The metagenome of the gut microbiome encodes tremendous potential for biosynthesizing and transforming small-molecule metabolites through the activities of enzymes expressed by intestinal bacteria. Accordingly, elucidating this metabolic network is critical for understanding how the gut microbiota contributes to health and disease. Bile acids, which are first biosynthesized in the liver, are modified in the gut by enzymes expressed by commensal bacteria into secondary bile acids, which regulate myriad host processes, including lipid metabolism, glucose metabolism, and immune homeostasis. The gateway reaction of secondary bile acid biosynthesis is mediated by bile salt hydrolases (BSHs), bacterial cysteine hydrolases whose action precedes other bile acid modifications within the gut. To assess how changes in bile acid metabolism mediated by certain intestinal microbiota impact gut physiology and pathobiology, methods are needed to directly examine the activities of BSHs because they are master regulators of intestinal bile acid metabolism. Here, we developed chemoproteomic tools to profile changes in gut microbiome-associated BSH activity. We showed that these probes can label active BSHs in model microorganisms, including relevant gut anaerobes, and in mouse gut microbiomes. Using these tools, we identified altered BSH activities in a murine model of inflammatory bowel disease, in this case, colitis induced by dextran sodium sulfate, leading to changes in bile acid metabolism that could impact host metabolism and immunity. Importantly, our findings reveal that alterations in BSH enzymatic activities within the gut microbiome do not correlate with changes in gene abundance as determined by metagenomic sequencing, highlighting the utility of chemoproteomic approaches for interrogating the metabolic activities of the gut microbiota.

Guanosine 5'-monophosphate, (5'-GMP), is a self-assembling natural nucleotide that has unique potential to form ordered supramolecular structures. We herein describe an intriguing property of Na2(5'-GMP) to form blue emitting chiral carbon dots (G-dots) that exhibit excitation dependent down-conversion and up-conversion fluorescence signature and self-assemble to form fluorescent hydrogels.

Summary Expression of tumor suppressor p53 is regulated at multiple levels, disruption of which often leads to cancer. We have adopted an approach combining computational systems modeling with experimental validation to elucidate the translation regulatory network that controls p53 expression post DNA damage. The RNA-binding protein HuR activates p53 mRNA translation in response to UVC-induced DNA damage in breast carcinoma cells. p53 and HuR levels show pulsatile change post UV irradiation. The computed model fitted with the observed pulse of p53 and HuR only when hypothetical regulators of synthesis and degradation of HuR were incorporated. miR-125b, a UV-responsive microRNA, was found to represses the translation of HuR mRNA. Furthermore, UV irradiation triggered proteasomal degradation of HuR mediated by an E3-ubiquitin ligase tripartite motif-containing 21 (TRIM21). The integrated action of miR-125b and TRIM21 constitutes an intricate control system that regulates pulsatile expression of HuR and p53 and determines cell viability in response to DNA damage.

Regioselective dimerization of terminal aryl alkynes to produce conjugated enynes has been achieved using FeCl3 and KO(t)Bu in the presence of either DMEDA or dppe. The reaction proceeds smoothly in toluene at 145 °C for 2 h to give the corresponding head-to-head dimers in good to excellent yields (54 to 99%) with high E-selectivity (67 : 33 to 83 : 17 E/Z). Both strongly electron-donating and electron-withdrawing groups are compatible with this procedure. The bidentate phosphine (dppe) ligand exhibits better catalytic activity than the bidentate amine (DMEDA). The aliphatic acetylene fails to react under this catalytic system which suggests that potassium tertiary butoxide activates the conjugated system of aryl acetylene through cation-pi interaction and pi-pi interaction. A radical inhibitor (galvinoxyl or TEMPO) completely suppresses the reaction. Employing FeCl2 as a catalyst instead of FeCl3, only phenyl acetylene afforded the corresponding head to head dimer in good yield. Mechanistic pathways for both FeCl3 catalyzed dimerization of aryl alkynes and FeCl2 catalyzed dimerization of phenyl acetylene have been proposed.

A photocaged histone deacetylase inhibitor was developed as a strategy to inhibit activation of macrophages in a spatiotemporal manner.