Microbial Chemistry Research Foundation

Mono-rhamnolipids are glycolipid biosurfactants that exhibit both antibacterial and surface-active properties. In this study, we achieved the total synthesis of a mono-rhamnolipid library consisting of 12 members that differ in fatty chain length, number, and stereochemistry via organophotoacid-catalyzed glycosylation. We then performed a structure-activity relationship study to evaluate their antibacterial activities.

Catalytic enantioselective benzoin condensation conditions that are potentially useful for the total synthesis of cycloimidamicins and structure-activity relationship studies of these natural products were developed. A triazole-based NHC catalyst promoted the transformation to afford the cyclization products. To make the reactions applicable to substrates with complex structural features, a Lewis acidic additive, B(OMe)Et2, was used, but fine-tuning of the base and solvent conditions was required to attain a good chemical yield and excellent enantioselectivity. These conditions showed a broad substrate scope and were not limited to substrates useful for the synthesis of cycloimidamicins and their related compounds. This study also clearly demonstrates the utility of N-heterocyclic carbene organocatalysts that have not been reported to exhibit perfect enantioselectivity in intramolecular benzoin condensation.

ABSTRACT Skeletal muscle regeneration is critically shaped by lipid remodeling, yet regulatory mechanisms involved remain unexplored. We identify MBOAT2, a lysophospholipid acyltransferase highly induced in activated satellite cells, as a key enzyme that limits the amounts of polyunsaturated fatty acids (PUFAs) in phosphatidylcholine (PC). Lipidomic profiling reveals a characteristic PC signature—high in monounsaturated fatty acids (MUFAs) and low in PUFAs—in dystrophic, injured, and neonatal muscle, paralleling elevated Mboat2 expression. Given the susceptibility of PUFAs to oxidative damage and the emerging role of lipid peroxidation in driving muscle atrophy during denervation, disuse, and aging, MBOAT2-mediated enrichment of MUFA-PC may represent a protective and pro-regenerative lipid environment. Loss- and gain-of-function approaches confirm that MBOAT2 remodels PC and promotes myogenic repair. Our findings uncover a lipid remodeling circuit in muscle stem cells that buffers oxidative stress and highlight that MBOAT2 may improve regenerative capacity in muscular dystrophy, sarcopenia, and other muscle-wasting conditions. Abstract Figure

Abstract In mammals, autophagosome formation, a central event in autophagy, is initiated by the ULK complex comprising ULK1/2, FIP200, ATG13, and ATG101. However, the structural basis and mechanism underlying the ULK complex assembly have yet to be fully clarified. Here, we predicted the core interactions organizing the ULK complex using AlphaFold, which proposed that the intrinsically disordered region of ATG13 engages the bases of the two UBL domains in the FIP200 dimer via two phenylalanines and also binds the tandem MIT domain of ULK1, thereby yielding the 1:1:2 stoichiometry of the ULK1–ATG13–FIP200 complex. We validated the predicted interactions by point mutations and demonstrated direct triad interactions among ULK1, ATG13, and FIP200 in vitro and in cells, wherein each interaction was additively important for autophagic flux. These results indicate that the ULK1–ATG13– FIP200 triadic interaction is crucial for autophagosome formation and provide a structural basis and insights into the regulation mechanism of autophagy initiation in mammals.

A new miniaturized framework for graphitic material featuring three neighboring pyridinic nitrogen atoms is disclosed. The quinoline/quinazoline hybridized pseudo trimeric macrocycle, DiQuinoline(Q)-MonoQuinazolines(Qz), Q2Qz1, was readily synthesized from the key macrocyclic amide precursor in a modular fashion. Its central cavity strongly captures a proton, and the thus-formed positively charged, highly planar architecture exhibits supramolecular complexation through π-interactions. Q2Qz1, with its unique properties, was applied as a scavenger for toxic polyaromatic hydrocarbons and as a G-quartet ligand for potential therapeutic agent for cancer chemotherapy.

The first enantioselective copper-catalyzed conjugate addition of α-substituted benzyl nitriles to alkyl acrylates is described. This protocol allows the direct and 100% atom-economic generation of a nitrile-containing quaternary stereogenic center in a highly enantioselective manner. The practical application of our methodology was demonstrated through the concise formal synthesis of (-)-aphanorphine.

To define cellular immunity to the intracellular pathogen Toxoplasma gondii, we performed a genome-wide CRISPR loss-of-function screen to identify genes important for (interferon gamma) IFN-γ-dependent growth restriction. We revealed a role for the tumor suppressor NF2/Merlin for maximum induction of Interferon Stimulated Genes (ISG), which are positively regulated by the transcription factor IRF-1. We then performed an ISG-targeted CRISPR screen that identified the host E3 ubiquitin ligase RNF213 as necessary for IFN-γ-mediated control of T. gondii in multiple human cell types. RNF213 was also important for control of bacterial (Mycobacterium tuberculosis) and viral (Vesicular Stomatitis Virus) pathogens in human cells. RNF213-mediated ubiquitination of the parasitophorous vacuole membrane (PVM) led to growth restriction of T. gondii in response to IFN-γ. Moreover, overexpression of RNF213 in naive cells also impaired growth of T. gondii. Surprisingly, growth inhibition did not require the autophagy protein ATG5, indicating that RNF213 initiates restriction independent of a previously described noncanonical autophagy pathway. Mutational analysis revealed that the ATPase domain of RNF213 was required for its recruitment to the PVM, while loss of a critical histidine in the RZ finger domain resulted in partial reduction of recruitment to the PVM and complete loss of ubiquitination. Both RNF213 mutants lost the ability to restrict growth of T. gondii, indicating that both recruitment and ubiquitination are required. Collectively, our findings establish RNF213 as a critical component of cell-autonomous immunity that is both necessary and sufficient for control of intracellular pathogens in human cells.

A copper-catalyzed asymmetric vinylogous conjugate addition of butenolide to 2-ester-substituted chromones is described, and it delivers syn- or anti-chromanone lactones with high stereoselectivities. The enantioselectivity-determining step varied with the use of B(OMe)3 as an additive, resulting in enhanced stereoselectivities, as revealed by density functional theory calculations, which also provided theoretical insight into the origin of the ligand-dependent diastereodivergence.

Two structures of paddlewheel rhodium complexes displaying either syn or anti conformations are shown in the cover picture. Each of them stands on a separated podium, indicating that two conformations are not in an equilibrium and thus do not undergo interconversion. The conformational fixation has proven to be useful for the development of selective nitrene transfer catalysts, as demonstrated by Xinxin Tang, Hidetoshi Noda, and Masakatsu Shibasaki in their Research Article (e202311027).