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  1. Article ; Online: Physiological and pharmacological modulation of BAX.

    Spitz, Adam Z / Gavathiotis, Evripidis

    Trends in pharmacological sciences

    2021  Volume 43, Issue 3, Page(s) 206–220

    Abstract: Bcl-2-associated X protein (BAX) is a critical executioner of mitochondrial regulated cell death through its lethal activity of permeabilizing the mitochondrial outer membrane (MOM). While the physiological function of BAX ensures tissue homeostasis, ... ...

    Abstract Bcl-2-associated X protein (BAX) is a critical executioner of mitochondrial regulated cell death through its lethal activity of permeabilizing the mitochondrial outer membrane (MOM). While the physiological function of BAX ensures tissue homeostasis, dysregulation of BAX leads to aberrant cell death. Despite BAX being a promising therapeutic target for human diseases, historically the development of drugs has focused on antiapoptotic BCL-2 proteins, due to challenges in elucidating the mechanism of BAX activation and identifying druggable surfaces of BAX. Here, we discuss recent studies that have provided structure-function insights and identified regulatory surfaces that control BAX activation. Moreover, we emphasize the development of small molecule orthosteric, allosteric, and oligomerization modulators that provide novel opportunities for biological investigation and progress towards drugging BAX.
    MeSH term(s) Apoptosis/physiology ; Humans ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; bcl-2-Associated X Protein/metabolism
    Chemical Substances Proto-Oncogene Proteins c-bcl-2 ; bcl-2-Associated X Protein
    Language English
    Publishing date 2021-11-27
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 282846-7
    ISSN 1873-3735 ; 0165-6147
    ISSN (online) 1873-3735
    ISSN 0165-6147
    DOI 10.1016/j.tips.2021.11.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1513: Show issues Location:
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  2. Article ; Online: Eltrombopag directly inhibits BAX and prevents cell death.

    Spitz, Adam Z / Zacharioudakis, Emmanouil / Reyna, Denis E / Garner, Thomas P / Gavathiotis, Evripidis

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 1134

    Abstract: The BCL-2 family protein BAX has essential activity in mitochondrial regulation of cell death. While BAX activity ensures tissue homeostasis, when dysregulated it contributes to aberrant cell death in several diseases. During cellular stress BAX is ... ...

    Abstract The BCL-2 family protein BAX has essential activity in mitochondrial regulation of cell death. While BAX activity ensures tissue homeostasis, when dysregulated it contributes to aberrant cell death in several diseases. During cellular stress BAX is transformed from an inactive cytosolic conformation to a toxic mitochondrial oligomer. Although the BAX transformation process is not well understood, drugs that interfere with this process are useful research tools and potential therapeutics. Here, we show that Eltrombopag,  an FDA-approved drug,  is a direct inhibitor of BAX. Eltrombopag binds the BAX trigger site distinctly from BAX activators, preventing them from triggering BAX conformational transformation and simultaneously promoting stabilization of the inactive BAX structure. Accordingly, Eltrombopag is capable of inhibiting BAX-mediated apoptosis induced by cytotoxic stimuli. Our data demonstrate structure-function insights into a mechanism of BAX inhibition and reveal a mechanism for Eltrombopag that may expand its use in diseases of uncontrolled cell death.
    MeSH term(s) 3T3 Cells ; Animals ; Apoptosis/drug effects ; Benzoates/chemistry ; Benzoates/pharmacology ; Cell Death/drug effects ; Humans ; Hydrazines/chemistry ; Hydrazines/pharmacology ; Magnetic Resonance Spectroscopy ; Mice ; Models, Biological ; Models, Molecular ; Protein Stability/drug effects ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; bcl-2-Associated X Protein/antagonists & inhibitors ; bcl-2-Associated X Protein/chemistry ; bcl-2-Associated X Protein/metabolism
    Chemical Substances Benzoates ; Hydrazines ; Pyrazoles ; bcl-2-Associated X Protein ; eltrombopag (S56D65XJ9G)
    Language English
    Publishing date 2021-02-18
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-21224-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Progress in targeting the BCL-2 family of proteins.

    Garner, Thomas P / Lopez, Andrea / Reyna, Denis E / Spitz, Adam Z / Gavathiotis, Evripidis

    Current opinion in chemical biology

    2017  Volume 39, Page(s) 133–142

    Abstract: The network of protein-protein interactions among the BCL-2 protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Anti-apoptotic BCL-2 proteins are considered promising targets for drug discovery and exciting ... ...

    Abstract The network of protein-protein interactions among the BCL-2 protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Anti-apoptotic BCL-2 proteins are considered promising targets for drug discovery and exciting clinical progress has stimulated intense investigations in the broader family. Here, we discuss recent developments in small molecules targeting anti-apoptotic proteins and alternative approaches to targeting BCL-2 family interactions. These studies advance our understanding of the role of BCL-2 family proteins in physiology and disease, providing unique tools for dissecting these functions. The BCL-2 family of proteins is a prime example of targeting protein-protein interactions and further chemical biology approaches will increase opportunities for novel targeted therapies in cancer, autoimmune and aging-associated diseases.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Biomimetic Materials/pharmacology ; Biomimetic Materials/therapeutic use ; Humans ; Molecular Targeted Therapy/methods ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2/metabolism
    Chemical Substances Proto-Oncogene Proteins c-bcl-2
    Language English
    Publishing date 2017-08-17
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1439176-4
    ISSN 1879-0402 ; 1367-5931
    ISSN (online) 1879-0402
    ISSN 1367-5931
    DOI 10.1016/j.cbpa.2017.06.014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4986: Show issues Location:
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  4. Article: Continuous Fluorescence Assays for Reactions Involving Adenine

    Firestone, Ross S / Cameron Scott A / Ducati Rodrigo G / Schramm Vern L / Spitz Adam Z / Tyler Peter C

    Analytical chemistry. 2016 Dec. 06, v. 88, no. 23

    2016  

    Abstract: 5′-Methylthioadenosine phosphorylase (MTAP) and 5′-methylthioadenosine nucleosidase (MTAN) catalyze the phosphorolysis and hydrolysis of 5′-methylthioadenosine (MTA), respectively. Both enzymes have low KM values for their substrates. Kinetic ... ...

    Abstract 5′-Methylthioadenosine phosphorylase (MTAP) and 5′-methylthioadenosine nucleosidase (MTAN) catalyze the phosphorolysis and hydrolysis of 5′-methylthioadenosine (MTA), respectively. Both enzymes have low KM values for their substrates. Kinetic assays for these enzymes are challenging, as the ultraviolet absorbance spectra for reactant MTA and product adenine are similar. We report a new assay using 2-amino-5′-methylthioadenosine (2AMTA) as an alternative substrate for MTAP and MTAN enzymes. Hydrolysis or phosphorolysis of 2AMTA forms 2,6-diaminopurine, a fluorescent and easily quantitated product. We kinetically characterize 2AMTA with human MTAP, bacterial MTANs and use 2,6-diaminopurine as a fluorescent substrate for yeast adenine phosphoribosyltransferase. 2AMTA was used as the substrate to kinetically characterize the dissociation constants for three-transition-state analogue inhibitors of MTAP and MTAN. Kinetic values obtained from continuous fluorescent assays with MTA were in good agreement with previously measured literature values, but gave smaller experimental errors. Chemical synthesis from ribose and 2,6-dichloropurine provided crystalline 2AMTA as the oxalate salt. Chemo-enzymatic synthesis from ribose and 2,6-diaminopurine produced 2-amino-S-adenosylmethionine for hydrolytic conversion to 2AMTA. Interaction of 2AMTA with human MTAP was also characterized by pre-steady-state kinetics and by analysis of the crystal structure in a complex with sulfate as a catalytically inert analogue of phosphate. This assay is suitable for inhibitor screening by detection of fluorescent product, for quantitative analysis of hits by rapid and accurate measurement of inhibition constants in continuous assays, and pre-steady-state kinetic analysis of the target enzymes.
    Keywords absorbance ; adenine ; adenine phosphoribosyltransferase ; crystal structure ; dissociation ; fluorescence ; humans ; hydrolysis ; kinetics ; oxalates ; phosphates ; phosphorylase ; quantitative analysis ; ribose ; screening ; sulfates ; synthesis ; yeasts
    Language English
    Dates of publication 2016-1206
    Size p. 11860-11867.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 1508-8
    ISSN 1520-6882 ; 0003-2700
    ISSN (online) 1520-6882
    ISSN 0003-2700
    DOI 10.1021%2Facs.analchem.6b03621
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Continuous Fluorescence Assays for Reactions Involving Adenine.

    Firestone, Ross S / Cameron, Scott A / Tyler, Peter C / Ducati, Rodrigo G / Spitz, Adam Z / Schramm, Vern L

    Analytical chemistry

    2016  Volume 88, Issue 23, Page(s) 11860–11867

    Abstract: 5'-Methylthioadenosine phosphorylase (MTAP) and 5'-methylthioadenosine nucleosidase (MTAN) catalyze the phosphorolysis and hydrolysis of 5'-methylthioadenosine (MTA), respectively. Both enzymes have low ... ...

    Abstract 5'-Methylthioadenosine phosphorylase (MTAP) and 5'-methylthioadenosine nucleosidase (MTAN) catalyze the phosphorolysis and hydrolysis of 5'-methylthioadenosine (MTA), respectively. Both enzymes have low K
    MeSH term(s) 2-Aminopurine/analogs & derivatives ; 2-Aminopurine/chemistry ; 2-Aminopurine/metabolism ; Adenine/analogs & derivatives ; Adenine/analysis ; Adenine/metabolism ; Adenine Phosphoribosyltransferase/metabolism ; Enzyme Assays/methods ; Fluorescence ; Humans ; Kinetics ; Saccharomyces cerevisiae/enzymology ; Substrate Specificity
    Chemical Substances 2-Aminopurine (452-06-2) ; 2,6-diaminopurine (49P95BAU4Z) ; Adenine Phosphoribosyltransferase (EC 2.4.2.7) ; Adenine (JAC85A2161)
    Language English
    Publishing date 2016-11-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1508-8
    ISSN 1520-6882 ; 0003-2700
    ISSN (online) 1520-6882
    ISSN 0003-2700
    DOI 10.1021/acs.analchem.6b03621
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4033: Show issues Location:
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