In This Issue Cite This: ACS Chem. Biol. 2018, 13, 841−841
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NEW KETOAMIDE LABELS FOR PROTEINS
responsible for the synthetic path. The N-methyltransferase that catalyzes trimethylammonium formation is characterized in more detail using phylogenetic comparisons. Tyrobetaines and chlorotyrobetaines are tested for biological activity by several cell growth inhibition assays. These all show negative results, so the target of these natural products remains a mystery.
■ Photoaffinity labeling of proteins can be a powerful tool for target identification or probing interactions, but off-target proteins can complicate analyses. Many photoreactive groups are bulky or hydrophobic in nature, causing both a drop in target interaction affinity and a boost in nonspecific labeling. Ota et al. (DOI: 10.1021/acschembio.7b00988) present promising results for a hydrophilic photoaffinity label based on the carbonyl-reactive α-ketoamide moiety. The electrophilicity of this group makes it susceptible to formation of a photoinactive hydrate, so a variety of modifications are tested to stabilize the photoactive form. The biological testing ground is the interaction between mannose derivatives and concanavalin A using an alkyne-modified mannose attached to various ketoamide candidates. Experiments to label concanavalin in the presence of other cellular proteins show that the most selective of the probe candidates harbors a thienyl substitution on the ketoamide.
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Ferroptosis is an iron-dependent nonapoptotic form of cell death where an accumulation of lipid peroxidation is observed. Ferrostatin compounds inhibit this process, and structure− activity studies have led to analogs with increased potency. These could constitute new therapeutic routes for treating diseases involving regulated cell death, but there is much about ferroptosis and how ferrostatins function that remains unknown. Now, Gaschler et al. (DOI: 10.1021/acschembio.8b00199) add a new dimension to the puzzle by observing where ferrostatins localize in tissue culture cells. Instead of using large fluorescent tags which could lead to artifacts, small vibrational tags are appended to ferrostatin-1 for visualization with stimulated Raman scattering (SRS) microscopy. The tagged ferrostatins localize to lysosomes, mitochondria, and the endoplasmic reticulum (ER). Follow-up experiments show that lysosome accumulation decreases the potency of the compounds and that mitochondria are not required for ferroptosis or ferrostatin’s protective effects. Given these observations, the researchers postulate that ER localization of ferrostatins may lead to the protective effects due to their strong reducing potential in the face of oxidative stress.
MINING GENOMES AND METABOLITES FOR NATURAL PRODUCTS
Most commonly prescribed antibiotics were discovered as natural products produced by bacteria and fungi. Borrowing these compounds from nature fundamentally changed the course of human health, and now modern technologies show tremendous potential for finding new bioactive products. Among the approaches is metabologenomics, a combination of metabolite profiling and genome sequencing. The goal is to connect biosynthetic gene clusters and pathways with the small molecule families they produce. In this issue, Parkinson et al. (DOI: 10.1021/acschembio.7b01089) use metabologenomics along with molecular networking analysis to uncover a family of Streptomyces natural products known as tyrobetaines. Structural analysis uncovers an unusual tyrosine residue bearing a trimethylammonium group, while genomics data help tease apart the biosynthetic cluster © 2018 American Chemical Society
WHERE IN THE CELL ARE FERROSTATINS?
Published: April 20, 2018 841
DOI: 10.1021/acschembio.8b00310 ACS Chem. Biol. 2018, 13, 841−841
