Volume 18 Issue 5, May 2022

Pharmacological agents exert their therapeutic effects by altering the biochemical activities of drug targets and, consequently, manipulating cell and organism physiology. A new study combines CRISPR interference with metabolomic profiling to rapidly elucidate drug mechanisms of action.

Natural enzyme complexes can rapidly change configurations to respond to intracellular cues. Now CRISPR enzymes and programmable RNA scaffolds allow synthetic enzyme complexes to be assembled and disassembled on demand.

Natural self-cleaving RNAs employ a wide range of catalytic strategies, but it is not known whether artificial ribozymes are capable of the same catalytic diversity. New structures of a methyltransferase ribozyme reveal the potential variety of RNA reactions and mechanisms.

Inflammasomes are cytosolic immune complexes that initiate inflammatory signaling upon pathogen recognition. A new paper reveals that inhibition of M24B aminopeptidases drives the selective activation of the CARD8 inflammasome, providing new insights into its regulation.

New research has revealed a wealth of small molecules that target cancer-specific metabolic vulnerabilities by targeting allosteric sites. Here, a Perspective discusses how their application has provided insights into cancer metabolism and therapy.

This Perspective discusses the genetically encoded tools for measuring and manipulating metabolism, highlighting the tools that are available, guidelines for their use and key areas for future development.

Succinate may have evolved as a signaling modality because its concentration reflects the redox state of the mitochondrial coenzyme Q pool, thus communicating to the rest of the cell and beyond about electron supply, oxygen tension and ATP demand.

Lipid metabolism is a major regulator of T cell biology, and this Review Article highlights mechanisms by which diverse lipids modulate T cell signaling and opportunities for therapeutic intervention on targets within these immunological pathways.

Development of a multiplexed framework using metabolic changes from CRISPR interference in essential biological process genes combined with drug-induced metabolic changes enabled the identification of antibacterials with unique modes of action.

Combining the RNA binding and processing capability of Cas6 proteins with toehold-mediated strand displacement enables the dynamic assembly and disassembly of metabolons to control enzyme function and metabolite synthesis.

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.

Identification of venom insulins with A-chain elongations inspired hybrid analogs with similar activity to human insulin. Cryo-EM structure analysis revealed the basis of the hybrid peptide activity.

Engineering the biosynthesis, compartmentalization and recycling of three cofactors enables increased production of caffeic acid and ferulic acid in yeast, suggesting that these strategies could improve metabolic flux to other desirable compounds.

Ribofuranose residues are installed on O-antigens of bacterial polysaccharides by a dual-activity enzyme that uses phosphoribosyl-5-phospho-d-ribosyl-α-1-diphosphate as a sugar donor and also catalyzes phosphate hydrolysis.

Biochemical and structural characterization of a standalone ketosynthase, SalC, reveals that it serves as a critical intramolecular aldolase and β-lactone synthase during biosynthesis of the core of the marine natural product salinosporamide A.

The crystal structure of the methyltransferase ribozyme MTR1 reveals a cofactor-binding site reminiscent of purine riboswitches and suggests a catalytic mechanism involving nucleobase protonation, resulting in accelerated methyl transfer rates.

The authors present the crystal structure of the MTR1 ribozyme that transfers the methyl group from O⁶-methylguanine to an adenine N1 in the target RNA and propose a catalytic mechanism based upon proximity, orientation and general acid catalysis.

CQ31 inhibits the M24B aminopeptidases prolidase and Xaa-Pro aminopeptidase 1 leading to increased proline-containing peptides that block dipeptidyl peptidases 8 and 9 activity resulting in the activation of the CARD8 inflammasome.