In This Issue pubs.acs.org/acschemicalbiology
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TAKING APART TEIXOBACTIN
Teixobactin is a recently discovered antibiotic from soil Aquabacteria, and it displays potent activity against a wide variety of Gram-positive bacteria. Antibiotic synthesis in the bacteria involves a multienzyme biosynthetic cluster, but since its discovery, chemists have successfully synthesized teixobactin by solid-phase peptide synthesis. This advance makes for simplified construction of derivatives to help elucidate the functional groups important for its antimicrobial activity. Here, building upon knowledge gained from studies of an arginine-modified teixobactin, Yang et al. (DOI: 10.1021/ acschembio.6b00295) synthesize seven new homologues varying in functional group composition and stereochemistry. They then test these new potential antibiotics on four species of Gram-positive bacteria and the Gram-negative workhorse E. coli as a negative control. The results indicate that the macrolactone ring and a long hydrophobic N-terminal tail are necessary features, but the exact stereochemistry and the composition of the tail can be varied while still maintaining activity. They describe lipobactin, a reductionist derivative of teixobactin which maintains reasonable activity despite its simpler structure.
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BLOOD ANTIGENS AT ATOMIC DETAIL Blood types are determined by more than just the proteins expressed on the outside of red blood cells. The term blood group antigens also encompasses the carbohydrates, better known as glycans, that decorate these proteins. Glycans adopt different compositions and conformations as a result of an individual’s genes. For example, in the Lewis antigen system, individuals with a dominant allele express a fucosyltransferase enzyme that modifies red blood cell proteins, while those with recessive alleles do not produce functional enzyme. This is relevant beyond blood typing because specific Lewis antigens installed by this enzyme’s activity can act as receptors for bacterial pathogens. Here, Topin et al. (DOI: 10.1021/acschembio.6b00333) dissect the interaction of the Lewis antigen with bacterial leptins through a variety of structural, biophysical, and computational techniques. They uncover an alternative state for the glycan that is not thermodynamically favored but is stabilized upon binding to a leptin. The study demonstrates that a central N-acetyl-glucosamine ring is distorted with a conserved leptin tryptophan playing a key role in stabilizing this conformation.
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SEARCHING OUT SIRT6 SUBSTRATES Mammalian sirtuins, or Sirts, are a family of deacetylases responsible for removing lysine acetyl marks on histones. While some Sirts have deacetylase activity toward most histone lysines or even acetyl-peptides, Sirt6 acts only on specific lysines. This observation that has been difficult to study in depth because in vivo observations paint a picture of high activity on H3K9 and H3K56, whereas in vitro studies show low activity on purified proteins or peptides. Recent studies indicated that Sirt6 deacetylase activity is improved when the substrate histones are packaged with DNA into nucleosomes. Wang et al. (DOI: 10.1021/acschembio.6b00243) extend on these observations with a chemical biology approach aimed at identifying which particular acetyl-lysines are Sirt6 substrates. They begin by site-specifically installing lysines carrying an alkene group into recombinant histone H3. This affords a handle for dye labeling, but the handle disappears when Sirt6 deacetylates that particular residue. Their in vitro studies in nucleosomes and follow up work in cells extend the known repertoire of lysine substrates. © 2016 American Chemical Society
Published: July 15, 2016 1769
DOI: 10.1021/acschembio.6b00578 ACS Chem. Biol. 2016, 11, 1769−1769
