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A generative artificial intelligence-powered method enables de novo design of highly active enzymes based on information about the geometry of residues in the active site, without requiring protein backbone or sequence information.

Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme conditions. Here, the authors show that the natural product P57 induces hypothermia by targeting pyridoxal kinase and has a potential application in therapeutic hypothermia.

Large-scale computational and in vitro analyses identify commensal type III secretion systems and substrates in the human gut microbiome that can interact with human proteins to modulate immune pathways.

DNA damage tolerance is regulated by ubiquitination of PCNA. Here, the authors present kinetic and structural studies showing that USP1/UAF1 prefers trimming K63- and K48-ubiquitin chains down over cleavage of monoubiquitinated PCNA. Mutant analysis suggests evolutionary preservation of this mechanism.

Cas12a3 nucleases constitute a distinct clade of type V CRISPR–Cas bacterial immune systems that preferentially cleave the 3′ tails of tRNAs after recognition of target RNA to induce growth arrest and block phage dissemination.

The enzyme PCMT1 was found to install a C-terminal cyclic imide modification on proteins that marks them for degradation by CRBN, uncovering a conserved protein turnover pathway with implications in metabolism and neurological function.

Catalytic mechanisms of enzymes are well understood, but achieving diverse reaction chemistries in re-engineered proteins can be difficult. Here the authors show a highly efficient and thermostable artificial enzyme that catalyzes a diverse array of substrate oxidations coupled to the reduction of H₂O₂.

Artificial genetic polymers (XNAs) have been explored for their nuclease activity, but XNAzymes have proven challenging to discover by in vitro selection. Here, the authors generate an efficient RNA-cleaving 2’-fluoroarabino nucleic acid enzyme (FANAzyme) by in vitro evolution using natural DNA polymerases.

Authors utilise a metabolomics approach to identify microbial-derived metabolites that synergistically inhibit urease activity in Proteus mirabilis, a cause of urease-induced kidney stones. They reveal that two metabolites prevented urinary catheter encrustation and improved antimicrobial efficacy against catheter biofilm.

Many enzymes form homo-oligomers, but it is often not clear why. This study follows the evolution self-assembly in citrate synthases across their phylogeny and finds it to be variable and not obviously related to enzyme function.

APOBEC3A mutates its host DNA in human cancers to evolve drug resistance. Modified-DNA inhibitors suppress this mutagenic activity in cells, suggesting use as conjuvants in anti-cancer therapies. Here the authors reveal structural insights into how these inhibitors bind APOBEC3A.

The dysregulation of the inositol-requiring enzyme 1 alpha (IRE1α) has been associated with multiple human diseases, so IRE1α-targeting small molecules present great therapeutic potential. Here, the authors report a series of substituted indoles as IRE1α inhibitors of good potency and selectivity, and show that the inhibitor IA107 allosterically inhibits IRE1α RNase activity via binding to the IRE1α kinase domain but without inhibiting the IRE1α dimerization.

Ubiquitin-specific protease USP4 regulates several cellular signalling pathways. Here, Clerici et al.show that the DUSP–Ubl domain of USP4 is required for full catalytic activity, by enhancing the release of ubiquitin from the catalytic site after substrate hydrolysis.

Nitrospira inopinata and probably most other comammox microorganisms can grow on the non-conventional substrate guanidine as the sole source of energy, reductant and nitrogen.

The enterococcal cytolysin is a two-component toxin that is responsible for a fatal form of alcoholic hepatitis. Here, authors used knowledge of the toxin’s biosynthesis to develop small molecule inhibitors of toxin production.

Asparaginyl endopeptidases (AEPs) catalyze the cyclization step during the biosynthesis of cyclic peptides in plants. Here, the authors report a recombinantly produced AEP that catalyzes the backbone cyclization of a linear cyclotide precursor and an engineered analog with high efficiency and in a pH-dependent manner.

Although small molecule tyrosine kinase inhibitors are effective in lung cancer driven by mutated EGFR, some receptor variants fail to respond. Here, the authors identify structural features of an important set of EGFR variants with reduced inhibitor sensitivity, guiding future inhibitor selection.

Rashan, Bartlett and colleagues show that mammalian 4-hydroxy fatty acids are primarily catabolized by ACAD10 and ACAD11 (atypical mitochondrial and peroxisomal acyl-CoA dehydrogenases, respectively) that use phosphorylation in their reaction mechanisms.

Integrating heterogeneous single atom nanozyme (SAzyme) configurations and homogeneous enzyme-like mechanism is promising for optimizing SAzymes but elusive. Here the authors address this issue by developing a spatial engineering strategy to fabricate dual-sites SAzymes incorporating single atom Fe active centers (Fe–N₄) and Cu atomic sites (Cu–N₄) in a vertically stacked Fe–N₄ and Cu–N₄ geometry.

Florfenicol amine hijacks intrinsic resistance in Mycobacterium abscessus, highlighting that antimicrobial resistance mechanisms can be harnessed for antibiotic activation.

Here, Kropp et al. use cryo-electron microscopy and structural modeling to show that the enzyme [MoCu]-CO dehydrogenase interacts with its partner, the membrane-bound quinone-binding protein CoxG, to facilitate electron transfer from atmospheric CO oxidation to the respiratory chain. This interaction is conserved across diverse bacteria and archaea.

The main protease (M^pro) plays a crucial role in the replication of SARS-CoV-2, thereby making it an attractive target for COVID-19 treatment. Here, the authors develop a colorimetric screening platform for discovering M^pro inhibitors using engineered amyloid peptide-based nanocomplexes.

A pure culture of the complete nitrifier Nitrospira inopinata shows a high affinity for ammonia, low maximum rate of ammonia oxidation, high growth yield compared to canonical nitrifiers and genomic potential for alternative metabolisms, probably reflecting an important role in nitrification in oligotrophic environments.

A two-enzyme complex works as a cyclodehydratase to form TOMM natural products, but the roles of each protein have been unclear. Structural and biochemical analysis deconvolutes the roles of each protein and identifies a new ATP-binding motif.

Vanadium-dependent haloperoxidases (VHPOs) are versatile enzymes that catalyze oxidation of halides followed by halogenation of electron-rich substrates, but the factors dictating substrate and halogen specificity were unknown. Here, the authors show that a single-point mutation in the cyanobacterial bromoperoxidase AmVHPO facilitates a selectivity switch to allow aryl chlorination and elucidate the structural basis for this switch.

Here the authors investigate the regulatory mechanisms of acetyl-CoA (Ac-CoA) biosynthesis in Bacillus subtilis, probing the interaction between acetyl-CoA synthetase (AcsA) and acetyltransferase (AcuA). They capture a stable AcsA-AcuA complex that inhibits AcsA activity in the absence of Ac-CoA.

Characterization of the polysaccharide utilization loci from two Bacteroides species from the human gut microbiota define biochemical and structural features underlying the catabolism of a hybrid algal polysaccharide found in edible seaweed.

TfuA, YcaO and thiol donor protein, ThiS, collaborate in peptide backbone thioamidation of McrA and during the biosynthesis of certain ribosomally synthesized and post-translationally modified peptide (RiPP) natural products.

The gut microbiota can impact the bioavailability of therapeutic drugs. Here, the authors show that bacterial tyrosine decarboxylases (TDC) decrease the levels of levodopa, the primary treatment in Parkinson’s disease, by conversion to dopamine, and suggest TDC as a potential predictive biomarker for treatment.

Microbes drive the Earth’s biogeochemical cycles. Here, Li et al. present a framework for integrating genome-inferred microbial kinetic traits into ecosystem mechanistic models, and use it to benchmark predictions against observed greenhouse gas emissions at an Arctic wetland.

Isotope tracing, kinetics and transcriptomics show how members of the four AOM lineages employ different nitrogen use strategies that minimize competition for nitrogen substrates.

Considering the intrinsic toxicities of transition metals, their incorporation into drug therapies must operate at minimal amounts while ensuring adequate catalytic activity within complex biological systems. This study investigates the design of synthetic prodrugs that not only can be tuned to be harmless, but are robustly transformed in vivo to reach therapeutically relevant levels.

Lithium is commonly used to treat bipolar disorder, but it exerts side effects at doses close to the therapeutic range. Singh and colleagues screen a collection of clinical compounds and find that ebselen induces lithium-like effects on mouse models of bipolar disorder by inhibiting inositol monophosphatase.

The connection between protein dynamics and catalysis is an issue of vigorous debate in enzymology. Conformational motions are known to be important for the physical steps in the catalytic cycle of dihydrofolate reductase, however, it is now reported that there is no evidence of a correlation between such motions and the actual chemical step, hydride transfer.

Borosins are ribosomally encoded and posttranslationally modified peptide (RiPP) natural products featuring amide-backbone α-N-methylation. Here, the authors report the discovery and characterization of type IV borosin ‘split’ pathways encoding distinct, separate α-N-methyltransferases and precursor peptide substrates.

Peptide macrocycles are attracting increasing attention as tools for research and as potential therapeutics. The highly efficient butelase 1—homologous to proteases but specific for ligations—offers a new method for peptide cyclization.

The specificity constant of a promiscuous enzyme was raised by over 1,000-fold by using computational protein design to place a substrate recruitment domain adjacent to the enzyme active site.

The ability to rationally remodel enzyme conformational landscapes to modify catalytic properties is limited. Here, the authors, using a computational procedure, redesign the conformational landscape of an aminotransferase to stabilize a less populated but reactive conformation and thereby increase catalytic efficiency with a non-native substrate.

Structural, functional and in silico analyses of the chloroquine-resistance transporter PfCRT of Plasmodium falciparum suggest that distinct mechanistic features mediate the resistance to chloroquine and piperaquine in drug-resistant parasites.

An NNMT inhibitor reduces tumour burden and metastasis in multiple mouse cancer models and restores immune checkpoint blockade efficacy by decreasing cancer-associated-fibroblast-mediated recruitment of myeloid-derived suppressor cells and reinvigorating CD8⁺ T cell activation.

A chemically induced dimerization strategy was used to recruit SUMOylation enzymes into condensates, enabling quantification of the effect of phase separation on the activity of a SUMOylation enzyme cascade reaction.