Dataset Information

The neutral sphingomyelinase family: identifying biochemical connections.

ABSTRACT: Neutral sphingomyelinases (N-SMases) are considered to be key mediators of stress-induced ceramide production. The extended family of N-SMases is a subset of the DNaseI superfamily and comprises members from bacteria, yeast and mammals. In recent years, the identification and cloning of mammalian N-SMase family members has led to significant advances in understanding their physiological roles and regulation. However, there is still limited information on their regulation at the biochemical and molecular level. In this review, we summarize current knowledge about the biochemical regulation of the eukaryotic N-SMases and identify the major areas where knowledge is lacking. In recent years, research into the roles and regulation of N-SMases has moved in great strides with the cloning and characterization of multiple N-SMase isoforms and the development of knockout mice. However, as researchers continue to move forward in understanding the physiological functions of these various N-SMase isoforms, it has become exceedingly important to define howthese isoforms are regulated at the biochemical and molecular level. This is crucial for the development of future tools to study N-SMase signaling such as, for example, phospho-specific antibodies designating activation states. This is also an important part of identifying novel roles of N-SMases in physiological and pathological states. Finally, only by obtaining a more complete understanding of the workings of these enzymes at the molecular level, will investigators be able to design appropriate compounds that can target and inhibit their activity both efficiently and specifically. Certainly, the last of these is crucial when considering the potential of N-SMases as therapeutic targets. With this in mind, we sincerely hope that the next decade of research will even surpass the last ten years in advancing our understanding of the eukaryotic N-SMase family.

SUBMITTER: Clarke CJ

PROVIDER: S-EPMC3078995 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The neutral sphingomyelinase family: identifying biochemical connections.

Clarke Christopher J CJ Wu Bill X BX Hannun Yusuf A YA

Advances in enzyme regulation 20101028 1

Neutral sphingomyelinases (N-SMases) are considered to be key mediators of stress-induced ceramide production. The extended family of N-SMases is a subset of the DNaseI superfamily and comprises members from bacteria, yeast and mammals. In recent years, the identification and cloning of mammalian N-SMase family members has led to significant advances in understanding their physiological roles and regulation. However, there is still limited information on their regulation at the biochemical and m ...[more]

PMID: 21035485

Similar Datasets

Project description:Ceramide is a bioactive lipid that plays an important role in stress responses leading to apoptosis, cell growth arrest and differentiation. Ceramide production is due in part to sphingomyelin hydrolysis by sphingomyelinases. In brain, neutral sphingomyelinase 2 (nSMase2) is expressed in neurons and increases in its activity and expression have been associated with pro-inflammatory conditions observed in Alzheimer's disease, multiple sclerosis and human immunodeficiency virus (HIV-1) patients. Increased nSMase2 activity translates into higher ceramide levels and neuronal cell death, which can be prevented by chemical or genetic inhibition of nSMase2 activity or expression. However, to date, there are no soluble, specific and potent small molecule inhibitor tool compounds for in vivo studies or as a starting point for medicinal chemistry optimization. Moreover, the majority of the known inhibitors were identified using bacterial, bovine or rat nSMase2. In an attempt to identify new inhibitor scaffolds, two activity assays were optimized as screening platform using the recombinant human enzyme. First, active hits were identified using a fluorescence-based high throughput compatible assay. Then, hits were confirmed using a 14C sphingomyelin-based direct activity assay. Pharmacologically active compounds and approved drugs were screened using this strategy which led to the identification of cambinol as a novel uncompetitive nSMase2 inhibitor (Ki = 7 μM). The inhibitory activity of cambinol for nSMase2 was approximately 10-fold more potent than for its previously known target, silence information regulator 1 and 2 (SIRT1/2). Cambinol decreased tumor necrosis factor-α or interleukin-1 β-induced increases of ceramide and cell death in primary neurons. A preliminary study of cambinol structure and activity allowed the identification of the main structural features required for nSMase2 inhibition. Cambinol and its analogs may be useful as nSMase2 inhibitor tool compounds to prevent ceramide-dependent neurodegeneration.

Dataset Information

The neutral sphingomyelinase family: identifying biochemical connections.

Publications

The neutral sphingomyelinase family: identifying biochemical connections.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets