Abstract
Here, we present the main features of human acid sphingomyelinase (ASM), its biosynthesis, processing and intracellular trafficking, its structure, its broad substrate specificity, and the proposed mode of action at the surface of the phospholipid substrate carrying intraendolysosomal luminal vesicles. In addition, we discuss the complex regulation of its phospholipid cleaving activity by membrane lipids and lipid-binding proteins. The majority of the literature implies that ASM hydrolyses solely sphingomyelin to generate ceramide and ignores its ability to degrade further substrates. Indeed, more than twenty different phospholipids are cleaved by ASM in vitro, including some minor but functionally important phospholipids such as the growth factor ceramide-1-phosphate and the unique lysosomal lysolipid bis(monoacylglycero)phosphate. The inherited ASM deficiency, Niemann-Pick disease type A and B, impairs mainly, but not only, cellular sphingomyelin catabolism, causing a progressive sphingomyelin accumulation, which furthermore triggers a secondary accumulation of lipids (cholesterol, glucosylceramide, GM2) by inhibiting their turnover in late endosomes and lysosomes. However, ASM appears to be involved in a variety of major cellular functions with a regulatory significance for an increasing number of metabolic disorders. The biochemical characteristics of ASM, their potential effect on cellular lipid turnover, as well as a potential impact on physiological processes will be discussed.
Highlights
Amphiphilic phospholipids (PLs) and proteins are the main and crucial building blocks of eukaryotic cellular membranes [1,2]
In the acidic environment of endosomes and lysosomes, complex lipids and other amphiphilic macromolecules are degraded on intralysosomal luminal vesicles (ILVs), and their components are released into the cytosol of the cell as fuel for energy metabolism and substrates for biosynthetic pathways
The PL-cleaving activity of acid sphingomyelinase (ASM) is stimulated by Sap C [42] (Figure 3C) and by Sap D [98] and by anionic lipids of the substrate carrying luminal vesicles such as BMP (Figure 3, Table 1)
Summary
Amphiphilic phospholipids (PLs) and proteins are the main and crucial building blocks of eukaryotic cellular membranes [1,2]. (b) the curvature of the membrane vesicles (e.g., the ILVs) [44], (c) the hydrolysis stimulating lipid binding proteins (the sphingolipid activator proteins) [49], (d) stimulating lipids, such as BMP [43,48,50,51], and (e) inhibiting lipids such as SM [43,46,50] All these factors hardly affect the cleavage of soluble synthetic substrates in a comparable way in vitro, such as the cleavage of fluorescence generating 4-methylumbellyferyl containing soluble molecules, often used in the medical literature to assay the overall hydrolase activity in biological samples. Considering ASM’s many physiologically important PL-substrates and their catabolites, we should be cautious not to attribute ASM induced cellular processes solely to changes in SM and ceramide levels as prevailingly stated in the in the medical literature
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