Sphingomyelin phosphodiesterase 1 (Acid sphingomyelinase) (ASM)

Sphingomyelin phosphodiesterase 1, more commonly known as Acid sphingomyelinase (ASM), is a critical lysosomal enzyme responsible for the hydrolysis of sphingomyelin into ceramide and phosphorylcholine [4, 6, 24]. It is essential for maintaining sphingolipid homeostasis and participating in signal transduction pathways that regulate cell death, membrane organization, and inflammatory responses [11, 16, 19]. Genetic mutations in the SMPD1 gene lead to Acid Sphingomyelinase Deficiency (ASMD), also known as Niemann-Pick disease types A and B, which results in severe multi-organ damage due to the systemic accumulation of sphingomyelin in the liver, spleen, and lungs [1, 6, 11]. In clinical practice, ASM is the target of the approved enzyme replacement therapy olipudase alfa, which provides functional recombinant enzyme to metabolize accumulated lipids in patients with ASMD [2, 3, 5]. Furthermore, ASM can be functionally inhibited by a broad class of small molecules known as FIASMAs (Functional Inhibitors of Acid Sphingomyelinase), such as amitriptyline and fluoxetine, which displace the enzyme from lysosomal membranes and trigger its proteolytic degradation [7, 10, 17]. These inhibitors have shown potential in treating diverse conditions beyond storage disorders, including major depression, cancer, and certain viral infections [7, 14, 17].

Other names

Acid sphingomyelinaseaSMaseAcidic sphingomyelinaseSMPD1Sphingomyelin phosphodiesterase

Enzyme replacement therapy (ERT) using recombinant human ASM to metabolize accumulated sphingomyelin; Functional inhibition (FIASMA) via displacement from lysosomal membranes leading to proteolytic degradation; Direct enzymatic inhibition of sphingomyelinase activity.