Coenzyme A (CoA) is an essential cofactor that is emerging as a key regulator of energy metabolism and glucose homeostasis. CoA levels are tightly controlled and dynamically adjusted to support the changes in nutrient utilization that occur between the fed and fasted states. The importance of such a tight control over the concentration of this cofactor is underscored by the fact that loss of regulation and abnormally high CoA levels in the liver of diabetic mice significantly contribute to the excessive glucose production and hyperglycemia of these animals. Conversely, genetic manipulations that reduce the concentration of hepatic CoA decrease glucose synthesis and blood glucose. These findings underscore the potential of modulating CoA levels in selected organs to correct deranged metabolism and hyperglycemia. Nudix hydrolase 7 and 19, Nudt7 and Nudt19, are two recently identified CoA-degrading enzymes whose expression is limited to the liver and kidneys, respectively. This expression pattern and their ability to degrade CoA specifically make Nudt7 and Nudt19 ideal targets to manipulate CoA levels and energy metabolism in organs that play a key role in the maintenance of glucose homeostasis. Indeed, our preliminary results support the conclusion that these peroxisomal enzymes actively contribute to the regulation of tissue CoA, glucose and fatty acid metabolism in vivo; however, critical mechanistic details are currently missing. Our goal is to characterize the mechanisms through which Nudt7 and Nudt19 regulate lipid and carbohydrate metabolism in liver and kidney and to develop approaches to modulate the activity of these enzymes. To achieve this, we will characterize 1) the biochemical and structural properties of Nudt7 and Nudt19, 2) the signaling pathways that regulate Nudt7 gene expression in the liver, 3) the role of Nudt7-mediated degradation in carbohydrate and lipid metabolism in the liver and 4) the role of Nudt19-mediated degradation in carbohydrate and lipid metabolism in the kidneys. This research program will advance our understanding of the mechanisms that control a key metabolic regulator like CoA and define the so far under-appreciated role of peroxisomal pathways in the regulation of glucose metabolism. Additionally, these studies on Nudt7 and Nudt19 will aid the development of pharmacological and/or nutritional strategies to manipulate CoA levels and reverse dysregulated metabolism.
Coenzyme A (CoA) is a key regulator of energy metabolism and a cofactor whose levels need to be tightly regulated to maintain whole-body glucose homeostasis. Although two recently discovered enzymes, Nudt7 and Nudt19, can modulate the concentration of this cofactor by accelerating its degradation in liver and kidney, critical details about the structure, regulation and in vivo function of these CoA-degrading enzymes are currently missing. The research program described herein will fill this knowledge gap and establish the potential of targeting the activity of Nudt7 and Nudt19 to correct deranged metabolism and hyperglycemia, conditions characterized by the loss of CoA regulation.
|Shumar, Stephanie A; Kerr, Evan W; Geldenhuys, Werner J et al. (2018) Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform. J Biol Chem 293:4134-4148|
|Corbin, Deborah R; Rehg, Jerold E; Shepherd, Danielle L et al. (2017) Excess coenzyme A reduces skeletal muscle performance and strength in mice overexpressing human PANK2. Mol Genet Metab 120:350-362|