The long-term goal is to define the mechanisms that control the intracellular concentration of CoA and understand the physiological significance of this regulatory system. CoA is an essential acyl group carrier, and is produced by a universal series of reactions starting from the vitamin pantothenate (Pan). Pan is an abundant vitamin and under normal physiological circumstances is present in significant excess over the amounts needed to support CoA biosynthesis. Fine control over CoA levels is important to support physiological adjustments in intermediary metabolism not only because CoA and its thioesters are key cofactors in energy generating pathways, but they also allosterically control carbon flux at key metabolic control points. It is clear that the cellular activity of Pan kinase (PanK) regulates CoA biosynthesis and there are two mechanisms that govern this parameter. First, feedback inhibition of PanK by CoA and its thioesters establishes the upper limit for the cellular CoA concentration at a specific level of PanK expression. Second, the steady state CoA level is adjusted by altering PanK gene expression. The intracellular CoA levels fluctuate in response to hormones, diet, and drugs, and are also dysregulated in metabolic disorders. There are multiple PanK genes that exhibit tissue specific expression, and the importance of specific isozyme expression is underscored by the finding that mutations in the human PANK2 gene are responsible for a hereditary neuropathy. We hypothesize that changes in CoA levels are a prerequisite for altering the balance between fatty acid utilization and storage, and that elevation of PanK isozyme expression is necessary for functional peroxisome proliferation and fatty acid oxidation. CoA biosynthesis has been a neglected research area, but our recent identification and preliminary characterization of the PanK genes, cDNAs and proteins open the door to the molecular dissection of the importance of these gene products to the control of mammalian intermediary metabolism. The Research Plan is organized around two aims: 1) To characterize the PanK isozymes and define the biochemical mechanisms that regulate their activity; and 2) To define the mechanisms that lead to altered PanK gene expression and the metabolic importance of controlling CoA levels. This research will contribute to the understanding of global metabolic control and human disease by defining the importance of CoA regulation by specific PanK isozymes. ? ?
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