Diversity Supplement for Bernandie Jean: Neutral sphingomyelinases and bioactive ceramides

必须维持存在于各种信号通路中的复杂平衡 人类细胞的存活和正常功能。导致人类疾病的有害影响可能 这是由于平衡中的障碍造成的。例如，一个重要的信号通路是 鞘磷脂代谢途径。神经酰胺和鞘氨醇都是具有生物活性的鞘磷脂。 两人都与细胞生长停滞有关。神经酰胺的产生有两条主要途径 在细胞中：一种缓慢的从头合成途径，由神经酰胺合成酶和一种 相对较快的方法，其中鞘磷脂被鞘磷脂酶，如 中性鞘磷脂酶2(NSMase2)。此外，鞘氨醇激酶1(SK1)是两种 鞘氨醇激动酶，是一种受高度调控的酶，由于SK1的S在 神经酰胺和鞘氨醇的清除和生物活性鞘磷脂的生产， 鞘氨醇-1-磷酸(S1P)。NSMase2和SK1都是膜相关酶 参与了几个细胞和生理过程。的长期目标是 这个项目是为了了解nSMase2和SK1的活性是如何在一个分子上调节的 以及如何从药理上调节这些酶以用于未来的治疗用途。 此外，nSMase2是抗癌和神经保护药物的一个有吸引力的靶点，因为有 目前还没有已知的nSMase2类药物抑制剂。本项目旨在了解 开发nSMase2和SK1抑制剂所需的分子参数。这 提案将调查以下假设：新的假定的nSMase2和nSMase2的选择性抑制剂 SK1将利用获得的催化结构信息被鉴定为治疗药物 NSMase2和SK1的域以及对接、虚拟 筛选和分子动力学。预计这项工作将实现两个目标：一 目标是这项研究将为靶向nSMase2的新位点提供原理证明 参与脂质激活，并在SK1上有一个新的位置来抑制与膜的结合 最终停止SK1和nSMase2的激活。第二个预期结果是，这 工作将发现对SK1和nSMase2具有强大而特异的抑制作用的小分子 这可以在活体环境中发挥作用。现有的晶体结构可能有助于硅学的发现 或创建治疗性的点击到铅的化合物和化学探针，或阐明配体的 蛋白质结合部位。此外，这项工作可以对癌症产生重大的积极影响。 这是因为它可能被用作癌症的替代疗法。

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.