Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Int J Mol Sci. 2021 Aug 20;22(16):9001. doi: 10.3390/ijms22169001.

PMID: 34445706

Bernadette Breiden, Konrad Sandhoff

Highlights: In this article, the biochemical characteristics of acid sphingomyelinase (ASM), their potential effect on cellular lipid turnover, as well as a potential impact on physiological processes are discussed.

Abstract

Objective: This study outlines the key characteristics of human acid sphingomyelinase (ASM), including its structure, broad substrate specificity, biosynthesis, processing, and intracellular trafficking, as well as the suggested mode of action at the surface of the phospholipid substrate carrying intraendolysosomal luminal vesicles. Additionally, we go through the complex regulation that membrane lipids and lipid-binding proteins exert over this activity's phospholipid cleaving. Most of the literature makes the assumption that ASM only hydrolyzes sphingomyelin to produce ceramide and ignores its capacity to degrade additional substrates. In fact, ASM cleaves more than twenty different phospholipids in vitro, some of which are small but nevertheless have vital functions. Examples include the growth factor ceramide-1-phosphate and the unique lysosomal lysolipid bis(monoacylglycero)phosphate. Niemann-Pick disease types A and B, which are caused by an inherited ASM deficiency, primarily but not exclusively affect cellular sphingomyelin catabolism. This impairment results in a progressive sphingomyelin accumulation, which in turn causes a secondary accumulation of lipids (cholesterol, glucosylceramide, and GM2) by impairing their turnover in late endosomes and lysosomes. But it seems that ASM plays a role in a number of crucial cellular processes that are important for the regulation of an expanding number of metabolic diseases. The biochemical properties of ASM, their potential impact on cellular lipid turnover, and their effects on physiological systems will be discussed in this article.

Keywords: ASM inhibitors, Niemann-Pick disease, acid sphingomyelinase deficiency (ASMD), lipid accumulation, lysosomal phospholipase C, membrane lipids, sphingomyelin