Genome mining of sulfonated lanthipeptides reveals unique cyclic peptide sulfotransferases.

Although sulfonation plays crucial roles in various biological processes and is frequently utilized in medicinal chemistry to improve water solubility and chemical diversity of drug leads, it is rare and underexplored in ribosomally synthesized and post-translationally modified peptides (RiPPs). Biosynthesis of RiPPs typically entails modification of hydrophilic residues, which substantially increases their chemical stability and bioactivity, albeit at the expense of reducing water solubility. To explore sulfonated RiPPs that may have improved solubility, we conducted co-occurrence analysis of RiPP class-defining enzymes and sulfotransferase (ST), and discovered two distinctive biosynthetic gene clusters (BGCs) encoding both lanthipeptide synthetase (LanM) and ST. Upon expressing these BGCs, we characterized the structures of novel sulfonated lanthipeptides and determined the catalytic details of LanM and ST. We demonstrate that SslST-catalyzed sulfonation is leader-independent but relies on the presence of A ring formed by LanM. Both LanM and ST are promiscuous towards residues in the A ring, but ST displays strict regioselectivity toward Tyr5. The recognition of cyclic peptide by ST was further discussed. Bioactivity evaluation underscores the significance of the ST-catalyzed sulfonation. This study sets up the starting point to engineering the novel lanthipeptide STs as biocatalysts for hydrophobic lanthipeptides improvement.

Synthesis of 1,2-Disubstituted C-Aryl Glycosides via Palladium/Norbornene Cooperative Catalysis.

The Catellani reaction offers an opportunity to address multiple chemical bonds in a single pot. However, it is still quite a challenge to construct fully substituted olefins via this strategy, especially in electron-rich, unstable, and highly functionalized glycals. Herein we report the first palladium-catalyzed Catellani reaction for the direct preparation of 1,2-disubstituted C-aryl glycosides from easily available 2-iodoglycals, bromoaryl, and alkene/alkyne substrates. This transformation exhibits a wide substrate scope, accommodating diverse functional groups and intricate molecular frameworks. This innovative reactivity offers an efficient pathway to valuable 1,2-disubstituted carbohydrate analogues and molecular building blocks, facilitating novel strategic bond disconnections and broadening the reactivity landscape of palladium catalysis.

Divergent Biosynthesis of Bridged Polycyclic Sesquiterpenoids by a Minimal Fungal Biosynthetic Gene Cluster.

The bridged polycyclic sesquiterpenoids derived from sativene, isosativene, and longifolene have unique structures, and many chemical synthesis approaches with at least 10 steps have been reported. However, their biosynthetic pathway remains undescribed. A minimal biosynthetic gene cluster (BGC), named bip, encoding a sesquiterpene cyclase (BipA) and a cytochrome P450 (BipB) is characterized to produce such complex sesquiterpenoids with multiple carbon skeletons based on enzymatic assays, heterologous expression, and precursor experiments. BipA is demonstrated as a versatile cyclase with (-)-sativene as the dominant product and (-)-isosativene and (-)-longifolene as minor ones. BipB is capable of hydroxylating different enantiomeric sesquiterpenes, such as (-)-longifolene and (+)-longifolene, at C-15 and C-14 in turn. The C-15- or both C-15- and C-14-hydroxylated products are then further oxidized by unclustered oxidases, resulting in a structurally diverse array of sesquiterpenoids. Bioinformatic analysis reveals the BipB homologues as a discrete clade of fungal sesquiterpene P450s. These findings elucidate the concise and divergent biosynthesis of such intricate bridged polycyclic sesquiterpenoids, offer valuable biocatalysts for biotransformation, and highlight the distinct biosynthetic strategy employed by nature compared to chemical synthesis.

Highly Diastereoselective Synthesis of C-Glycosides from Glycal Anomers.

This Letter presents a highly diastereoselective synthesis of C-hydroxymethine glycosides from glycal anomers using a chiral N-heterocyclic carbene-copper catalyst. The high diastereoselectivity was synergistically controlled by the stereocenter of the substrate and chirality of the N-heterocyclic carbene-copper complex without being interrupted by the stereochemistry of C5 and the anomeric position. This approach enables the production of a diverse array of C-hydroxymethine glycosides using synthetically versatile glycals and various functionalized aldehydes.

Synthesis of the Disaccharide Core of Ezomycin Nucleosides.

The ezomycins make up a class of complex nucleoside antibiotics that share a common disaccharide core. Herein we present an efficient synthesis of this core from diacetone-d-allose, using a ruthenium-catalyzed asymmetric allylic etherification and a de novo carbohydrate synthesis based on the diastereoselective Henry reaction. Our strategy overcomes several challenges, such as introducing a dense array of functional groups and creating consecutive stereocenters with high selectivity. This approach enables the rapid preparation of disaccharides and paves the way for the total synthesis of ezomycins.

Structurally diverse diterpenoids from the roots of Euphorbia fischeriana Steud.

Four new diterpenoids (1-4), and 18 known ones were isolated from the roots of Euphorbia fischeriana Steud (Euphorbiaceae). These diterpenoids shared six skeleton types, including ent-atisane, kaurane, 3,4-secokaurane, lathyrane, 4,5-secoatisane and ingenane diterpenoids. The structures of the new diterpenoids were characterized by a combination of spectroscopic techniques and X-ray crystallography. Moreover, biological evaluation revealed that compounds (16S*)-atisan-3ß,16,17-triol (7), (16S*)-3ß,16,17,18-tetrahydroxykaurane (12) and (16S*)-3α-hydroxykauran-16,17-acetonide (15) showed inhibitory activity against the interferon regulatory factors (IRFs) involved pathway.

Antisense oligonucleotide targeting of mRNAs encoding ENaC subunits α, ß, and γ improves cystic fibrosis-like disease in mice.

BACKGROUND: The epithelial sodium channel ENaC consists of three subunits encoded by Scnn1a, Scnn1b, and Scnn1g and increased sodium absorption through this channel is hypothesized to lead to mucus dehydration and accumulation in cystic fibrosis (CF) patients. METHODS: We identified potent and specific antisense oligonucleotides (ASOs) targeting mRNAs encoding the ENaC subunits and evaluated these ASOs in mouse models of CF-like lung disease. RESULTS: ASOs designed to target mRNAs encoding each ENaC subunit or a control ASO were administered directly into the lungs of mice. The reductions in ENaC subunits correlated well with a reduction in amiloride sensitive channel conductance. In addition, levels of mucus markers Gob5, AGR2, Muc5ac, and Muc5b, periodic acid-Schiff's reagent (PAS) goblet cell staining, and neutrophil recruitment were reduced and lung function was improved when levels of any of the ENaC subunits were decreased. CONCLUSIONS: Delivery of ASOs targeting mRNAs encoding each of the three ENaC subunits directly into the lung improved disease phenotypes in a mouse model of CF-like lung disease. These findings suggest that targeting ENaC subunits could be an effective approach for the treatment of CF.

Correlation analysis of gene polymorphisms and ß-lactam allergy.

A total of 64 patients with ß-lactam allergy and 30 control subjects were enrolled in a case-control study. This study is aimed to analyze the relationship between ß-lactam allergy and 10 single nucleotide polymorphisms (SNPs) in interleukin-10 (IL-10), IL-13, IL-4Rα, high-affinity immunoglobulin E-receptor ß chain (FcεRIß), interferon γ receptor 2 (IFNGR2), and CYP3A4, and within the Han Chinese population of Northwest China. Genotyping for the SNPs was conducted using the Sequenom MassARRAY(®) platform. SPSS 17.0 was employed to analyze the statistical data and SHEsis was used to perform the haplotype reconstruction and analyze linkage disequilibrium of SNPs of IL-10 and IL-13. The results showed that the genotype distribution of CYP3A4 rs2242480/CT differed significantly between case and control groups of males (P=0.022; odds ratio (OR)=0.167, 95% confidence interval (CI): 0.032-0.867). Further analysis showed that CCA, CCG, and TAA haplotypes of IL-10 had no significant correlation in patients with ß-lactam allergy. The correlation between CCT and CAC haplotypes of IL-13 and ß-lactam allergy needs to be further studied. The analysis did not reveal any differences in the distribution of others gene polymorphisms between cases and controls.