Volume 11 Issue 7, July 2015

Recent studies suggest that iron-sulfur (Fe-S) proteins may be unexpectedly abundant and functionally diverse in mammalian cells, but their identification still remains difficult. The use of informatics along with traditional spectroscopic analyses could be key to discovering new Fe-S proteins and validating their functional roles.

We asked a collection of chemical biologists: “What would you say have been the most important historical contributions of chemical biology to broader areas of science”?

Biosensors are emerging as an important tool to evolutionarily engineer metabolic pathway enzymes for the microbial production of chemicals. A colorimetric biosensor used to increase dopamine levels in yeast now enables the production of benzylisoquinoline alkaloids from glucose.

The ability to vary a drug's residence time on a target is important for drug optimization. A series of reversible covalent inhibitors of select kinases demonstrates the feasibility of tuning residence time from minutes to days through modification of noncovalent features of the molecules.

A modified amphotericin antifungal that is less toxic to human cells, owing to its increased preference for its fungal ergosterol target versus human cholesterol, can still evade the evolution of resistance.

The spliceosome is an immensely complex molecular machine tasked with stitching together coding regions of genes. New work reveals how a small molecule can affect this machinery in a model of spinal muscular atrophy, a disease linked to aberrant splicing.

The molecular basis of biomaterial assembly and function can provide inspiration for new materials science designs. New research explains the squid beak's transition from soft to hard through the identification of two new families of proteins with unusual physical properties.

Sulfide signaling is biologically important, but the identity and source of reactive sulfur species (RSS) remains unclear. An analysis of sulfur reactivity now suggests that oxidation pathways thought to dispose of sulfur may actually create RSS.

The biosynthesis of benzylisoquinoline alkaloids such as morphine requires tyrosine oxidases, which are prone to overoxidation. A colorimetric readout that co-opts betaxanthin enzymes now enables discovery of an improved oxidase that, with other enzymes, makes reticuline in yeast.

Topoisomerase inhibitors are genome-targeting drugs that induce DNA double-strand breaks or evict histones at sites of action. Genomic mapping of their target sites by ChIP-Seq and FAIRE-Seq and integration with ENCODE data identifies the target specificities of topoisomerase inhibitors and suggests ways to optimize their therapeutic properties.

An amphotericin antifungal that is less toxic to human cells due to its increased capacity for binding the fungal ergosterol over the human cholesterol can still evade resistance mechanisms, challenging the resistance-toxicity yin-yang of antimicrobials.

The squid beak displays a 200-fold stiffness gradient across its length. A battery of experiments, including ‘omics analysis and rheological measurements, now identifies two protein families that infiltrate and cross-link a porous chitin network to generate variable stiffness.

A newly engineered phosphoserine synthetase/tRNA pair allows quantitative insertion of phosphoserine or, when coupled with metabolic rewiring, a non-hydrolyzable analog into protein sequences, leading to high yields of modified constructs for functional analysis.

NO₂⁻ has been viewed primarily as a reservoir for NO and NO-modified species, activated by acids or metal catalysis. Isotopic labeling of NO and NO₂⁻ modifications in vitro and in vivo now demonstrates that NO₂⁻ also participates directly in these reactions through a symmetric N₂O₃ intermediate.

A high-throughput screen identified a small molecule that promoted inclusion of SMN2 exon 7, increased SMN2 protein levels and extended survival in a SMA mouse model through stabilization of the interaction between SMN2 pre-mRNA and U1 snRNP complex.

A computational analysis of cryo-EM data defines the binding mode of capsaicin on TRPV1. A mutational analysis validates these findings, showing specific van der Waals and hydrogen-bonding interactions with the head, neck and tail regions of capsaicin.

Structural changes in the capping groups of inverted cyanoacrylamide-based kinase inhibitors resulted in alterations in residence time, with some compounds exhibiting sustained pharmacological effects in vivo.