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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.

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.

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.

The collapse of tropical forests during the Permian–Triassic Mass Extinction weakened carbon sequestration, sustaining high CO2 and extreme global warmth for millions of years: an example of a runaway feedback in Earth’s climate-carbon system.

Recent studies have shown that energy transfer photoenzymes can be engineered to promote stereocontrolled [2 + 2] cycloadditions; however, existing systems rely on ultraviolet light and display limited photochemical efficiencies. A generation of thioxanthone-containing photoenzymes now harnesses visible light to drive challenging photochemical conversions with high efficiencies and selectivities.

Several independent lines of evidence demonstrated long-term potentiation induction by a structural function of calmodulin-dependent protein kinase II rather than by its enzymatic 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.

Single-molecule measurements of synaptic vesicles show that V-ATPases do not pump continuously in time but instead stochastically switch between ultralong-lived proton-pumping, inactive and proton-leaky modes.

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.

Acetyl-CoA assimilation pathways are usually associated with the loss of carbon in the form of CO₂. Here, the authors report a new metabolic pathway enabled by an engineered B₁₂-dependent acyl-CoA mutase, in which CO₂ is fixed during acetyl-CoA assimilation.

In the context of enviromental applications, refining enzymes into more minimalist structures could ease production costs, improve stability, and improve reusability. Here, the authors report a single amino acid bionanozyme that can catalyze the rapid oxidation of environmentally toxic phenolic contaminates and serves as a tool to detect biologically important neurotransmitters similar to the laccase enzyme.

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.

An analysis of T cell responses in people with amyotrophic lateral sclerosis shows that the C9orf72 antigen is a key target of autoimmune responses in the disease, and identifies C9orf72 epitopes that are recognized.

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.

This study presents DNA-origami biocatalytic modular nanocompartments for programmed regulation of protein unfolding and degradation. These artificial nanofactories augment reaction kinetics, improve enzyme performance and reduce off-target effects.

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.

Despite widespread use of azides across material science and various areas across chemistry, the underlying biosynthetic pathways for its formation have so far been unknown. Now, a promiscuous ATP-utilizing enzyme, Tri17, capable of synthesizing various azide molecules has been identified. Biochemical, structural and computational analyses support a potential molecular mechanism for azide formation by Tri17.

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.

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.

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.

Carbohydrate esterases alter polysaccharides by removing ester groups. Here, the authors resolved crystal structures of two CE20 enzymes and discovered a novel, water-mediated catalytic triad essential for activity, offering insights into enzyme function and mechanism.

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.

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.

The responses of phytoplankton growth rates to ocean acidification were investigated in a meta-analysis. A marine ecosystem model calibrated with the results indicates that these different responses will result in changes in community structure.

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.

Trees come in all shapes and size, but what drives this incredible variation in tree form remains poorly understood. Using a global dataset, the authors show that a combination of climate, competition, disturbance and evolutionary history shape the crown architecture of the world’s trees and thereby constrain the 3D structure of woody ecosystems.

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 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.

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.

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.

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.

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.

Experimental data on enzyme turnover numbers is sparse and noisy. Here, the authors use machine learning to successfully predict enzyme turnover numbers for E. coli, and show that using these to parameterize mechanistic genome-scale models enhances their predictive accuracy.

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.

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.

A high-throughput chemical–genetic screening approach for the discovery of targets and chemicals to treat Mycobacterium tuberculosis yields tenfold more hit compounds than conventional whole-cell screening methods.

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

Helicobacter pylori is a major cause of gastric diseases, but the standard therapy is limited by continuously decreased therapeutic efficacy and side effects to symbiotic bacteria. Here, the authors develop a pH-responsive graphitic nanozyme that is active under low pH gastric conditions, but inactive in intestines, for selective treatment of H. pylori infections.