Secretory sphingomyelinase in health and disease

Abstract

Acid sphingomyelinase (ASM), a key enzyme in sphingolipid metabolism, hydrolyzes sphingomyelin to ceramide and phosphorylcholine. In mammals, the expression of a single gene, SMPD1, results in two forms of the enzyme that differ in several characteristics. Lysosomal ASM (L-ASM) is located within the lysosome, requires no additional Zn 2+ ions for activation and is glycosylated mainly with high-mannose oligosaccharides. By contrast, the secretory ASM (S-ASM) is located extracellularly, requires Zn 2+ ions for activation, has a complex glycosylation pattern and has a longer in vivo half-life. In this review, we summarize current knowledge regarding the physiology and pathophysiology of S-ASM, including its sources and distribution, molecular and cellular mechanisms of generation and regulation and relevant in vitro and in vivo studies. Polymorphisms or mutations of SMPD1 lead to decreased S-ASM activity, as detected in patients with Niemann-Pick disease B. Thus, lower serum/ plasma activities of S-ASM are trait markers. No genetic causes of increased S-ASM activity have been identified. Instead, elevated activity is the result of enhanced release (e.g., induced by lipopolysaccharide and cytokine stimulation) or increased enzyme activation (e.g., induced by oxidative stress). Increased S-ASM activity in serum or plasma is a state marker of a wide range of diseases. In particular, high S-ASM activity occurs in inflammation of the endothelium and liver. Several studies have demonstrated a correlation between S-ASM activity and mortality induced by severe inflammatory diseases. Serial measurements of S-ASM reveal prolonged activation and, therefore, the measurement of this enzyme may also provide information on past inflammatory processes. Thus, S-ASM may be both a promising clinical chemistry marker and a therapeutic target.

Structural Basis for Nucleotide Hydrolysis by the Acid Sphingomyelinase-like Phosphodiesterase SMPDL3A

“…Millimolar concentrations of zinc block the active site of the enzyme, and optimal activity is only possible at lower concentrations in the micromolar range, consistent with the physiological serum levels of zinc (5). Excessive zinc concentrations are known to also inhibit ASMase (34).…”

“…Unlike SMPDL3A and SMPDL3B, ASMase contains a saposin domain that facilitates binding to membranes and lipids (5). SMPDL3B, in turn, is attached to the membrane via a glycosylphosphatidylinositol anchor (6).…”

“…The lone alkaline SMase metabolizes SM in the intestinal tract (3), whereas neutral SMases are active on the cytosolic side of the plasma membrane and in various organelles (4). The acid sphingomyelinase (ASMase) is found mainly in lysosomes; however, a fraction of this protein is secreted where it can act on the extracellular side of the plasma membrane and on lipoproteins in the circulation (5).…”

“…An anti-inflammatory role as a moderator of nucleotide-based purinergic signaling was, therefore, proposed for this protein. Furthermore, SMPDL3A was shown to be inhibited by zinc, whereas its close homolog, ASMase, is a zinc-dependent enzyme (5). A recently discovered bacterial ASMase-like protein, RsASML, also displayed no activity against SM but was able to hydrolyze ATP and ADP (23).…”

Elevation of Serum Acid Sphingomyelinase Activity in Acute Kawasaki Disease

“…Reports on the relationship between S-ASM and human diseases suggest that diseases with endothelial involvement appear to preferentially present a marked elevation of peripheral S-ASM activity (Kornhuber et al 2015). An in vitro study also showed that human vascular endothelial cells are a rich source of S-ASM (Marathe et al 1998).…”