This Perspective highlights how metabolic states regulate diverse protein modifications that affect physiology. In addition, the roles of subcellular localization of metabolic enzymes and the importance of untargeted omics approaches are discussed.

Aromatic side-chain crosslinking is emerging as a widespread and biosynthetically diverse feature in the RiPP natural products. This Review summarizes and unifies recent advancements, focusing on key enzymes that catalyze these modifications.

Poly(ester amide)s (PEAs) have various applications but their synthesis is currently limited to chemical methods. Now, the biosynthesis of various PEAs in engineered Escherichia coli is presented. The PEAs incorporate different amino acid monomers in varying fractions, which influences their physical, thermal and mechanical properties.

Trans-splicing enables the ligation of exons from different pre-mRNAs into a single transcript. A recent study harnesses this process and develops riboregulators that, upon binding programmable external guide sequences (EGSs), allow customizable, orthogonal and predictable gene circuit construction.

Polyketide synthases are powerful assembly line enzymes for the production of organic compounds. Here, the authors develop a versatile engineering strategy for assembly line reprogramming, enabling custom biosynthesis of designer molecules.

Polyketide synthases are powerful multidomain enzymes for the synthesis of organic compounds. Here, the authors present a strategy to use the thioester reductase domain in polyketide synthases for the stereoselective and customizable production of non-natural alcohols.

Cells undergoing ferroptosis secrete Galectin-13, which binds to CD44 and inhibits the plasma membrane localization of SLC7A11 in neighboring cells, thereby accelerating neighboring cell death and promoting ferroptosis propagation.

TDP-43 aggregates are a hallmark of neurodegeneration. Wagner et al. show that SUMOylation/ubiquitylation of TDP-43, mediated by its recruitment to the promyelocytic leukemia protein nuclear bodies, prevents its aggregation under proteotoxic stresses.

Locally elevated cholesterol in colorectal cancer cells with adenomatous polyposis coli truncation was observed to drive Wnt–β-catenin signaling through Dishevelled (Dvl). Inhibitors targeting the cholesterol–Dvl interaction potently suppress tumor growth without adverse side effects.

Temporal oscillations in the abundance of different phospholipid species during the yeast cell cycle are reported, suggesting regulation and interplay of phospholipid synthesis, membrane fluidity and metabolic efficiency during cell division.