Date of Award
Master of Science (MS)
Understanding how conformational dynamics play a role in metabolic regulation is an important objective in various biological disciplines. Using Molecular Dynamics (MD) simulations, we attempt to elucidate the dynamics involved in regulating two glycolytic enzymes: human liver pyruvate kinase (hL-PYK) and human enolase. Despite being metabolically coupled, both enzymes are regulated quite differently: hL-PYK can undergo allosteric modulation, while enolase is competitively inhibited. In the hL-PYK study, we discern a mechanism of allostery induced by the allosteric activator fructose-1,6-bisphosphate, and the inhibitor alanine. In the case of enolase, previous studies have attempted to make isoform-specific inhibitors of the enzyme; to further explore this objective, we compare the dynamics of two conserved isozymes, enolase 1 and 2, through MD simulations. As a proof of concept, we find compounds that discriminate between the two homologues by performing ensemble virtual screening on MD derived free enolase structures.
Shouaib, Abdullah, "Exploring the Dynamics of Glycolytic Regulation Through Two Enzymes: Human Enolase and Liver Pyruvate Kinase." Thesis, Georgia State University, 2019.
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