An intricate balance existing within the various signaling pathways has to be maintained for survival and normal functioning of human cells. Detrimental effects causing human disease can occur due to obstruction in this equilibrium. For instance, an important signaling pathway is the sphingolipid metabolism pathway. Ceramide and sphingosine are both bioactive sphingolipids and have both been implicated in cell growth arrest. Ceramide is produced via two major pathways in cells: a slow de novo synthesis pathway that is catalyzed by ceramide synthases and by a relatively faster method wherein sphingomyelin is hydrolyzed by sphingomyelinases such as neutral sphingomyelinase 2 (nSMase2). Additionally, sphingosine kinase 1 (SK1), one of two sphingosine kinase enzymes, is a highly regulated enzyme due to SK1's critical role in the clearance of ceramide and sphingosine and the production of the bioactive sphingolipid, sphingosine-1-phosphate (S1P). Both nSMase2 and SK1 are membrane-associated enzymes that have been implicated in several cellular and physiological processes. The long-term goal of this project is to understand how the activities of nSMase2 and SK1 are regulated on a molecular basis and how these enzymes can be modulated pharmacologically for future therapeutic uses. Additionally, nSMase2 is an attractive target for anti-cancer and neuro-protective drugs as there are currently no known drug-like inhibitors of nSMase2. This project aims to understand the molecular parameters necessary for the development of nSMase2 and SK1 inhibitors. This proposal will investigate the hypothesis that: new putative selective inhibitors of nSMase2 and SK1 will be identified as therapeutics using the structural information obtained for the catalytic domains of nSMase2 and SK1 along with computational methods such as docking, virtual screening, and molecular dynamics. It is expected that this work will accomplish two goals: one goal is that this research will provide a proof-of-principle for targeting a novel site of nSMase2 involved in lipid activation and a novel site on SK1 to inhibit association with the membrane and ultimately stop the activation of SK1 and nSMase2. The second expected outcome is that this work will discover small molecules that are potent and specific inhibitors of SK1 and nSMase2 that can work in an in vivo setting. The existing crystal structures may afford in silico discovery or creation of therapeutic hit-to-lead compounds and chemical probes, or elucidation of a ligand's protein binding site. Additionally, this work can have a significant positive impact on cancer patients because of the potential use as alternative cancer therapeutics.
The role of nSMase2 has been studied in neuronal death and neurological conditions such as Alzheimer's and Parkinson's diseases. The ability of SK1 to regulate the balance of the pro- apoptotic and pro-survival sphingolipids has made it a major contributor to oncogenesis and valid target in cancer biology. The goal of this work is to study the mechanism of regulation of the lipid molecule ceramide and sphingosine in inducing cell death by studying how the activities of nSMase2 and SK1 are regulated on a molecular basis and how these enzymes can be modulated pharmacologically for future therapeutic uses.
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|Airola, Michael V; Shanbhogue, Prajna; Shamseddine, Achraf A et al. (2017) Structure of human nSMase2 reveals an interdomain allosteric activation mechanism for ceramide generation. Proc Natl Acad Sci U S A 114:E5549-E5558|
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