RESUMO
Metabolomics analysis detected tambjamine alkaloids in aqueous and EtOAc extracts of the marine invertebrates Virididentula dentata, Tambja stegosauriformis, Tambja brasiliensis, and Roboastra ernsti. Among several tambjamines, the new amino acid derivatives tambjamines M-O (17-19) were identified by Marfey's advanced analysis, UPLC-MS/MS analyses, and total synthesis. The tambjamine diversity increased from the bryozoan V. dentata to its nudibranch predators T. stegosauriformis and T. brasiliensis and attained a higher diversity in R. ernsti, the nudibranch that preys upon T. stegosauriformis and T. brasiliensis. The total tambjamine content also increases among the trophic levels, probably due to biomagnification. Tambjamines A (1), C (3), and D (4) are the major metabolites in the tissues of V. dentata, T. stegosauriformis, T. brasiliensis, and R. ernsti and are likely the main chemical defenses of these marine invertebrates.
Assuntos
Alcaloides/isolamento & purificação , Gastrópodes/química , Pirróis/isolamento & purificação , Animais , Organismos Aquáticos/química , Brasil , Cromatografia Líquida de Alta Pressão , Cadeia Alimentar , Metabolômica , Estrutura Molecular , Espectrometria de Massas em TandemRESUMO
Posttranslational modifications (PTMs) of histones play an important role in the complex regulatory mechanisms governing gene transcription, and their dysregulation can cause diseases such as cancer. The lack of methods for site-selectively modifying native chromatin, however, limits our understanding of the functional roles of a specific histone PTM, not as a single mark, but in the intertwined PTM network. Here, we report a synthetic catalyst DMAP-SH (DSH), which activates chemically stable thioesters (including acetyl-CoA) under physiological conditions and transfers various acyl groups to the proximate amino groups. Our data suggest that DSH, conjugated with a nucleosome ligand, such as pyrrole-imidazole-polyamide and LANA (latency-associated nuclear antigen)-peptide, promotes both natural (including acetylation, butyrylation, malonylation, and ubiquitination) and non-natural (azido- and phosphoryl labeling) PTMs on histones in recombinant nucleosomes and/or in native chromatin, at lysine residues close to the DSH moiety. To investigate the validity of our method, we used LANA-DSH to promote histone H2B lysine-120 (K120) acylation, the function of which is largely unknown. H2BK120 acetylation and malonylation modulated higher-order chromatin structures by reducing internucleosomal interactions, and this modulation was further enhanced by histone tail acetylation. This approach, therefore, may have versatile applications for dissecting the regulatory mechanisms underlying chromatin function.
Assuntos
Cromatina/química , Histonas/química , Processamento de Proteína Pós-Traducional , Acetilação , Catálise , Modelos Moleculares , EstereoisomerismoRESUMO
Protein degradation induced by small molecules by recruiting endogenous protein degradation systems, such as ubiquitin-proteasome systems, to disease-related proteins is an emerging concept to inhibit the function of undruggable proteins. Protein targets without reliable ligands and/or existing outside the cells where ubiquitin-proteasome systems do not exist, however, are beyond the scope of currently available protein degradation strategies. Here, we disclose photooxygenation catalyst 7 that permeates the blood-brain barrier and selectively and directly degrades an extracellular Alzheimer's disease-related undruggable protein, amyloid-ß protein (Aß). Key was the identification of a compact but orange color visible light-activatable chemical catalyst whose activity can be switched on/off according to its molecular mobility, thereby ensuring high selectivity for aggregated Aß. Chemical catalyst-promoted protein degradation can be applied universally for attenuating extracellular amyloids and various pathogenic proteins and is thus a new entry to induced protein degradation strategies.
RESUMO
Studies of secondary metabolites (natural products) that cover their isolation, chemical synthesis and bioactivity investigation present myriad opportunities for discovery. For example, the isolation of novel secondary metabolites can inspire advances in chemical synthesis strategies to achieve their practical preparation for biological evaluation. In the process, chemical synthesis can also provide unambiguous structural characterization of the natural products. Although the isolation, chemical synthesis and bioactivity studies of natural products are mutually beneficial, they are often conducted independently. Here, we demonstrate the benefits of a collaborative study of the phomactins, diterpenoid fungal metabolites that serve as antagonists of the platelet activating factor receptor. Our isolation of novel phomactins has spurred the development of a bioinspired, unified approach that achieves the total syntheses of six congeners. We also demonstrate in vitro the beneficial effects of several phomactins in suppressing the rate of repopulation of tumour cells following gamma radiation therapy.