo this modification, its physiological significance remained unknown. We found that protein lysine succinylation predominantly accumulates in the heart when Sirt5 is absent. Sirt5-deficient mice exhibited defective fatty acid metabolism, decreased ATP production, and hypertrophic cardiomyopathy. Taken together, these findings revealed that a major physiological role of lysine succinylation and SIRT5 is to regulate cardiac metabolism and function. Finally, I will conclude with a glimpse of novel chemical biology approaches that we are developing in our lab at IIT Indore to further advance the understanding on regulatory mechanism of other important PTMs by designing small molecule inhibitors as well as activity-based probes. I will also talk about the chemoproteomics approach that we are establishing to elucidate the mechanism of action of various phytochemicals such as curcumin, and epigallocatechin-3-gallate (EGCG), a green tea polyphenol.

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