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FIASMA

January 01, 1970

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 edit

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 edit

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 edit

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]

References edit

  1. ^ a b c 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. ^ a b c d e 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.

January 01, 1970
fiasma, functional, inhibitors, acid, sphingomyelinase, large, group, pharmacological, compounds, inhibiting, enzyme, acid, sphingomyelinase, this, enzyme, mainly, located, within, lysosome, where, cleaves, sphingomyelin, ceramide, sphingosine, latter, which, . 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 Contents 1 Mechanism of action of FIASMAs 2 Properties of FIASMAs 3 Known drugs acting as FIASMAs 4 ReferencesMechanism of action of FIASMAs editFIASMAs 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 editFIASMAs 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 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 editCell 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 Alverine Amiodarone Amitriptyline Amlodipine Aprindine Astemizole AY 9944 Benzatropine Bepridil Biperiden Camylofin Carvedilol Cepharanthine Chlorpromazine Chlorprothixene Cinnarizine Clemastine Clofazimine Clomiphene Clomipramine Cloperastine Conessine Cyclobenzaprine Cyproheptadine Desipramine Desloratadine Dicycloverine Dicyclomine Dilazep Dimebon Doxepin Drofenine Emetine Fendiline Flunarizine Fluoxetine Flupentixol Fluphenazine Fluvoxamine Hydroxyzine Imipramine Lofepramine Loperamid Loratadin Maprotiline Mebeverine Mebhydrolin Mepacrine Mibefradil Norfluoxetine Nortriptyline Paroxetine Penfluridol Perhexiline Perphenazine Pimethixene Pimozide Profenamine Promazine Promethazine Protriptyline Sertindole Sertraline Solasodine Suloctidil Tamoxifen Terfenadine Thioridazine Tomatidine Trifluoperazin Triflupromazine Trimipramine ZolantidineReferences edit a b c Kornhuber J Tripal P Reichel M Muhle 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 Kolzer 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 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 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 Inhibitors of Secretory Acid Sphingomyelinase S ASM qHTS https pubchem ncbi nlm nih gov assay assay cgi aid 504937 a b c d e Kornhuber J Muehlbacher M Trapp S Pechmann S Friedl A Reichel M Muhle 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 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 Teichgraber V Ulrich M Endlich N Riethmuller Wilker JB de Oliveira Munding CC van Heeckeren AM Barr ML von Kurthy 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 Becker KA Riethmuller J Luth A Doring 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 Retrieved from https en wikipedia org w index php title FIASMA amp oldid 1171004187, wikipedia, wiki, book, books, library,

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