This Perspective details how genome-wide association studies and metabolomics enabled the discovery of structures, bioactivities and pathways of modular metabolite biosynthesis originates from the ‘hijacking’ of conserved detoxification mechanisms by nematodes.

Biased signaling gives hormones, probes or drugs distinct functional outcomes via the same receptor. The Biased Signaling Atlas (https://BiasedSignalingAtlas.org) provides a community hub with data and tools to advance this paradigm, which may yield safer and more potent drugs.

A new review article details how new structural insight regarding modular polyketide synthases (PKSs) helps us better understand the organization of catalytic events within a PKS module. The plausible models discussed will likely influence future PKS engineering efforts.

Tricyclic peptides have reduced conformational flexibility, making them well suited for ligand development. Researchers have now generated large combinatorial libraries of tricyclic peptides using a disulfide-directing motif. Screening these libraries discovered binders to challenging protein targets.

Systematically culturing combinations of auxotrophic yeast mutants leads to the identification of pairs that form obligatory cross-feeding relationships, some of which are stable over time and can divide metabolic labor for biotechnological applications.

The use of chemical proteomics and cell-based assays enabled the discovery of gut microbiota-derived aromatic monoamines and synthetic agonists for an orphan G protein-coupled receptor GPRC5A that stimulated beta-arrestin recruitment.

Chemoproteomics reveals a vast expanse of ligandable cysteine sulfenic acids in the human proteome, highlighting the utility of nucleophilic small molecules in the fragment-based covalent ligand discovery pipeline.

Lowering the levels of disease-promoting proteins is generally assumed to be beneficial. The authors developed a two-step strategy to integrate protein-level tuning, noise-aware synthetic gene circuits into a well-defined human genomic locus. This approach was used to study the effect of BACH1 levels on MDA-MB-231 human breast metastatic cells.

Using a neural network trained on bacterial growth inhibition data, in silico prediction of molecules with activity against Acinetobacter baumannii led to the identification of the narrow-spectrum abaucin, which perturbs lipoprotein trafficking.

The structure, molecular and mechanistic details of the human α1,3-fucosyltransferase FUT9 provide insight into the synthesis of diverse and modified glycan-capping Lewis antigen structures by a conserved family of mammalian fucosyltransferases.