FIASMA

Functional inhibitors of acid sphingomyelinase, or FIASMA,^[1] is a large group of pharmacological compounds inhibiting the enzyme acid sphingomyelinase (ASM, EC 3.1.4.12). This enzyme is mainly located within the lysosome, where it cleaves sphingomyelin to ceramide and sphingosine, the latter of which is then phosphorylated to sphingosine-1-phosphate. These metabolites, and subsequent inhibition of the enzyme, influence the balance between cell death (apoptosis) and cell growth (proliferation). A lack of regulation of this sensitive equilibrium can lead to serious clinical consequences.

The acronym "FIASMA" was introduced by Kornhuber and coworkers; it is derived from the term Functional Inhibitor of Acid SphingoMyelinAse.^[1]

Mechanism of action of FIASMAs

FIASMAs inhibit the ASM via an indirect, functional mechanism. They insert into the inner leaf of the lysosomal membrane and subsequently cause membrane-associated enzymes, such as ASM, to detach.

In contrast to FIASMAs, a screen of over 346,000 small molecules found only 20 that were direct inhibitors of acid sphingomyelinase. These 20 included amiodarone and etidronic acid.^[5]

Properties of FIASMAs

FIASMAs are structurally diverse, but have common physicochemical properties. All FIASMAs identified so far share a

• In patients with major depressive disorder, elevated ASM activity has been observed.^[7]
• In cystic fibrosis, accumulation of ceramide can be lowered using FIASMAs such as amitriptyline.^[8][9]

Known drugs acting as FIASMAs

Cell culture-based experiments identified the listed compounds as FIASMAs (

References