Volume 19 Issue 7, July 2023

The NADP⁺/NADPH coenzyme couple powers cellular biosynthesis and oxidative defense. A new study tracing glucose-derived deuterium during proline biosynthesis analyzes subcellular perturbations in NADPH utilization, revealing that NADP⁺/NADPH coenzyme pools in the cytosol and mitochondria are regulated independently.

New biochemical and structural studies into the capsule biosynthesis pathway of Haemophilus influenzae serotype b (Hib) provide invaluable insights into a unique, basket-shaped multi-modular enzymatic machinery, allowing accelerated development of fermentation-free production methods for Hib glycoconjugate vaccine.

The mechanisms responsible for replicative misincorporation of an adenine into DNA opposite 8-oxoguanine (8OG) remain obscure. A new study suggests that 8OG redistributes the balance between several mispair conformations, enabling the high rates of misincorporation of adenine paired with 8OG by DNA polymerases.

Tricyclic peptides have reduced conformational flexibility, making them well suited for ligand development. Researchers have now generated large combinatorial libraries of tricyclic peptides using a disulfide-directing motif. Screening these libraries discovered binders to challenging protein targets.

Creatine kinases (CKs) have emerged as a metabolic liability in many rapidly proliferating cancers. We have developed a class of covalent inhibitors that impair creatine phosphagen energetics by targeting a redox-regulated cysteine residue in the active site of CKs.

We identified small molecules that rewire the transcriptional state of cancer cells by covalently targeting the RNA-binding protein NONO. These small molecules stabilize the interactions of NONO with its target mRNAs, thereby overriding the compensatory action of paralog proteins and revealing a pharmacological strategy for disrupting previously undruggable oncogenic pathways.

The use of atomic-level simulations reveals a molecular mechanism by which a ligand can achieve selectivity between nearly identical receptors, enabling the rational design of targeted drugs.

A first-in-class covalent inhibitor of creatine phosphagen energetics was developed that induced toxicity in creatine kinase-dependent AML cell lines and regulated proinflammatory cytokine production in macrophages.

Integrated phenotypic screening and activity-based protein profiling identifies small molecules that decrease the expression of oncogenic transcription factors and suppress cancer cell growth by covalently targeting the RNA-binding protein NONO.

An approach using glucose tracers and labeling of proline metabolites is applied to assess compartmentalized NADPH fluxes. The results show that NADPH fluxes in the cytosol and mitochondria are independently regulated, with no evidence of a shuttle.

Using an integrated metabologenomics approach, the biosynthetic pathway for the pestalamides is revealed and over 200 high-confidence targets are identified for future studies.

Yu et al. identified sulfation modification that occurs on the tyrosine 99 residue of histone H3 (H3Y99sulf) and which is installed by histone sulfotransferase SULT1B1 and regulates gene transcription by recruiting PRMT1.

Polymerase Bcs3, which allows the fermentation-free synthesis of Haemophilus influenzae type b capsule for vaccine development, adopts a basket-like shape with all six active sites facing the interior, creating a protected environment for catalysis.

The bacterium Proteus mirabilis natively forms a bullseye colony pattern by swarming. Doshi et al. engineered this bacterium to encode environmental inputs, including copper, into its pattern features, and decoded them with image processing and deep learning.

Lowering the levels of disease-promoting proteins is generally assumed to be beneficial. The authors developed a two-step strategy to integrate protein-level tuning, noise-aware synthetic gene circuits into a well-defined human genomic locus. This approach was used to study the effect of BACH1 levels on MDA-MB-231 human breast metastatic cells.

Replicative errors contribute to genetic diversity needed for evolution but in high frequency lead to genomic stability. Here, NMR is used to show via a kinetic model that DNA dynamics can determine the misincorporation of A•G and A•8OG mismatches.

A combination of enzyme discovery for nonheme diiron N-monooxygenases, metabolic engineering and genetic code expansion enables the construction of a live bacterial producer of synthetic nitrated proteins containing para-nitro-l-phenylalanine.