دورية أكاديمية
أعرض في EDS

The covalent reactivity of functionalized 5-hydroxy-butyrolactams is the basis for targeting of fatty acid binding protein 5 (FABP5) by the neurotrophic agent MT-21.

التفاصيل البيبلوغرافية
العنوان: The covalent reactivity of functionalized 5-hydroxy-butyrolactams is the basis for targeting of fatty acid binding protein 5 (FABP5) by the neurotrophic agent MT-21.
المؤلفون: Svenningsen EB; Department of Chemistry, Aarhus University, DK-8000 Aarhus C Denmark thpou@chem.au.dk., Ottosen RN; Department of Chemistry, Aarhus University, DK-8000 Aarhus C Denmark thpou@chem.au.dk., Jørgensen KH; Department of Chemistry, Aarhus University, DK-8000 Aarhus C Denmark thpou@chem.au.dk., Nisavic M; Department of Chemistry, Aarhus University, DK-8000 Aarhus C Denmark thpou@chem.au.dk.; Department of Clinical Medicine - Research Unit for Molecular Medicine, Aarhus University Hospital DK-8200 Aarhus N Denmark., Larsen CK; Department of Engineering - Microbial Biosynthesis, Aarhus University DK-8000 Aarhus C Denmark., Hansen BK; Department of Chemistry, Aarhus University, DK-8000 Aarhus C Denmark thpou@chem.au.dk.; Interdisciplinary Nanoscience Center (iNANO), Aarhus University DK-8000 Aarhus C Denmark., Wang Y; Copenhagen Biocenter, University of Copenhagen DK-2200 Copenhagen N Denmark., Lindorff-Larsen K; Copenhagen Biocenter, University of Copenhagen DK-2200 Copenhagen N Denmark., Tørring T; Department of Engineering - Microbial Biosynthesis, Aarhus University DK-8000 Aarhus C Denmark., Hacker SM; Leiden Institute of Chemistry, Leiden University NL-2333 CC Leiden The Netherlands., Palmfeldt J; Department of Clinical Medicine - Research Unit for Molecular Medicine, Aarhus University Hospital DK-8200 Aarhus N Denmark., Poulsen TB; Department of Chemistry, Aarhus University, DK-8000 Aarhus C Denmark thpou@chem.au.dk.
المصدر: RSC chemical biology [RSC Chem Biol] 2022 Sep 07; Vol. 3 (10), pp. 1216-1229. Date of Electronic Publication: 2022 Sep 07 (Print Publication: 2022).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Royal Society of Chemistry Country of Publication: England NLM ID: 101768727 Publication Model: eCollection Cited Medium: Internet ISSN: 2633-0679 (Electronic) Linking ISSN: 26330679 NLM ISO Abbreviation: RSC Chem Biol Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Cambridge : Royal Society of Chemistry, [2020]-
مستخلص: Covalently acting compounds experience a strong interest within chemical biology both as molecular probes in studies of fundamental biological mechanisms and/or as novel drug candidates. In this context, the identification of new classes of reactive groups is particularly important as these can expose novel reactivity modes and, consequently, expand the ligandable proteome. Here, we investigated the electrophilic reactivity of the 3-acyl-5-hydroxy-1,5-dihydro-2 H -pyrrole-2-one (AHPO) scaffold, a heterocyclic motif that is e.g. present in various bioactive natural products. Our investigations were focused on the compound MT-21 - a simplified structural analogue of the natural product epolactaene - which is known to have both neurotrophic activity and ability to trigger apoptotic cell death. We found that the central N -acyl hemiaminal group of MT-21 can function as an electrophilic centre enabling divergent reactivity with both amine- and thiol-based nucleophiles, which furthermore translated to reactivity with proteins in both cell lysates and live cells. We found that in live cells MT-21 strongly engaged the lipid transport protein fatty acid-binding protein 5 (FABP5) by direct binding to a cysteine residue in the bottom of the ligand binding pocket. Through preparation of a series of MT-21 derivatives, we probed the specificity of this interaction which was found to be strongly dependent on subtle structural changes. Our study suggests that MT-21 may be employed as a tool compound in future studies of the biology of FABP5, which remains incompletely understood. Furthermore, our study has also made clear that other natural products containing the AHPO-motif may likewise possess covalent reactivity and that this property may underlie their biological activity.
Competing Interests: There are no conflicts to declare.
(This journal is © The Royal Society of Chemistry.)
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تواريخ الأحداث: Date Created: 20221102 Latest Revision: 20221104
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC9533406
DOI: 10.1039/d2cb00161f
PMID: 36320884
قاعدة البيانات: MEDLINE
الوصف
تدمد:2633-0679
DOI:10.1039/d2cb00161f