Pyruvate carboxylase is a mitochondrial enzyme that converts pyruvate into oxaloacetate by adding a carboxyl group. Oxaloacetate is an essential metabolite in the tricarboxylic acid cycle (Utter and Keech, 1960) which fuels several anabolic biosynthetic reactions such as gluconeogenesis, lipogenesis, insulin secretion, and synthesis of glutamate neurotransmitter (Jitrapakdee et al., 2008). Malfunction of this enzyme is associated to metabolic disorders that predominantly manifest with lactic acidemia and neurological dysfunction (Marin-Valencia et al., 2010).
In this project, I combined cryo-electron microscopy and molecular dynamics flexible fitting in order to reveal the conformational landscape of this important metabolic enzyme during its catalytic cycle.
Publications related to this project
- Lasso G, Yu LP, Gil D, Lázaro M, Tong L, Valle M (2014). Functional conformations for pyruvate carboxylase during catalysis explored by cryoelectron microscopy. Structure. Jun 10;22(6):911-22
- Lasso G, Yu LP, Gil D, Xiang S, Tong L, Valle M (2010). Cryo-EM analysis reveals new insights into the mechanism of action of pyruvate carboxylase. Structure. 18(10):1300-10.
- Yu LP, Xiang S, Lasso G, Gil D, Valle M, Tong L (2009). A symmetrical tetramer for S. aureus pyruvate carbosylase in complex with coenzyme A. Structure. 10;17(6):823-32.