A Selective Chemical Probe for Coenzyme A-Requiring Enzymes
ABSTRACT Transferasen markiert: Eine auf dem Coenzym A (CoA) basierende Affinitätssonde mit einer Sulfoxycarbamat-Funktion erkennt eine Reihe von Acetyltransferasen selektiv gegenüber anderen Enzymen und Proteinen. Es verbleibt eine Desthiobiotin-Markierung, die für Western-Blots und die massenspektrometrische Charakterisierung genutzt werden kann (siehe Bild; Nu=Nucleophil).
- SourceAvailable from: Tatiana N Boronina
[Show abstract] [Hide abstract]
- "As all cysteines of HSP90 are located within its middle domain, small molecules that react with those cysteines may represent a new class of inhibitors distinct from those that target either the N-terminal ATP-binding pocket or the C-terminal domain of the chaperone. It was previously shown that cysteine residues of coenzyme A (CoA)-utilising enzymes can be selectively targeted by a mildly electrophilic sulphoxythiocarbamate-CoA analogue with the formation of stable thiocarbamate adducts (Hwang et al, 2007). "
ABSTRACT: Background: Heat shock protein 90 (HSP90) has a key role in the maintenance of the cellular proteostasis. However, HSP90 is also involved in stabilisation of oncogenic client proteins and facilitates oncogene addiction and cancer cell survival. The development of HSP90 inhibitors for cancer treatment is an area of growing interest as such agents can affect multiple pathways that are linked to all hallmarks of cancer. This study aimed to test the hypothesis that targeting cysteine residues of HSP90 will lead to degradation of client proteins and inhibition of cancer cell proliferation. Methods: Combining chemical synthesis, biological evaluation, and structure–activity relationship analysis, we identified a new class of HSP90 inhibitors. Click chemistry and protease-mass spectrometry established the sites of modification of the chaperone. Results: The mildly electrophilic sulphoxythiocarbamate alkyne (STCA) selectively targets cysteine residues of HSP90, forming stable thiocarbamate adducts. Without interfering with the ATP-binding ability of the chaperone, STCA destabilises the client proteins RAF1, HER2, CDK1, CHK1, and mutant p53, and decreases proliferation of breast cancer cells. Addition of a phenyl or a tert-butyl group in tandem with the benzyl substituent at nitrogen increased the potency. A new compound, S-4, was identified as the most robust HSP90 inhibitor within a series of 19 derivatives. Conclusion: By virtue of their cysteine reactivity, sulphoxythiocarbamates target HSP90, causing destabilisation of its client oncoproteins and inhibiting cell proliferation.British Journal of Cancer 12/2013; 110(1). DOI:10.1038/bjc.2013.710 · 4.84 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of these neurons is associated with a glial response composed mainly of activated microglial cells and, to a lesser extent, of reactive astrocytes. This glial response may be the source of trophic factors and can protect against reactive oxygen species and glutamate. Alternatively, this glial response can also mediate a variety of deleterious events related to the production of pro-oxidant reactive species, and pro-inflammatory prostaglandin and cytokines. We discuss the potential protective and deleterious effects of glial cells in the SNpc of PD and examine how those factors may contribute to the pathogenesis of this disease.Movement Disorders 02/2003; 18(2):121-9. DOI:10.1002/mds.10332 · 5.68 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: We describe herein a new method for covalent labeling of proteins using a complementary recognition pair of peptide tag and synthetic molecular probe. The rapid and specific covalent labeling of a tag-fused protein was achieved by the reaction on the tag site with the probe through their selective molecular recognition. The advantages of this method involve the facile functional modification and the high labeling specificity of the tag-fused protein, which are demonstrated in the labeling experiments in various conditions even inside cells.Journal of the American Chemical Society 01/2008; 129(51):15777-9. DOI:10.1021/ja074176d · 12.11 Impact Factor