Seminar: Understanding structure of Pyruvate kinase for an effective drug for cancers

Dr. Ashok Kumar Patel a Post Doctoral Research Associate at Department of Biophysics, John Hopkins University, Baltimore, USA, will visit the Department of Chemistry and Department of Physics. Dr. Patel is a protein crystallographer and working on chromatin remodeling, gene regulation, DNA repair and development of novel therapeutics for cancer.He obtained his PhD in 2009 under the mentorship of Prof. J. V. Medicherla from Molecular Biology Unit, Institute of Medical Sciences, BHU, Varanasi.

Title: (a) “Understanding remodeler to influence chromatin organization, providing novel tools for studying and potentially reversing chromatin abnormalities in cancerous cells”.

Abstract:
The packaging of eukaryotic chromosomes into chromatin controls gene expression. Activating gene expression requires removal of nucleosomes, and dynamic switching between repressive and permissive chromatin packaging depends on ATP- dependent machines called chromatin remodelers, which assemble, move, and evict nucleosomes from DNA. Disrupting remodelers and associated proteins that alter chromatin structure perturb gene regulation and can lead to cancer. At present, it is not understood how remodelers shift nucleosomes along DNA, nor how competition among remodelers gives rise to nucleosome positioning in vivo. Our goal is to use chromatin remodelers to gain a molecular understanding of nucleosome sliding, and to learn how competition between remodelers defines chromatin environments in vivo. A clear understanding of remodeling is essential for interpreting imbalances in genome-wide expression profiles in tumors, and developing treatments that rationally alter gene expression to block cancer cell proliferation. So, we are understanding how remodelers are targeted to either activate or repress gene transcription to enable development of new therapeutics that slow or stop the growth of cancerous cells through changes in chromatin structure.

Title: (b): “Understanding structure of Pyruvate kinase for an effective drug for cancers”
Abstract:
Cancerous cells result from a loss in proper regulation of gene expression: inhibition of tumor suppressors and cell-death pathways, and overexpression of oncogenes that stimulate proliferation. Pyruvate kinase catalyzes the last step within glycolysis, the dephosphorylation of phosphoenolpyruvate to pyruvate and is responsible for net ATP production. It is reported that Pyruvate kinase M2 (PKM2) isoform is responsible for the Warburg effect and various cancers like lung, renal, lever, gastrointestinal etc. Further By chemically modifying histone proteins and changing histone positioning on DNA, PKM2 affects gene expression and silencing and results in brain tumor. We are understanding the structure of PKM2 and finding a drug for the cancer therapy. We are studying the mechanism of drug by co-crystallizing it with the PKM2 protein.