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Deubiquitinating enzymes (DUBs) are critical regulators of cellular processes by removing ubiquitin from specific targets. Here global kinetic modelling reveals the mechanism by which the low intrinsic activity of USP7 is substantially enhanced on a specific physiological target.

Non-active site mutations such as L50F are crucial for restoring the viral fitness of SARS-CoV-2 main protease. Here, the authors use full-length Mpro protein as substrate and demonstrate that L50F can promote the formation of enzyme-substrate complex and thus contribute to nirmatrelvir resistance.

Several 17B-HSD13 variants have been identified as protective against NASH/MASH. However the protein’s endogenous function is unknown. Here authors describe sulfonamide-based inhibitors and synthetic substrates, then apply to multiple cellular systems revealing that the most prevalent IsoD variant maintains NAD-dependent catalytic activity.

Although Hippo signaling restricts regeneration in many mammalian organs, the pharmaceutical tools available to modulate the pathway have been limited. Here, the authors report a small molecule that may inhibit a key element in the Hippo cascade and may activate regenerative responses in several mammalian tissues.

PKU patients have elevated phenylalanine levels which can result in neurological impairment. Here the authors utilize biosensor-based ultra-high-throughput screening to optimize PAL activity in a synthetic biotic platform for improved in vivo performance.

PcdA interacts with DivIVA and FtsZ, promoting Z-ring formation and division plane selection in Staphylococcus aureus, which increases virulence in mice and reduces sensitivity to cell-wall-targeting antibiotics.

The design of artificial organelles for applications in living cells faces several challenges such as cellular uptake, stability and biocompatibility. Now, fusion of exosomes creates beneficial nanoreactors and their use for compartmentalized biocatalytic cascade reactions in cells is demonstrated.

To program intercellular communication for biomedicine, it is crucial to regulate the secretion and surface display of signaling proteins. Here the authors develop RELEASE, a modular approach to control intercellular signals using protein-based circuits.

Here the authors reveal how telomeres signal mitotic stress. A key protein network alters their structure exposing telomere ends to signal mitotic stress, ultimately triggering a controlled DNA damage response to remove faulty cells.

Abiological catalytic components can increase the synthetic potential of enzymes. This work reports an enzyme with two different abiological catalytic moieties—an organocatalytic unnatural amino acid and a metal complex—that act synergistically to achieve highly enantioselective Michael addition reactions.

Gene rv3722c is essential for in vitro growth of Mycobacterium tuberculosis, but its function is unclear. Here, Jansen et al. show that Rv3722c is the primary aspartate aminotransferase of this pathogen, mediates nitrogen distribution, and is important for virulence during infection of macrophages and mice.

Azetidine-2-carboxylic acid synthases catalyse the formation of the proline analogue azetidine-2-carboxylic acid (AZE) in bacteria. In this work, the authors combine structural and biochemical analyses with quantum mechanical calculations and mutagenesis studies to obtain catalytic insights into AZE synthases.

Anaplerotic reactions constantly refill metabolic networks with essential intermediates. This concept was adapted to enable a 54-step in vitro biosynthesis of the macrolide backbone of the antibiotic erythromycin from CO₂.

Mutations in the sodium/iodide symporter (NIS) cause congenital hypothyroidism, and our results yield insights into how NIS selects, couples and translocates anions, thereby establishing a framework for understanding NIS function.

The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.

The SARS-CoV-2 main protease (M^pro) is one of two cysteine proteases essential for viral replication. Here, the authors determine the crystal structure of an M^pro acyl intermediate with its native C-terminal autocleavage sequence and the structure of a product bound active site mutant (C145A), which are of interest for antiviral drug development.

The biochemical pathways of central carbon metabolism are highly conserved across all domains of life. Here, Courtet al. use a computational approach to test all possible pathways of glycolysis and gluconeogenesis and find that the existing trunk pathways may represent a maximal flux solution selected for during evolution.

Citrate synthase from the cyanobacterium Synechococcus elongatus is shown to self-assemble into Sierpiński triangles, a finding that opens up the possibility that other naturally occurring molecular-scale fractals exist.

Post translational modifications are involved in the regulation of a number of proteins and can be themselves modified by the cellular environment. Here the authors implicate citrullination of glucokinase in autoimmune diabetes

The ancient expansion of savannahs has long been examined through models and palaeorecords, but this new experiment combining CO₂ and drought finds the physiological mechanisms priming the forest-to-savannah transition.

Here, using cryo-EM, the authors reveal the mechanism by which RecA filamented on single-stranded DNA binds to and induces LexA cleavage, the key signal governing the bacterial DNA damage response pathway implicated in antibiotic resistance.

The early stages of transcription-coupled DNA repair are observed at single-molecule resolution; the Escherichia coli DNA translocase molecule Mfd is shown to promote RNA polymerase dissociation by catalysing two irreversible, ATP-dependent transitions.

Functional metagenomic screening identified a pair of enzymes from the gut bacterium Flavonifractor plautii that can efficiently convert A antigen to the H antigen of universal O type blood.

By creating synthetic strains of Saccharomyces cerevisiae that differ in their sucrose metabolism strategies, the authors show that private-metabolizers may outcompete communities of public-metabolizers and cheater-strains, but their lower growth rate ultimately causes instability and population decline.

Bioinformatic analysis coupled to substrate-reactivity profiling for the glycosyltransferase (GT) enzyme superfamily supports the development of ‘GT-Predict’ as a tool for functional prediction of GT–substrate relationships.

A screen of a human gut microbiome metagenomic library reveals a cluster of enzymes with an unconventional mechanism and an extremely broad substrate scope.

The docking of a 1.7 billion- versus a 99 million-molecule virtual library against β-lactamase revealed that the larger-sized library produced improved hit rates and potency along with an increased number of scaffolds.

Enzyme reactions at interfaces are common in both Nature and industrial applications but no general kinetic framework exists for interfacial enzymes. Here, the authors kinetically characterize 83 cellulases and identify a scaling relationship between ligand binding strength and maximal turnover, a so-called linear free energy relationship, which may help rationalize cellulolytic mechanisms and guide the selection of technical enzymes.

Here, via screening of a polypeptide library from bronchoalveolar lavage, the authors identify and characterize α₁-antitrypsin (α₁AT) as SARS-CoV-2 inhibitor and show that α₁AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion.

Electrospinning is a useful method of biomaterial fabrication, but a lack of bioactivity in the final construct can limit their application as mimics for biological matrices. Here, the authors fabricate a degradable electrospun scaffold as an in vitro and in vivomimic of the extracellular matrix.

Bacterial resistance to sulfonamide antibiotics (sulfas) is mediated by acquisition of sul genes, which encode sulfa-insensitive versions of the target enzyme, dihydropteroate synthase. Here, Venkatesan et al. study Sul enzymes using biochemical, structural, mutational and functional analyses, revealing the molecular basis for Sul-mediated drug resistance.

Cancer genetics has benefited from the advent of next generation sequencing, yet a comparison of sequencing and analysis techniques is lacking. Here, the authors sequence a normal-tumour pair and perform data analysis at multiple institutes and highlight some of the pitfalls associated with the different methods.

The development of a first-in-class non-covalent small-molecule inhibitor of SARS-CoV-2 replication that targets the viral guanine-N7 methyltransferase NSP14 is reported.

Here the authors show mutants of isocitrate dehydrogenase 1 (IDH1), an enzyme implicated in various cancers, have distinct catalytic and structural features that drive their ability to generate an oncometabolite.

WbbB is a structurally unusual retaining glycosyltransferase. Here, the authors show that WbbB forms an Asp232-Kdo adduct prior to transfer to the saccharide acceptor. Therefore, unlike any previously studied glycosyltransferase, WbbB uses the double-displacement mechanism first proposed in 1953.

The iron chaperone poly(rC)-binding protein 1 (PCBP1) coordinates ferrous iron via its KH3 domain and, together with BolA2 and glutathione, forms a complex that is required for the assembly of [2Fe–2S] clusters on the cytosolic BolA2–Glrx3 chaperone.

Ubiquitous mammalian enzymes can scavenge uracil analogs, leading to non-specific background in cell-type-specific RNA labeling. This work reveals the enzymes involved and describes the uridine/cytidine kinase 2 and 2′-azidouridine pair as a highly specific and non-toxic alternative.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate determining step for NAD⁺ synthesis and is of interest as a drug target. Here the authors identify and characterize a small molecule NAMPT activator SBI-797812, elucidate its mode of action and show that it increases intracellular NMN and NAD⁺ levels in cultured cells and elevates liver NAD⁺ in mice.

Methane emissions are determined by the balance of microbial methane production relative to consumption. Warming drives larger increases in methane production than consumption in experimental ponds, suggesting that natural ecosystems may represent a positive feedback under climate change.