Roberta Leonardi, PhD

Research Interests

Coenzyme A (CoA) is an essential and universally distributed cofactor that acts as the major acyl group carrier in the cell, from bacteria to humans. Free CoA and the derived acyl-CoAs are substrates for hundreds of metabolic reactions and for the post-translational modification (acylation) of histones and thousands of non-histone proteins. This allows CoA to regulate the output of metabolic pathways through both substrate availability, modulation of the activity of metabolic enzymes, and gene expression. Consistent with the essential function of this cofactor in metabolism, total CoA levels are tightly regulated and dynamically adjusted to respond to changes in the metabolic state (fasting, feeding, diabetes). In the liver, such regulation is important to control lipid and glucose metabolism, with abnormally high or abnormally low CoA levels leading to hyperglycemia and hypoglycemia, respectively. Decreased CoA synthesis and CoA levels are suspected to underlie the neurodegeneration that characterizes two rare genetic disorders called PKAN and CoPAN; however, the disease mechanisms are currently unclear. In skeletal muscle, excess CoA is associated with decreased ATP levels, oxidative damage, and muscle weakness. This evidence points to the importance of maintaining CoA levels within a fairly narrow and ‘healthy’ range.

Regulation of CoA levels occurs through the coordination of synthesis and degradation. CoA synthesis occurs in every cell and organ and is the universal source of this cofactor for all metabolic reactions. Based on the localization and tissue distribution of the known CoA-degrading enzymes of the Nudix family, CoA degradation is expected to be a very active process in select organs, such as the liver, kidneys, heart and brown adipose tissue, and to occur in specific subcellular compartments, i.e. mitochondria and peroxisomes. These properties of the CoA-degrading enzymes we study in the lab, Nudt7, Nudt8 and Nudt19, provide an opportunity to selectively manipulate specific CoA-dependent processes and avoid the adverse effects linked to a global imbalance in CoA levels. The goal of our research is to characterize the structural and regulatory properties of Nudt7, Nudt8 and Nudt19, and to establish the role that these enzymes play in the regulation of 1) total and subcellular (mitochondrial and peroxisomal) CoA levels and 2) nutrient utilization in the liver, kidneys, heart and brown adipose tissue, organs that play a key role in the regulation of whole-body energy homeostasis. This knowledge will allow us to devise strategies to manipulate CoA levels and correct the dysregulated metabolism that underlies a variety of diseases, including diabetes, cancer, and neurodegeneration. In our research, we combine multiple in vitro and in vivo approaches including enzymology, structural biology, metabolomics, cell culture, and genetic manipulations in mice.

Publications

Selected Peer-Reviewed Articles:

Naquet, P.,  Kerr,  E. W.,  Vickers, S. D. , and Leonardi R. (2020)  “Regulation of coenzyme A levels by degradation: the 'Ins and Outs'”. Prog. Lipid Res  78, 101028

Kerr, E. W., Shumar, S. A., and Leonardi, R. (2019) "Nudt8 is a novel CoA diphosphohydrolase that resides in the mitochondria". FEBS Lett. 593, 1133-1143

Shumar, S. A., Kerr, E. W., Fagone, P., Infante, A. M., and Leonardi, R. (2019) "Overexpression of Nudt7 decreases bile acid levels and peroxisomal fatty acid oxidation in the liver". J. Lipid Res. 60, 1005-1019

Shumar, S. A., Kerr, E. W., Geldenhuys, W. J., Montgomery, G. E., Fagone, P., Thirawatananond, P., Saavedra, H., Gabelli, S. B., and Leonardi, R. (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, D.R., Rehg, J.E., Shepherd D.L., Stoilov, P., Percifield, R.J., Horner, L., Frase, S., Zhang, Y.M., Rock, C.O., Hollander, J.M., Jackowski, S. and Leonardi, R. (2017) "Excess coenzyme A reduces skeletal muscle performance and strength in mice overexpressing human PANK2" Mol. Genet. Metab. 120, 350-362

Shumar, S. A., Fagone, P., Alfonso-Pecchio, A., Gray, J. T., Rehg, J. E., Jackowski, S. and Leonardi, R. (2015) "Induction of Neuron-Specific Degradation of Coenzyme A Models Pantothenate Kinase-Associated Neurodegeneration by Reducing Motor Coordination in Mice", PLoS One. 2015 Jun 8;10(6):e0130013

Sharma, L. K., Leonardi, R., Lin, W., Boyd, V. A., Goktug, A., Shelat, A. A., Chen, T., Jackowski, S., and Rock, C. O. (2015) "A high-throughput screen reveals new small-molecule activators and inhibitors of pantothenate kinases", J. Med. Chem. 58, 1563-1568

Leonardi, R., Rock, C. O., and Jackowski, S., (2014) "Pank1 deletion in leptin-deficient mice reduces hyperglycaemia and hyperinsulinaemia and modifies global metabolism without affecting insulin resistance", Diabetologia 57, 1466-1475

Alfonso-Pecchio, A., Garcia, M., Leonardi, R., and Jackowski, S., (2012) "Compartmentalization of mammalian pantothenate kinases", PLoS One 7, e49509. PMCID: PMC3496714.

Garcia, M., Leonardi, R., Zhang Y.-M., Rehg, J. E., and Jackowski, S. (2012) "Deletion of pantothenate kinases 1 and 2 disturbs glucose and ketone metabolism", PLoS One 7, e40871. PMCID: PMC3398950.

Cherian, P. T, Yao, J., Leonardi, R., Maddox, M. M., Luna, V. A., Rock, C. O., and Lee, R. E. (2012) "Acyl-sulfamates target the essential glycerol-phosphate acyltransferase (PlsY) in Gram-positive bacteria", Bioorg. Med. Chem. 20, 4985-4994. PMCID: PMC3471809.

Leonardi, R., Subramanian, C., Jackowski, S., and Rock, C. O. (2012) "Cancer-associated isocitrate dehydrogenase mutations inactivate NADPH-dependent reductive carboxylation", J. Biol. Chem. 287, 14615-14620. PMCID: PMC3340216.

Zhang, K., Wang, S., Malhotra, J., Hassler, J. R., Back, S. H., Wang, G., Chang, L., Xu, W., Miao, H., Leonardi, R., Chen, Y. E., Jackowski, S., and Kaufman, R. J. (2011) "The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis", EMBO J. 30, 1357-1375. PMCID: PMC3094110.

Book Chapters, Reviews and Other Articles:

Jackowski, S., and Leonardi, R. (2014) "Deregulated coenzyme A, loss of metabolic flexibility and diabetes", Biochem. Soc. Trans. 42, 1118-1122

Leonardi, R., and Jackowski, S. (2013) "Coenzyme A: when small is mighty" ASBMB today 12, 56-57

Leonardi, R., and Jackowski, S. (2007) "Biosynthesis of Pantothenic acid and Coenzyme A, in: EcoSal-Escherichia coli and Salmonella: cellular and molecular biology". [Online] Module 3.6.3.4. http//www.ecosal.org. ASM Press, Washington, DC

Leonardi, R., Zhang, Y.-M., Rock, C. O., and Jackowski, S. (2005) "Coenzyme A: Back in action", Prog. Lipid Res. 44, 125-153