Inositol is a ubiquitous six-carbon cyclitol that is essential for viability of eukaryotic cells. Inositol compounds play pivotal roles in cell signaling and metabolism, and regulate virtually every aspect of cellular physiology. Consistent with its importance, perturbation of inositol metabolism is associated with pathologies as diverse as neurological and psychiatric illnesses, myopathies, cancer, and diabetes. In this light, it is striking that almost nothing is known about how inositol synthesis is regulated in mammalian cells. The goal of the proposed research is to elucidate the molecular mechanisms that regulate inositol synthesis. To this end, we have exploited yeast genetics to identify novel mechanisms of regulation of inositol synthesis, and mammalian cells to test hypotheses generated by the yeast studies. Using this approach, we identified three novel mechanisms of regulation of inositol synthesis, which are the focus of this proposal.
Aim 1 will elucidate the mechanism whereby phosphorylation regulates myo- inositol-3-phosphate synthase (MIPS), which catalyzes the rate-limiting step in inositol de novo synthesis.
Aim 2 will test our hypothesis that MIPS is regulated by metabolic channeling of the common intermediate, glucose-6-phosphate, and that down-regulation of inositol synthesis is triggered by increased demand for glycolysis.
Aim 3 will determine the physiological significance of transcriptional control of mammalian INO1 expression by inositol pyrophosphate synthase (IP6K1). We expect these studies to generate the first molecular model of regulation of inositol synthesis in mammalian cells. The model will suggest a new paradigm with which to understand how cross talk between glycolysis and inositol synthesis regulates these essential metabolic pathways. The outcome of these studies will contribute to our understanding of essential cellular processes that require inositol, and open the door to the development of new therapeutics for the treatment of bipolar disorder, epilepsy, and other illnesses in which inositol homeostasis is perturbed.
? PUBLIC HEALTH RELEVANCE Inositol is essential for the viability of eukaryotic cells. Myo-inositol is the precursor of all inositol compounds, which play pivotal roles in cell signaling and metabolism. Perturbation of inositol metabolism is associated with pathologies as diverse as neurological and psychiatric illnesses, myopathies, cancer, and diabetes. Surprisingly, almost nothing is known about how inositol synthesis is regulated in human cells. The proposed studies aim to generate the first molecular model of mammalian inositol synthesis. This knowledge will advance our basic understanding of this essential metabolic pathway and provide a foundation to understand numerous disease processes that result from perturbation of inositol homeostasis. These studies will also contribute new insights into the mechanism of action of the critically important inositol-depleting drug valproate, which is used to treat bipolar disorder, epilepsy, and other illnesses. The outcome of these studies may, thus, suggest new strategies for the design of second-generation pharmaceuticals to treat these illnesses.
| Yedulla, Nikhil R; Naik, Akshata R; Kokotovich, Keith M et al. (2018) Valproate inhibits glucose-stimulated insulin secretion in beta cells. Histochem Cell Biol 150:395-401 |
| Salsaa, Michael; Case, Kendall; Greenberg, Miriam L (2017) Orchestrating phospholipid biosynthesis: Phosphatidic acid conducts and Opi1p performs. J Biol Chem 292:18729-18730 |
