ChemBioChem最新文献

In article 10.1002/cbic.202400319, Simon H. Friedman and co-workers have shown that a di-zinc complex (green circles and purple lines) can selectively dissolve crystalline calcium pyrophosphate (blue circles and red/orange space filling structure), while minimally dissolving hydroxy apatite, the main inorganic component of bone (cyan). It is effective because the complex pre-organizes electrostatically complementary zinc ions which then displace the crystalline calcium ions. Calcium pyrophosphate is the causative agent in pseudo-gout, a disease that affects millions.

Dynamic DNA nanotechnology is appealing for membrane surface engineering due to their versatility and programmability. To modulate the dynamic interactions between the DNA functional units immobilized on membrane surface, membrane-anchored DNA functional units often come into close proximity each other due to DNA base pairing, which also leads to the close contact of the hydrophobic anchors in membrane. However, whether the close contact of hydrophobic anchors induces the dissociation of amphiphilic DNA structures from membrane surface is not concerned. Herein, we utilized cholesterol-labeled single-stranded DNA (ssDNA) as a simplified amphiphilic DNA structure to investigate the stability of membrane anchored DNA strands upon the closely contact of cholesterol anchors. The close contact of cholesterol-labeled ssDNA molecules driven by toe-hold mediated strand displacement reaction leads to approximately 41 % membrane anchored ssDNA dissociation from membrane surface, indicating the proximal cholesterol anchors in membrane could reduce the anchoring stability of cholesterol-modified DNA strands. This work enhances our understanding of the interactions between amphiphilic DNA and membranes, and provides valuable insights for the design of future DNA constructs intended for applications involving dynamic DNA reactions on membrane surface.

Nitrogenases catalyze dinitrogen (N2) fixation to ammonia (NH3). While these enzymes are highly sensitive to deactivation by molecular oxygen (O2) they can be produced by obligate aerobes for diazotrophy, necessitating a mechanism by which nitrogenase can be protected from deactivation. In the bacterium Azotobacter vinelandii, one mode of such protection involves an O2-responsive ferredoxin-type protein ("Shethna protein II", or "FeSII") which is thought to bind with Mo-dependent nitrogenase's two component proteins (NifH and NifDK) to form a catalytically stalled yet O2-tolerant tripartite protein complex. This protection mechanism has been reported for Mo-nitrogenase, however, in vitro assays with V-nitrogenase suggest that this mechanism is not universal to the three known nitrogenase isoforms. Here we report that the reductase of the V-nitrogenase (VnfH) can engage in this FeSII-mediated protection mechanism when cross-coupled with Mo-nitrogenase NifDK. Interestingly, the cross-coupling of the Mo-nitrogenase reductase NifH with the V-nitrogenase VnfDGK protein does not yield such protection.

Hepatocellular carcinoma (HCC) is recognized globally as one of the most lethal tumors, presenting a significant menace to patients' lives owing to its exceptional aggressiveness and tendency to recur. Transcatheter hepatic arterial chemoembolization (TACE) therapy, as a first-line treatment option for patients with advanced HCC, has been proven effective. However, it is disheartening that nearly 40% of patients exhibit resistance to this therapy. Consequently, this review delves into the metabolic aspects of glucose metabolism to explore the underlying mechanisms behind TACE treatment resistance and to propose potentially fruitful therapeutic strategies. The ultimate objective is to present novel insights for the development of personalized treatment methods targeting HCC.

Retraction: M. J. Solares, G. M. Jonaid, W. Y. Luqiu, S. Berry, J. Khadela, Y. Liang, M. C. Evans, K. J. Pridham, W. J. Dearnaley, Z. Sheng and D. F. Kelly, "High-Resolution Imaging of Human Cancer Proteins Using Microprocessor Materials," ChemBioChem, 23, no. 17 (2022), e202200310, https://doi.org/10.1002/cbic.202200310. The above article, published online on 5 July 2022 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Ruben Ragg; and Wiley-VCH GmbH. The retraction has been agreed following a thorough peer review process conducted by the author's institution, Penn State. The editors' own independent investigation confirmed that density map for the p53 dimer does not align well with the model for Figures 2B and S3 A. Furthermore, it was found that the coordinate and map files associated with the article available in the Protein Data Bank [PDB accession codes 8F2I (p53 monomer), 8F2H (p53 dimer)] and Electron Microscopy Data Bank [EMDB accession codes EMD28817 (p53 monomer), EMD28816 (p53 dimer)] exhibit poor alignment throughout. In addition, the authors did not provide original research data, maps and models in question, to justify the findings. The editors' own independent investigation confirmed that the conclusions of this manuscript are not sufficiently supported. Author D. F. Kelly responded to our notice of retraction, but did not state their agreement nor disagreement. Author G. M. Jonaid agrees with the retraction. All other authors did not respond to our notice regarding the retraction.

4-Hydroxyisochroman-1-ones belong to the class of the secondary metabolite 3,4-dihydroisocoumarins. They exhibit a wide range of biological activities. These compounds can be synthesized through halocyclization using hypervalent iodine species or N-bromosuccinimide, followed by hydrolysis. Nonetheless, the reactions required specific conditions and generated toxic byproducts. In this study, Curvularia inaequalis vanadium chloroperoxidase (CiVCPO) catalyzed the chemoenzymatic cyclization of 2-vinylbenzoic acids with different electron-donating groups (1 a-1 e) to produce good yields of 4-hydroxyisochroman-1-ones (3 a-3 e) by adding KBr and H₂O₂ in citrate buffer (pH 5). The reaction mixture contained 30 % DMSO to improve substrate solubility without enzyme activity loss. The condition is more environmentally friendly than chemical methods. Therefore, it offers an alternative approach for synthesizing 4-hydroxyisochroman-1-ones.

Amyloidosis is characterized by the abnormal accumulation of misfolded proteins, called amyloid fibrils, leading to diverse clinical manifestations. Recent studies on the amyloidogenesis of SARS-CoV‑2 protein segments have raised concerns on their potential link to post-infection neurodegeneration, however, the mechanisms remain unclear. Herein, we investigated the structure, stability, and amyloidogenic propensity of a nine-residue segment (SK9) of the SARS-CoV-2 envelope protein and their impact on neuronal protein α-synuclein (αSyn) aggregation. Specifically, the amino acid sequence of the SK9 wildtype has been modified from a basic and positively charged peptide (SFYVYSRVK), to a nearly neutral and more hydrophobic peptide (SAAVASAVK, labelled as SK9 var1), and to an acidic and positively charged peptide (SFYVYSRVK, labelled as SK9 var2). Our findings reveal that the SK9 wildtype exhibited a pronounced amyloidogenic propensity due to its disordered and unstable nature, while the SK9 variants possessed more ordered and stable structures preventing the amyloid formation. Significantly, the SK9 wildtype demonstrated distinct effect on αSyn aggregation kinetics and aggregate morphology to facilitate the formation of αSyn aggregates with enhanced resistance against enzymatic degradation. This study highlights the potential of modifying short peptide sequences to fine-tune their properties, providing insights into understanding and regulating viral-induced amyloid aggregations.

Human sialyltransferases primarily utilize CMP-Sias, especially transferring Neu5Ac from CMP-Neu5Ac to various acceptors. Advances in chemical biology have led to the synthesis of novel CMP-Sia donors suitable for bioorthogonal reactions in cell-based assays. However, the compatibility of these donors with all human enzymes remains uncertain. We synthesized a non-natural CMP-Sia donor with an alkyne modification on the N-acyl group of Neu5Ac, which was effectively used by human ST6Gal I and ST3Gal I. A sensitive MicroPlate Sialyltransferase Assay (MPSA) was developed and expanded to a panel of 13 human STs acting on glycoproteins. All assayed enzymes tolerated CMP-SiaNAl, allowing for the determination of kinetic parameters and turnover numbers. This study enhances the biochemical characterization of human sialyltransferases and opens new avenues for developing sialyltransferase inhibitors.

Oligonucleotide gene therapy (OGT) can be used to suppress specific RNA in cells and thus have been explored for gene therapy. Despite extensive effort, there is no clinically significant OGT for treating cancer. Low efficiency of OGT is one of the problems. Earlier, we proposed to address this problem by suppressing most vital genes in cancer cells e.g. housekeeping genes. To achieve specific activation of the OGT agents in cancer but not in normal cells, we designed binary (split) DNAzyme (BiDz), which is activated by cancer-related nucleic acid sequences. This work is devoted to BiDz optimization using cancer marker-related sequence as an activator and three folded RNA targets. To achieve efficient binding of folded RNA, the BiDz design was equipped with RNA binding/unwinding arms, a construction that was dabbed 'BiDz machines' (BiDM). BiDM was designed to have improved both iRNA cleavage rates and RNA recognition in comparison with BiDz. Further development of DNA nanotechnology-inspired agents can advance OGT technology in treating cancer, viral infections, and genetic disorders.

Hydrolysis-resistant RNA-peptide conjugates that mimic peptidyl-tRNAs are often required for structural and functional studies of protein synthesis at the ribosome. These conjugates can be synthesized by solid-phase chemical synthesis, which allows maximum flexibility in both the peptide and RNA sequence. The commonly used strategy is based on (3'-N-aminoacyl)-3'-amino-3'-deoxyadenosine solid supports, which already contain the first C-terminal amino acid of the target peptidyl chain. This is a limitation in the sense that different individual supports must be synthesized for different C-terminal amino acids. In this study, we demonstrate a solution to this problem by introducing a novel universal support. The key is a free ribose 3'-NH₂ group that can be coupled to any amino acid. This is made possible by a photocleavable ether moiety that links the ribose 2'-O to the support, thus avoiding the typical O-to-N migration that occurs when using 2'-O-acyl linked solid supports. Once assembled, the conjugate is readily cleaved by UV irradiation. The structural integrity of the obtained peptidyl-RNA conjugates was verified by mass spectrometry analysis. In conclusion, the new photocleavable solid support makes the synthesis of 3'-peptidyl tRNA mimics of different peptidyl chains significantly more efficient compared to the commonly used approaches.