Discovery of Chirally-dependent Protein -2-Hydroxyglutarylation by D2HG and L2HG.

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are common in multiple types of human cancer, leading to the accumulation of D-2-hydroxyglutarate (D2HG) and the promotion of tumorigenesis. Here we discovered a novel -2-hydroxyglutarylation by D2HG using chemical proteomics and further revealed distinct chiral preferences for D/L2HG modifications. Notably, we identified two kinases, MRCKA and SLK, modified by D2HG and L2HG respectively, and detected reduced phosphorylation of their substrates, suggesting an inhibitory effect of D/L 2HG modifications on the kinases' activity.

Cyclic Peptide Natural Product Inspired Inhibitors of the Free-Living Amoeba .

is a pathogenic free-living amoeba (pFLA) that can cause infection of the central nervous system (CNS), called amoebic encephalitis (BAE), as well as cutaneous and systemic diseases. Patients infected with have a high mortality rate due to a lack of effective treatments. A nonoptimized antimicrobial drug regimen is typically recommended; however, it has poor antiparasitic activity and can cause various and severe side effects.

Design, Synthesis, and Evaluation of Trihalomethyl Ketone Derivatives of Neocarzilin A as Improved Antimetastatic Agents.

Vesicle Amine Transport-1 (VAT1) is a protein that is overexpressed in many cancers, including breast cancer, glioblastoma, and angiosarcoma. High VAT1 expression correlates with poor overall survival, and genetic knockout models of VAT1 indicate potent antimigratory activity, suggesting that VAT1 is a promising antimetastasis target. Recently, the natural product neocarzilin A (NCA) from was reported to be the first validated small-molecule inhibitor of VAT1, having strong activity in metastasis models of angiosarcoma and breast cancer.

Biocatalytic Tetrapeptide Macrocyclization by Cryptic Penicillin-binding Protein-type Thioesterases.

Cyclic tetrapeptides (CTPs) are a diverse class of natural products with a broad range of biological activities. However, they are extremely challenging to synthesize due to the ring strain associated with their small ring size. While chemical methods have been developed to access CTPs, they generally require the presence of certain amino acids, limiting their substrate scopes.

Long-term Survival of Bladder Augmentation is Influenced by its Shape and Mucosal Lining.

Introduction: Bladder augmentation in the UK has been largely by enterocystoplasty or ureterocystoplasty (UC). Ileocystoplasty can be simple patch placement (SPP), or formation of an ileal cup (IC). Urothelium is the "right" mucosa, whereas intestinal mucosa exhibits absorption, mucus production, malignancy.