Spotlights Cite This: J. Am. Chem. Soc. 2017, 139, 17701−17702
pubs.acs.org/JACS
Spotlights on Recent JACS Publications
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UNRAVELING PROTEIN STABILITY ONE MOLECULE AT A TIME By building extracellular scaffolds that have a dual purpose of organizing enzymes and tethering themselves to cellulose fibers, bacteria adeptly degrade cellulose, a polymer indigestible by humans. Michael Nash and colleagues combine single-molecule techniques with steered molecular dynamics to provide insight into the stability of the molecular scaffold used by bacteria to digest cellulose (DOI: 10.1021/jacs.7b07574). Using atomic force microscopy, the authors systematically pull on single protein domains to precisely measure the force required to unravel each of the cohesins, which make up the bulk of the scaffolds. They provide the first evidence that, despite highly conserved sequences, cohesins proximal to the bacteria could withstand the greatest unfolding force, while the ones that hang from the scaffold on the distal end unfold under minimal force. Remarkably, substitution of a single amino acid is sufficient to stabilize the weakest cohesin by more than 2fold. This study shows that teaming up molecular simulations with single-molecule analysis enables a deeper level of understanding into how protein stability can be tuned. The combined strategy would have utility for wider applications in protein engineering and bionanotechnology. Sue Min Liu, Ph.D.
AN UNEXPECTED METHYLATION MECHANISM ON THE PATH TO AN ANTIBIOTIC Hung-wen Liu and colleagues have determined an unexpected mechanism for a step in the biosynthesis of the antibiotic gentamicin (DOI: 10.1021/jacs.7b09890). Methyltransferases catalyze methylation in many important biosynthetic pathways. Although the classical mechanism of methylation occurs via an SN2-like reaction involving nucleophilic attack, some methyltransferases have been shown to behave differently. For example, the so-called radical S-adenosyl-L-methionine (SAM) methyltransferases operate via radical chemistry. Liu and co-workers have investigated the mechanism of GenK, a member of a large class of radical SAM methyltransferases (RSMTs), known as cobalamin-dependent RSMTs. GenK catalyzes methylation of an intermediate in the biosynthesis of the antibiotic gentamicin, which can be used to treat pneumonia and other bacterial infections. By synthesizing a set of labeled substrate analogues as probes, the authors reveal a stereoselective mechanism for GenK that is different from that proposed for other cobalamin-dependent RSMTs. In this case, methylation occurs with the retention of stereochemistry rather than the inversion, as is more frequently observed. This unique mechanism of GenK adds another layer of complexity to RSMTs which are worthy of being explored more. Deirdre Lockwood, Ph.D.
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HOST−GUEST CHEMISTRY MANIPULATES AN EPIGENETIC TARGET By targeting an important epigenetic mark with a host−guest system, Tian Tian, Xiang Zhou, and colleagues demonstrate reversible control of several key reactions in molecular biology (DOI: 10.1021/jacs.7b09635). The 5-formylcytosine moiety in DNA is a known intermediate on the pathway to DNA demethylation and also a significant epigenetic mark in mammals, with several known cellular functions. To learn more about its effect on biochemical reactions, researchers want to reversibly manipulate its function through chemical intervention, but so far that has proved challenging. Now Zhou’s team has developed a multipart system to do the job. First, a supramolecular aldehyde reactive probe tags 5formylcytosine with an adamantane group. The macrocycle cucurbit[n]uril then recognizes this tag via a host−guest interaction. In the process, it creates a steric hindrance that interferes with normal enzymatic activity at the modified residue. This obstruction can be reversed by treatment with adamantanamine. The researchers show that the system reversibly disrupts three important processes: digestion of DNA by restriction endonucleases, elongation of DNA polymerase, and polymerase chain reaction. This innovative work may plausibly be extensible to the control of gene expression at a cellular level by intervention with small molecules. Deirdre Lockwood, Ph.D. © 2017 American Chemical Society
CREATING CHEMICALS THAT MIMIC CHLOROPHYLL In nature, many light-harvesting systems are composed of circular aarangements of π-conjugated macrocycles, like the cyclic arrays of chlorophyll units that harvest sunlight and funnel electronic excitation to the reaction center during photosynthesis. There are numerous challenges when it comes to synthesizing artificial cyclic light harvesters. π-Conjugated nanorings, for example, can be assembled by cross-coupling reactions of aromatic building blocks, but it is difficult to prevent competing side-reactions such as homo-coupling, and cyclization can lead to a high level of molecular strain, resulting in a high activation energy. Researchers led by Harry Anderson report the first examples of synthetic ethynylene-linked porphyrin nanorings (DOI: 10.1021/jacs.7b10710). The team creates macrocycles comprised of six or eight porphyrins linked together by single acetylene bridges via palladium-catalyzed Sonagashira crosscoupling to create new C−C bonds. Oligopyridine templates are used to direct the macrocyclization process, helping to preorganize the systems and to overcome the energy penalty associated with creating these rings. The resulting cyclic hexamers and octamers exhibit highly delocalized excited states, similar to chlorophyll arrays used in photosynthesis, as Published: December 13, 2017 17701
DOI: 10.1021/jacs.7b12693 J. Am. Chem. Soc. 2017, 139, 17701−17702
Journal of the American Chemical Society
Spotlights
seen by fluorescence spectral analysis. This work sheds light on developing new artificial light-harvesting systems. Christine Herman, Ph.D.
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FINDING THE ROOT OF AMYLOID FIBER FORMATION Several neurodegenerative diseases, such as Alzheimer’s disease, trace their origin to gnarly misfolded proteins that wreak havoc on the brain. The telltale sign of these illnesses are amyloid fibers, but the trouble starts even before these markers appear in the stages leading up to fibril formation. Identifying the pathways to amyloid formation may aid the development of novel therapeutics that can stop the assembly of these nefarious proteins. David Lynn, Martha Grover, and colleagues have made progress toward teasing out the forces that regulate amyloid formation (DOI: 10.1021/jacs.7b09362). To assess the influence of electrostatic forces on nucleation and propagation, the researchers perform a series of structural experiments on the Aβ(16−22) peptide, which forms the nucleating core of the Alzheimer’s amyloid, at neutral and acidic pHs. The results suggest that, while the pH environment is an important factor, it is not the only force driving peptides together to form stacked β sheets, the first step toward the formation of an amyloid. Based on data on the positioning of residues within these β stacks, the researchers conclude that facial complementarity of the β sheet stacking is a critical factor determining the direction of nucleation and propagation of amyloid. Erika Gebel Berg, Ph.D.
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DOI: 10.1021/jacs.7b12693 J. Am. Chem. Soc. 2017, 139, 17701−17702
