In This Issue Cite This: ACS Chem. Biol. 2019, 14, 822−823
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ENGINEERING A DEGRADATION RHEOSTAT
extreme potency and toxicity of the most common family member, saxitoxin (STX). Now, Lukowski et al. (DOI: 10.1021/acschembio.9b00123) explore how STX is naturally detoxified by a series of covalent modifications in cyanobacteria. The researchers explore the enzymes that carry out these reactions, an oxygenase and two sulfotransferases, in individual reactions and as a biosynthetic cascade that generates disulfated toxins. Binding studies with mouse brain extracts show that these modifications partly detoxify STX by reducing the binding affinity to membranes. The study also delves into the substrate requirements for the sulfotransferases, paving the way for further combinatorial screens to uncover toxin analogs with improved therapeutic potential.
Proteolysis targeting chimeras, or PROTACs, are a chemical biology trick for sending a target protein to the proteasome, the cell’s polypeptide garbage can. One recent, generalizable design for PROTAC engineering involves appending a Halo tag to the protein of interest. Then, a small molecule that reacts with this tag can recruit the ubiquitin-mediated proteolysis machinery to target the whole complex for degradation. Now, Tovell et al. (DOI: 10.1021/acschembio.8b01016) modify a prior HaloPROTAC design to introduce a potent new probe with improved degradation properties. To specifically target two endosomally localized proteins, SGK3 and VPS34, a HaloTag7 is added to the endogenous loci by CRISPR/Cas9 gene editing. Modifying genomic loci preserves the gene regulatory context to yield tagged versions expressed at similar levels. Finally, quantitative mass spectrometry demonstrates that this new system is highly selective. Only the levels of the PROTAC-targeted proteins or proteins that are known to interact with these proteins in vivo are depleted upon addition of the HaloPROTAC probe.
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A DETOX FOR TOXINS
FINDING NEW ANTIBIOTICS IN A PEPTIDE SOUP
In all kingdoms of life, biosynthetic pathways build increasingly complex compounds from small precursors through a series of concerted enzymatic activities. Synthetic fermentation borrows this concept from nature, replacing enzymatic reactions with coincubated chemical reactions that together generate a complex mixture of products. This mixture can then be screened for a particular affinity or activity and the active compounds must then be identified for further characterization. In this issue, Stepek et al. (DOI: 10.1021/acschembio.9b00227) bring together synthetic fermentation and phenotypic screening to discover new antimicrobial peptides. Parallel chemical soups perform peptide synthesis via reactive combinations of α-ketoacid initiators and elongation monomers harboring a wide variety of side chain moieties. Families of oligomers arise from hydroxylamine ligation prior to addition of a terminator. After selecting for mixtures that inhibit bacterial growth, the selected mixtures are deconvoluted by subsequent reactions with reduced complexity until a subset of peptides are selected for structure−activity studies. A
Bivalve shellfish are filter feeders that can accumulate a family of neurotoxins produced by marine dinoflagellates and cyanobacteria. The toxins act as selective blocking agents for voltage-gated sodium channels, a family of proteins that are essential for neurons to propagate action potentials. While their paralytic properties make these toxins particularly dangerous, their general mechanism of action has been explored for pharmacological purposes as anesthetics or new pain management drugs. Among the challenges, however, is the © 2019 American Chemical Society
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Published: May 17, 2019 822
DOI: 10.1021/acschembio.9b00352 ACS Chem. Biol. 2019, 14, 822−823
ACS Chemical Biology
In This Issue
photoaffinity probe of one peptide is synthesized and used to find the mode of action for the antimicrobial activity, an interaction with a common antibiotic target, an endogenous penicillin-binding protein.
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DOI: 10.1021/acschembio.9b00352 ACS Chem. Biol. 2019, 14, 822−823
