FIASMA

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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.

Contents

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. [2] Upon detachment from the membrane, these enzymes are cleaved and degraded within lysosomes. Inhibition of ASM by certain drugs has been known about for a long time, [3] but systematic studies which characterize the pharmacological group of FIASMAs are relatively recent. [4] ASM is not completely inhibited by FIASMAs [1] and a low residual activity remains, allowing sufficient metabolism for cellular survival to occur. Application of FIASMAs therefore do not result in a clinical condition like Niemann-Pick disease, where ASM-activity is completely lacking because of genetic mutations.

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 basic nitrogen atom [6] and lipophilic part, which characterizes them as “cationic amphiphilic drugs”. Additionally, they also violate Lipinski's Rule of Five more often than non-FIASMAs. [6] Still, they are highly bioavailable and reabsorbed by the gastrointestinal tract. In general, they also show high blood–brain barrier permeability. [6]

Ceramide and sphingomyelin have clinical relevance:

Known drugs acting as FIASMAs

Cell culture-based experiments identified the listed compounds as FIASMAs (antidepressants are in boldface). These experiments used the human cell line H4. The ASM activity was measured using a radiolabel assay. [6] In case of absent experimental data a chemoinformatic prediction system has been proposed, which enables identification of FIASMAs based on molecular properties. [6]

Related Research Articles

<span class="mw-page-title-main">Lysosome</span> Cell organelle

A lysosome is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane proteins, and its lumenal proteins. The lumen's pH (~4.5–5.0) is optimal for the enzymes involved in hydrolysis, analogous to the activity of the stomach. Besides degradation of polymers, the lysosome is involved in various cell processes, including secretion, plasma membrane repair, apoptosis, cell signaling, and energy metabolism.

<span class="mw-page-title-main">Benzatropine</span> Group of stereoisomers

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<span class="mw-page-title-main">Sphingolipid</span> Family of chemical compounds

Sphingolipids are a class of lipids containing a backbone of sphingoid bases, which are a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because of their enigmatic nature. These compounds play important roles in signal transduction and cell recognition. Sphingolipidoses, or disorders of sphingolipid metabolism, have particular impact on neural tissue. A sphingolipid with a terminal hydroxyl group is a ceramide. Other common groups bonded to the terminal oxygen atom include phosphocholine, yielding a sphingomyelin, and various sugar monomers or dimers, yielding cerebrosides and globosides, respectively. Cerebrosides and globosides are collectively known as glycosphingolipids.

<span class="mw-page-title-main">Sphingomyelin</span>

Sphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosphoethanolamine head group; therefore, sphingomyelins can also be classified as sphingophospholipids. In humans, SPH represents ~85% of all sphingolipids, and typically make up 10–20 mol % of plasma membrane lipids.

<span class="mw-page-title-main">Clemastine</span> Allergy medication

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<span class="mw-page-title-main">Ceramide</span> Family of waxy lipid molecules

Ceramides are a family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid joined by an amide bond. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer. Contrary to previous assumptions that ceramides and other sphingolipids found in cell membrane were purely supporting structural elements, ceramide can participate in a variety of cellular signaling: examples include regulating differentiation, proliferation, and programmed cell death (PCD) of cells.

<span class="mw-page-title-main">Chlorprothixene</span> Chemical compound

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<span class="mw-page-title-main">Clofazimine</span> Medication

Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to support its use in other conditions though a retrospective study found it 95% effective in the treatment of Mycobacterium avium complex (MAC) when administered with a macrolide and ethambutol, as well as the drugs amikacin and clarithromycin. However, in the United States, clofazimine is considered an orphan drug, is unavailable in pharmacies, and its use in the treatment of MAC is overseen by the Food and Drug Administration. It is taken orally.

<span class="mw-page-title-main">Biperiden</span> Group of stereoisomers

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<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

<span class="mw-page-title-main">Sphingomyelin phosphodiesterase</span> Class of enzymes

Sphingomyelin phosphodiesterase is a hydrolase enzyme that is involved in sphingolipid metabolism reactions. SMase is a member of the DNase I superfamily of enzymes and is responsible for breaking sphingomyelin (SM) down into phosphocholine and ceramide. The activation of SMase has been suggested as a major route for the production of ceramide in response to cellular stresses.

<span class="mw-page-title-main">Membrane lipid</span> Lipid molecules on cell membrane

Membrane lipids are a group of compounds which form the lipid bilayer of the cell membrane. The three major classes of membrane lipids are phospholipids, glycolipids, and cholesterol. Lipids are amphiphilic: they have one end that is soluble in water ('polar') and an ending that is soluble in fat ('nonpolar'). By forming a double layer with the polar ends pointing outwards and the nonpolar ends pointing inwards membrane lipids can form a 'lipid bilayer' which keeps the watery interior of the cell separate from the watery exterior. The arrangements of lipids and various proteins, acting as receptors and channel pores in the membrane, control the entry and exit of other molecules and ions as part of the cell's metabolism. In order to perform physiological functions, membrane proteins are facilitated to rotate and diffuse laterally in two dimensional expanse of lipid bilayer by the presence of a shell of lipids closely attached to protein surface, called annular lipid shell.

Ceramidase is an enzyme which cleaves fatty acids from ceramide, producing sphingosine (SPH) which in turn is phosphorylated by a sphingosine kinase to form sphingosine-1-phosphate (S1P).

In enzymology, a ceramide kinase, also abbreviated as CERK, is an enzyme that catalyzes the chemical reaction:

<span class="mw-page-title-main">Sphingomyelin phosphodiesterase 1</span> Protein-coding gene in the species Homo sapiens

Sphingomyelin phosphodiesterase 1 (SMPD1), also known as acid sphingomyelinase (ASM), is an enzyme that in humans is encoded by the SMPD1 gene.

<span class="mw-page-title-main">ENPP7</span> Protein-coding gene in the species Homo sapiens

Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 also known as alkaline sphingomyelin phosphodiesterase (Alk-SMase) or intestinal alkaline sphingomyelinase is an enzyme that in humans is encoded by the ENPP7 gene.

Niemann–Pick disease, SMPD1-associated refers to two different types of Niemann–Pick disease which are associated with the SMPD1 gene.

Acid sphingomyelinase is one of the enzymes that make up the sphingomyelinase (SMase) family, responsible for catalyzing the breakdown of sphingomyelin to ceramide and phosphorylcholine. They are organized into alkaline, neutral, and acidic SMase depending on the pH in which their enzymatic activity is optimal. Acid Sphingomyelinases (aSMases) enzymatic activity can be influenced by drugs, lipids, cations, pH, redox and other proteins in the environment. Specifically aSMases have been shown to have increased enzymatic activity in lysobisphosphatidic acid (LBPA) or phosphatidylinositol (PI) enriched environments, and inhibited activity when phosphorylated derivatives of PI are present.

Ceramide synthase 5 (CerS5) is the enzyme encoded in humans by the CERS5 gene.

<span class="mw-page-title-main">Johannes Kornhuber</span> German psychiatrist and psychotherapist

Johannes Kornhuber is a German psychiatrist and psychotherapist.

References

  1. 1 2 3 Kornhuber J, Tripal P, Reichel M, Mühle C, Rhein C, Muehlbacher M, Groemer TW, Gulbins E (2010). "Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications". Cell Physiol Biochem. 26 (1): 9–20. doi:10.1159/000315101. PMID   20502000.
  2. ↑ Kölzer M, Werth N, Sandhoff K (2004). "Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine". FEBS Letters. 559 (1): 96–98. doi:10.1016/S0014-5793(04)00033-X. PMID   14960314. S2CID   23974373.
  3. ↑ Sakuragawa N, Sakuragawa M, Kuwabara T, Pentchev PG, Barranger JA, Brady RO (1977). "Niemann-Pick disease experimental model: sphingomyelinase reduction induced by AY-9944". Science. 196 (4287): 317–319. Bibcode:1977Sci...196..317S. doi:10.1126/science.66749. PMID   66749.
  4. ↑ Kornhuber J, Tripal P, Reichel M, Terfloth L, Bleich S, Wiltfang J, Gulbins E (2008). "Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model". J Med Chem. 51 (2): 219–237. CiteSeerX   10.1.1.324.8854 . doi:10.1021/jm070524a. PMID   18027916.
  5. ↑ Inhibitors of Secretory Acid Sphingomyelinase (S-ASM): qHTS https://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=504937
  6. 1 2 3 4 5 Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P (2011). "Identification of novel functional inhibitors of acid sphingomyelinase". PLOS ONE. 6 (8): e23852. Bibcode:2011PLoSO...623852K. doi: 10.1371/journal.pone.0023852 . PMC   3166082 . PMID   21909365.
  7. ↑ Kornhuber J, Medlin A, Bleich S, Jendrossek V, Henkel A, Wiltfang J, Gulbins E (2010). "High activity of acid sphingomyelinase in major depression". J Neural Transm. 112 (11): 1583–1590. doi:10.1007/s00702-005-0374-5. PMID   16245071. S2CID   27972954.
  8. ↑ Teichgräber V, Ulrich M, Endlich N, Riethmüller Wilker JB, de Oliveira-Munding CC, van Heeckeren AM, Barr ML, von Kürthy G, Schmid KW, et al. (2008). "Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis" (PDF). Nat Med. 14 (4): 382–391. doi:10.1038/nm1748. PMID   18376404. S2CID   13251584.
  9. ↑ Becker KA, Riethmüller J, Lüth A, Döring G, Kleuser B, Gulbins E (2010). "Acid sphingomyelinase inhibitors normalize pulmonary ceramide and inflammation in cystic fibrosis". Am J Respir Cell Mol Biol. 42 (6): 716–724. doi:10.1165/rcmb.2009-0174OC. PMID   19635928.
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