Acetyl-coenzyme A (acetyl-CoA) carboxylases (ACCs), pyruvate carboxylase (PC), carnitine acyltransferases, and AMP-activated protein kinase (AMPK) play crucial roles in the metabolism of fatty acids and/or carbohydrates, as well as other important cellular processes. ACCs catalyze the biotin-dependent carboxylation of acetyl-CoA to produce malonyl-CoA, and are crucial for the biosynthesis and oxidation of long-chain fatty acids. ACC2-/- mice have elevated fatty acid oxidation and reduced body fat and body weight, suggesting that an inhibitor against ACC2 may be efficacious in the control of body weight and obesity. PC catalyzes the carboxylation of pyruvate to produce oxaloacetate. It is crucial for removing pyruvate from tissues, and the oxaloacetate product is important for gluconeogenesis, fatty acid biosynthesis, and glucose-induced insulin secretion. PC deficiency is linked to lactic acidosis and mental retardation in humans. Carnitine acyltransferases catalyze the exchange of acyl groups between carnitine and CoA. The carnitine palmitoyltransferases (CPTs) have crucial roles in the ?-oxidation of fatty acids in the mitochondria, and the malonyl-CoA product of ACC2 is a potent inhibitor of the CPT-I enzymes. Deficiencies in CPT-Is are linked to hypoketonemia, hypoglycemia and other diseases. AMPK is a master metabolic regulator and controls many processes in the cell. Mutations in its g subunit have been linked to many human diseases including Wolff-Parkinson-White (WPW) syndrome. The recent onset of the obesity epidemic has generated significant renewed interests in these important metabolic enzymes. During the previous funding period, we produced a large amount of structural and biochemical data on ACC and the carnitine acyltransferases that have greatly enhanced our understanding of these enzymes. However, many significant questions remain unanswered, and currently there is insufficient structural information on PC and AMPK. To fill these gaps in our knowledge, we propose to continue the biochemical, biophysical and structural studies on ACC and carnitine acyltransferases, as well as initiate such studies on PC and AMPK. The proposed research should provide significant new insights into the mechanism and regulation of these enzymes, and provide a foundation for the design and development of their inhibitors or agonists.
The recent onset of the obesity epidemic has generated significant renewed interests in fatty acid and carbohydrate metabolism. Our proposed research will produce detailed structural and biochemical information on these important metabolic enzymes, laying the foundation for the design and development of novel inhibitors/agonists that could be efficacious in the clinic.
|Lasso, Gorka; Yu, Linda P C; Gil, David et al. (2014) Functional conformations for pyruvate carboxylase during catalysis explored by cryoelectron microscopy. Structure 22:911-22|
|Sureka, Kamakshi; Choi, Philip H; Precit, Mimi et al. (2014) The cyclic dinucleotide c-di-AMP is an allosteric regulator of metabolic enzyme function. Cell 158:1389-401|
|Tong, Liang (2013) Structure and function of biotin-dependent carboxylases. Cell Mol Life Sci 70:863-91|
|Froese, D Sean; Forouhar, Farhad; Tran, Timothy H et al. (2013) Crystal structures of malonyl-coenzyme A decarboxylase provide insights into its catalytic mechanism and disease-causing mutations. Structure 21:1182-92|
|Tan, Dazhi; Crabb, Warren M; Whitman, William B et al. (2013) Crystal structure of DmdD, a crotonase superfamily enzyme that catalyzes the hydration and hydrolysis of methylthioacryloyl-CoA. PLoS One 8:e63870|
|Yu, Linda P C; Chou, Chi-Yuan; Choi, Philip H et al. (2013) Characterizing the importance of the biotin carboxylase domain dimer for Staphylococcus aureus pyruvate carboxylase catalysis. Biochemistry 52:488-96|
|Huang, Christine S; Ge, Peng; Zhou, Z Hong et al. (2012) An unanticipated architecture of the 750-kDa ?6?6 holoenzyme of 3-methylcrotonyl-CoA carboxylase. Nature 481:219-23|
|Fan, Chen; Chou, Chi-Yuan; Tong, Liang et al. (2012) Crystal structure of urea carboxylase provides insights into the carboxyltransfer reaction. J Biol Chem 287:9389-98|
|Chou, Chi-Yuan; Tong, Liang (2011) Structural and biochemical studies on the regulation of biotin carboxylase by substrate inhibition and dimerization. J Biol Chem 286:24417-25|
|Corbett, Jeffrey W; Freeman-Cook, Kevin D; Elliott, Richard et al. (2010) Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2. Bioorg Med Chem Lett 20:2383-8|
Showing the most recent 10 out of 33 publications