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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.

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.

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.

Enzymes that form a metabolic pathway in which the product of one enzyme is the substrate for the next have now been shown to associate through a process of sequential, directed chemotactic movement. The extent of enzyme migration is proportional to the exposure time to the substrate gradient.

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.

Here, Schubert et al. investigate the metabolic requirements for Salmonella Typhimurium colonization using a barcoded mutant pool across five different mouse models with varying microbiome complexity and identify several monosaccharides that are utilized in a context-(in)dependent manner.

The late-stage functionalization of unactivated carbon–hydrogen bonds is a difficult but important task, which has been met with promising but limited success through synthetic organic chemistry. Here the authors use machine learning to engineer WelO5* halogenase variants, which led to regioselective chlorination of inert C–H bonds on a representative polyketide that is a non-natural substrate for the enzyme.

Improved mass spectrometry–based detection of low-abundance proteins in complex proteomes is made possible with a method to selectively digest and deplete high-abundance proteins.

Protein glycation is a ubiquitous form of damage caused by reactive dicarbonyl byproducts of metabolism. Here, Jensen et al. show that dicarbonyl-mediated protein crosslinking is harnessed to activate a phospholipase toxin, demonstrating that glycation can also be beneficial for protein function.

Patrick et al. used single-molecule optical tweezers to study the enzymatic activity and dynamics of product release of telomerase and provide direct evidence for the presence of an anchor site in elongating telomerase.

In vitro assembly of out-of-equilibrium enzymatic reaction networks has proved challenging, limiting the development of autonomous synthetic systems. Now, a methodology has been developed to construct an enzymatic reaction network producing oscillations of active trypsin. The modular approach allows amplification or analog-to-digital conversion of the oscillations, and control over a self-assembly process.

Mitochondrial fatty acid synthesis (mtFAS) generates the precursor for lipoic acid synthesis, but the role of longer fatty acid products has remained unclear. Here, the authors generated an engineered variant of human 2E-enoyl-ACP reductase (MECR) of mtFAS to study the role of long chain fatty acids.

Post-translational modifications are critical for regulating the DNA damage response. Here, the authors identify a methylation-deubiquitination crosstalk between methyltransferase PRMT1 and deubiquitinase USP11, showing that the enzymes regulate each other’s functions in DNA repair.

Cbl RING ubiquitin ligases regulate receptor tyrosine kinase signal transduction and are in turn regulated by phosphorylation in their linker helix regions. Structural and biochemical analysis now shows that phosphorylation of c-Cbl leads to the release of an autoinhibited conformation, enhancing E2 binding and promoting ubiquitination activity.

New influenza neuramidase inhibitors may increase preparedness against influenza outbreaks. Vavricka et al.confirm the catalytic mechanism of neuramidase and show that it can be inhibited irreversibly with covalent inhibitors.

Reconstitution of the SARS-CoV-2 RNA 5′ cap reveals the unconventional mechanism by which SARS-CoV-2 caps its RNA genome, providing a new target in the development of antiviral agents to treat COVID-19.

Bacterial growth and division require remodelling of the cell wall, which generates free peptidoglycan fragments. Here, Moynihan et al. show that Mycobacterium tuberculosis can recycle components of their peptidoglycan, and characterise a crucial enzyme required for this process.

Lignin biosynthesis in higher plants relies upon a 3-hydroxylation reaction that can occur via shikimate esters of 4-coumarate. Here, Barros et al. define an alternative biosynthetic pathway via cytosolic ascorbate peroxidase that can catalyze direct 3-hydroxylation of 4-coumarate.

Engineering microbial cell factories for chemical manufacture remains challenging due to trade-offs between production and growth. Here, the authors uncover how to design genetic circuits in bacteria that maximise volumetric productivity and yield. 

A general protein language model guides protein evolution with 20 or fewer variants needed for testing.

Dysfunctional redox regulation in cancer can damage dNTPs so inhibiting dNTP pool sanitizing enzymes, such as MTH1, is a potential cancer treatment. Here, Carter et al.characterize MTH2 (NUDT15) and show that it is not a dNTP sanitizer, and so is unlikely to influence the efficacy of MTH1 inhibitors.

Lipoproteins are essential components of bacterial membranes. Here the authors present the crystal structures ofPseudomonas aeruginosa and Escherichia coliapolipoprotein N-acyltransferase, which catalyses the final step in the lipoprotein synthesis pathway, and give insights into its mechanism.

This protocol explains how to use and apply COMETS (computation of microbial ecosystems in time and space), which extends dynamic flux balance analysis to generate simulations of multiple microbial species in molecularly complex and spatially structured environments.

The human gut Bifidobacterium longum can use host N-glycans as carbon and energy sources via a specific and cooperative multienzymatic system.

Protein–ligand binding affinity is predicted quantitatively from sequencing data.

Terpene cyclases catalyze the formation of diverse hydrocarbon scaffolds found in terpenoids. Here, the authors report the cryptic function of class I terpene cyclases as aromatic prenyltransferases and the universality of this cryptic feature is confirmed using enzymes from different sources.

A cryo-electron microscopy structure provides insights into the activation of cullin–RING E3 ligases by NEDD8 and the consequent catalysis of ubiquitylation reactions.

The Polycomb Repressive-Deubiquitinase (PR-DUB) complex is responsible for the removal of the ubiquitin epigenetic modification from Histone 2A. Here the authors describe the structure of the Drosophila PR-DUB complex, providing new insight into its regulation and how cancer-associated mutations disrupt PR-DUB activity.

SAMHD1 catalyses the hydrolysis of dNTPs into 2′-deoxynucleosides and triphosphate and is an important regulator of cellular dNTP homeostasis. Here, the authors provide insights into the catalytic mechanism of SAMHD1 by performing kinetic measurements and determining crystal structures of α-β-imido-dNTP inhibitor complexes, which reveal a bi-metallic iron-magnesium centre and catalytic hydroxyl molecule in the active site of the enzyme.

Rotational deceleration has increased daylength on Earth, potentially linking the increased burial of organic carbon by cyanobacterial mats and planetary oxygenation, according to experiments and modelling of Precambrian benthic ecosystems.

The chemical synthesis of nucleoside analogues with modifications at the 2-position often requires multiple steps and the extensive use of protecting groups. Now, biocatalytic cascades are reported for the synthesis of 2-functionalized sugars and 2′-functionalized nucleosides, using enzymes derived from those of the purine nucleoside salvage pathway.

Identifying physiological substrates of proteases still poses a challenge. An unbiased approach using the heterologous Escherichia coli proteome now identifies the structural and sequence determinants for caspase-3 substrates, revealing a kinetic threshold that can distinguish relevant substrates.

Sex differences in reward processing are at present poorly understood. Calipari and Juarezet al. report oestrous cycle-dependent fluctuations in firing of VTA dopamine neurons that drive alterations in DAT function expressed in terminals in the NAc. These differences underlie enhanced cocaine reward processing during oestrus.

Cyclotides are plant backbone-cyclised peptides with potential as pharmaceutical scaffolds. Here the authors report on the efficient backbone cyclization of cyclotides and unrelated peptides by a newly identified asparaginyl endopeptidase from Oldenlandia affinis.

The tumor suppressor BAP1 is activated by ASXL1 to deubiquitinate mono-ubiquitinated H2A at K119 in Polycomb gene repression. Here, the authors show how BAP1’s C-terminal extension auto-recruits it to nucleosomes, where the DEUBAD domain of ASXL1 increases BAP1’s affinity for ubiquitin to drive deubiquitination.

Levels of the enzyme myeloperoxidase in the blood are considered a biomarker for the severity of cardiovascular disease. Here the authors report a rapid and inexpensive method for measuring myeloperoxidase activity in human plasma by luminescence, after adsorption of the enzyme to a polymer surface.

Oligonucleotide catalysts such as ribozymes and DNAzymes can cleave RNA efficiently and specifically but are typically dependent on high concentrations of divalent cations, limiting their biological applications. A modular XNAzyme catalyst composed of 2′-deoxy-2′-fluoro-β-d-arabino nucleic acid (FANA) has now been developed that can cleave long (>5 kb), highly structured mRNAs under physiological conditions and enables allele-specific catalytic RNA knockdown inside cells.