Volume 16 Issue 6, June 2020

We asked a collection of chemical biologists, “What was the most exciting research achievement or technology innovation in chemical biology in the last five years?” and reveal some of the perspectives we received.

We present a selection of papers published in Nature Chemical Biology over the past five years that reflect the diversity and excitement of chemical biology research.

The biological function and origin of m⁶A in DNA have been widely debated. A new study demonstrates that the majority of m⁶A in DNA originates from RNA catabolism via a nucleotide salvage pathway.

A combination of biochemical and biophysical techniques to document the asymmetric distribution of lipids, with a particular focus on the acyl tails, in mammalian cell membranes show that protein transmembrane domains are similarly asymmetric.

A pair of fluorescent indicator-tagged DNA-duplex scaffolds permit assessments of nitric oxide (NO) production on cell surfaces and in intracellular networks. The application of these nanoprobes indicates formations of local NO signals that might conserve cancer cell integrity.

The discovery of selective modulators of two Cryptochrome isoforms, CRY1 and CRY2, permits a deeper understanding of how circadian clock proteins impact diverse aspects of our daily 24-h rhythms and how this intersects with metabolic pathways relevant to disease.

This historical Perspective on continuous directed evolution focuses on laboratory approaches that enable greater understanding of evolving molecular populations and offer investigators tools to guide the emergence of new biomolecular systems.

This Perspective highlights emerging themes in the inter-regulation of the genome and metabolism via chromatin, including nonenzymatic histone modifications, cofactor-promiscuous chromatin-modifying enzymes, and subnucleocytoplasmic metabolite pools.

A metabolic labeling method reveals that genomic N⁶-methyl-deoxyadenosine in mammalian cell lines originates not from direct methylation in DNA, but from a misincorporation of the metabolite of ribo-N⁶-methyladenosine.

A highly selective inhibitor of the DCLK1/2 kinases is used to uncover the consequences of DCLK1 inhibition on viability, phosphosignaling and the transcriptome in patient-derived organoid models of pancreatic ductal adenocarcinoma.

Lipidomics across the bilayer membrane plus biophysical and fluorescence approaches find asymmetry in phospholipid unsaturation and localization of protein transmembrane domains based on their ability to pack within the different membrane leaflets.

Deep mutational scanning reveals that α-synuclein adopts a membrane-bound α-helix conformation with increasing dynamics towards the C terminus. This helical conformation is associated with its cytotoxicity.

A pair of fluorescent DNA-based probes for nitric oxide reveals that nitric oxide synthase 3 activity in the trans-Golgi network is essential for Golgi structural integrity, despite being tenfold less active there than at the plasma membrane.

An inhibitor of NAPE-PLD involved in lipid biosynthesis lowers levels of the endocannabinoid anandamide and other N-acylethanolamines in cells and mouse brain and activates the hypothalamus–pituitary–adrenal axis and impaired fear extinction.

Cell-based phenotypic screening of small-molecule circadian clock modulators identified isoform-selective compounds for highly homologous clock proteins CRY1 and CRY2, revealing a key role of the disordered C-terminal region in compound selectivity.

d-Cycloserine inactivates alanine racemase by forming an adduct with the pyridoxal 5′-phosphate cofactor, but structural and spectroscopic analyses reveal that reactivation occurs on adduct hydrolysis and product rearrangement to a stable oxime.

Synthetic circuit-host interactions affect the performance synthetic biology systems. Analysis of two bi-stable switch circuits reveals differential effects of host growth on circuit memory, which is dependent on the network topology of the circuit.

The authors develop a ribozyme, Tx2.1, that is capable of aminoacylating tRNA with specificity for the anticodon from directed evolution of a T-box riboswitch. Tx2.1 could be used to charge non-natural amino acids in an in vitro translation system.