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Metabolic signaling pathways in the regulation of cell division

Dr. Praveen Kumar, Malaviya Postdoctoral Fellow (MPDF), Department of Medicinal Chemistry Institute of Medical Sciences, Banaras Hindu University

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Location : Online
Abstract: Signaling and metabolic pathways orchestrate cellular responses which in turn dictates the cellular metabolome and phenotype. These play a central role in cellular behavior in diseases. In two of the projects that I completed will indicate how this supportive crosstalk affects the biological systems and provides vulnerabilities in metabolic and infectious diseases and can be targeted for drug development.
Cancer biology: A lack of understanding of Cell cycle-based heterogeneity in cell metabolism
poses severe challenges in cancer therapy. LC-MS based characterization of the cell cycle metabolome revealed significant cell cycle associated changes in 57 metabolites. Time resolved flux analysis revealed that activity of metabolic pathways oscillates in cyclic manner according to the cell cycle stages. Complementary cyclic oscillations in the glucose and glutamine metabolism were observed during the cell cycle, which revealed glutamine metabolism is essential for G1/S to S/G2 phase transition. Disruption of oscillations of the normal metabolic pathways during cell cycle hampered the cell cycle and thus limited cell growth, which can be further tailored for drug development. Identification of similar vulnerabilities in cancer metabolism will open new avenues for the discovery of novel chemotherapeutics.
Malaria: Malaria parasite has a paucity of transcription factors suggesting the role of signaling molecules such as kinases in developmental stage transitions. Calcium dependent protein kinases (CDPKs) are unique and important kinases of the human malaria parasite Plasmodium falciparum (Pf). PfCDPK7 is an effector of phosphoinositide signalling, which represents an attractive drug target and unique function. PfCDPK7 showed expression during all the blood stages but had a very specific perinuclear localization confined to single membrane bound vesicles. Complete gene deletion of PfCDPK7 hampered parasite growth as well as parasite maturation from rings to trophozoites. Proliferation of the parasite was also significantly altered in PfCDPK7-knock out (PfCDPK7-KO) parasites, which was attributed to malformed tubulovesicular network inside the parasite hampering nutrient uptake from the erythrocytes. Subsequently, phosphoproteomics and lipidomics analyses of PfCDPK7-KO parasites demonstrated that this kinase is involved in phospholipid biosynthesis downstream to PI4K, which was demonstrated using a PI4K inhibitor which is under phase 1 clinical trials. Developing a deeper understanding of the parasite signaling and metabolic networks is crucial for novel drug development and targeting drug resistant malaria.

Meeting ID: 930 3672 5576
Passcode: 685428

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