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Small molecules and drugs are not homogenously distributed across cells, and are instead enriched in distinct subcellular compartments and membraneless biomolecular condensates. A new study lays out the path to identifying chemical features or ‘rationales’ that confer condensate-selective partitioning of small molecules.

A workflow integrating tools from bioinformatics, structural biology and synthetic biology has been developed that enables the rapid design of pili-enabled living materials. This approach allows mining of pili-producing nonpathogenic chassis, understanding of the pili structure and assembly, and engineering of pili-enabled living materials in a systematic and sequential manner.

Efforts to rationally engineer nonribosomal peptide synthetase (NRPS) enzymes have focused on making individual modifications. Here the authors describe a targeted random engineering approach that uses thousands of NRPS domains amplified from the soil metagenome for mass substitution experiments.

Cells contain compartments composed of phase-separated protein condensates. We find that these condensates have a unique chemical microenvironment that enriches amphipathic metabolites such as phospholipids. Therefore, condensates are mixtures of proteins, nucleic acids and specific metabolites. The presence of phospholipids and other amphipathic metabolites might enable condensates to facilitate specific metabolic reactions.

Oxygen sensitivity hampers applications of metal-dependent CO₂ reductases. Here, Oliveira et al. describe how an allosteric disulfide bond controls the activity of a CO₂ reductase, preventing its physiological reduction during transient O₂ exposure and allowing aerobic handling of the enzyme.

Controlled interactions between macromolecules are fundamental regulatory layers. Hijacking these circuits via proximity-inducing small molecules offers many therapeutic opportunities. The organizers, Georg Winter and Cristina Mayor-Ruiz, report on the latest trends in this emerging field discussed at the 39th IRB-BioMed Conference in Barcelona.

Cui et al. developed LAUNCHER, a single-component switch using potyviral protease, which offers a high signal-to-noise ratio for precise payload release, enabling versatile cellular applications and enhanced synthetic circuit performance.

Here, the authors describe the mechanistic flexibility and substrate promiscuity of the apramycin resistance enzyme ApmA. They identify additional clinical drugs susceptible to modification through a molecular mechanism that diverges from other enzymes within the left-handed β-helix superfamily.

Dumelie et al. asked whether biomolecular phase-separated condensates can establish microenvironments with distinct metabolomes and found that amphipathic lipids are highly enriched in these microenvironments and influence the properties of the condensates.

Ye et al. reveal the critical role of micropolarity in controlling the structure and miscibility of subcompartments in multiphasic biomolecular condensates, thereby providing new insights into multiphasic condensation regulation.

Terpenoids bearing carbon skeletons derived from nonisoprene units are rare and considered noncanonical. Now, a genome-mining study has uncovered previously unknown noncanonical C₁₆ terpenes and their biosynthetic pathways from bacteria. The findings suggest that noncanonical terpenoids are diverse and widespread in nature.

Development of chemically responsive bandpass filters mimics the signal-processing abilities of electronic circuits in mammalian cells by responding to chemical concentrations within a specific range and rejecting ones outside that range.

Methyl jasmonate in the root volatile organic compounds (rVOCs) signals to the soil microbiome to form biofilms with altered composition that benefits plant growth. This cross-kingdom VOCs-mediated signaling expands the zone of rhizosphere influence.

The integrated stress response affects cell survival or death under stress conditions, and depends on the activity of the eukaryotic translation initiation factor eIF2B. New research identifies a protein helix that modulates this response by controlling the structural states of eIF2B.

A chemical screen identified a small molecule inhibitor of CHEK2 that boosts insulin secretion in human β cells, including those from both healthy and type 2 diabetic human islets, as well as in diabetic mouse models and cynomolgus macaques.

Cofactorless oxygenases are rare in nature and natural product biosynthesis. Here the authors describe the biochemical and structural characterization of two such oxygenases catalyzing deformylation, ring cleavage and epoxidation in the biosynthesis of the enediyne natural product tiancimycin A.