Volume 19 Issue 3, March 2023

Metabolic rewiring of activated macrophages promotes glycolysis and contributes to bacterial killing. A new study shows that reactive nitrogen species, released during macrophage activation, induce a profound inhibitory signal that facilitates metabolic reprogramming by modification of lipoate.

Studies of the microbiome–host interaction are uncovering the metabolic mutual crosstalk between host tissues and gut microbiota. Hepatic glutamine synthetase takes part in this interaction by metabolizing a bacterial substance and producing a molecule with interesting clinical potential.

Bacteria utilize stringent factors to metabolize the nucleotide alarmone guanosine tetra-/pentaphosphate, or (p)ppGpp, for stress adaptation. Now, a distinct conformation of these factors explaining their regulation and specialization has been unveiled.

A crucial step in the cell-death process of ferroptosis is the incorporation of free polyunsaturated fatty acids (PUFAs) into membrane phospholipids. An enzyme has now been identified that contributes to ferroptosis by directly transferring PUFAs from phospholipids to ether lysophospholipids to form ether phospholipids.

Reactive nitrogen species can cause profound inhibition of α-ketoacid dehydrogenase complexes via covalent S-modifications of the E2 subunit’s catalytic lipoic arm. The enzymes’ substrate, CoA, can mediate targeted delivery of such modifications.

Aminoadamantane compounds, delivered to cells via binding to viroporin channels, induce S-nitrosylation of the ACE2 protein, inhibiting binding to SARS-CoV-2 spike protein and viral infection.

Homotrimeric DARPin molecules neutralize SARS-CoV-2 variants of concern by targeting a critical ACE2-binding interface.

Glutamine synthetase is the only enzyme that synthesizes glutamine in mammals. In vivo metabolomics showed that glutamine synthetase utilizes methylamine to produce N⁵-methylglutamine, whose levels correlate with tumor burden in a β+catenin+mutant liver cancer model.

Velcrins kill cancer cells by inducing complex formation between PDE3A and SLFN12, upregulating SLFN12 RNase activity. Activated SLFN12 specifically cleaves tRNA^Leu(TAA), resulting in global inhibition of protein synthesis.

Akizuki et al. reveal an unexpected role for K63-linked ubiquitin chains and the E2 enzyme UBE2N in degrader-induced degradation of cIAP1 through the proteasome, demonstrating the diversity of the ubiquitin code used for targeted degradation.

Coupling haploid genetics with deep scanning mutagenesis, Hanzl et al. identified functional hotspots in E3 ubiquitin ligases that are selectively required for different proteolysis-targeting chimeras (PROTACs) or molecular glue degraders and found mutated in relapsing patients.

The structure of SpoT assumes a compact τ-shaped structure in which the regulatory domains wrap around a core subdomain that controls the conformational state of the enzyme and primes it for (p)ppGpp hydrolysis.

Coenzyme A (CoA) is a ubiquitous and essential cofactor. A biosensor for visualizing cytosolic and mitochondrial CoA in living cells was developed to address central questions concerning CoA homeostasis.

Development of a chemoproteomic platform to globally interrogate Fe–S cluster incorporation in a native proteome enables the elucidation of Fe–S biogenesis components and the identification of unannotated Fe–S proteins.

The authors present a framework for multiplexed optimization of metabolic pathways based on CRISPR–dCas12a-mediated genetic circuits, which can be generally applied in the construction of microbial cell factories for sustainable bioproduction.

The function of a poorly characterized transmembrane protein, TMEM164, was annotated by integrated genetic dependency mapping, AlphaFold2 structural modeling and lipidomics as an acyltransferase that generates ferroptotic C20:4 ether phospholipids.