Coenzyme A (CoA) is an essential cofactor required for hundreds of metabolic processes. Because it is such a critical cofactor, CoA levels are tightly regulated. In diabetic mice, an abnormally high concentration of CoA in the liver drives excess glucose production and contributes to the hyperglycemia of these animals. This phenotype is associated with constitutively low CoA degradation, a process that is emerging as a potentially important mechanism for CoA regulation. Nudt7 and Nudt19 are two mammalian peroxisomal enzymes with CoA-degrading activity, which are highly expressed in the liver and kidney, respectively. Limited information is available on the biochemistry of Nudt7 and Nudt19; the structural basis for their distinct features and the extent to which Nudt7 and Nudt19 contribute to maintaining homeostatic CoA levels in vivo are currently unknown. The proposed research will use a combination of techniques including mutagenesis, molecular modeling, enzymatic assays on purified proteins, and targeted metabolite analysis in whole tissue homogenates and subcellular fractions to: 1) characterize the biochemical, structural, and regulatory properties of Nudt7 and Nudt19 and 2) determine the effects that genetic manipulations of Nudt7 have on subcellular CoA levels in mouse liver and on glucose metabolism. This research will establish the importance of degradation in the regulation of CoA and the potential of targeting this process to control and correct dysregulated metabolism in the liver and kidneys.
Loss of CoA regulation, especially in the liver, disrupts lipid and glucose metabolism and underlies the hyperglycemia that characterizes the diabetic state. Not only will this study characterize the biochemical features of two enzymes, Nudt7 and Nudt19, which are responsible for degradation of CoA in the peroxisomes of the liver and kidneys, it will also determine the contribution of Nudt7-mediated CoA degradation to the regulation of hepatic CoA levels and glucose homeostasis.
| 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 |
