In This Issue, Volume 13, Issue 1 - American Chemical Society

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In This Issue Cite This: ACS Chem. Biol. 2018, 13, 4−4

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FISHING PROTEOMES OUT OF THE SEA

the NRPS machinery during the process before it is ultimately liberated, commonly through a cellular thioesterase activity. One outstanding question that remains is, how does this release activity coordinate with the maturation cascade so that the covalent bond is severed at the right time? Now, Peschke et al. (DOI: 10.1021/acschembio.7b00943) investigate this question as it pertains to teicoplanin, an antibiotic commonly used to fight tough infections in humans. They set up an in vitro system to characterize which of the biosynthesis intermediates can be cleaved by thioesterase. Their results indicate that the enzyme prefers to hydrolyze matured, cross-linked forms of the antibiotic from the NRPS machinery instead of the linear precursors. The rate of hydrolysis is increased by at least an order of magnitude in the case of the fully cross-linked aglycone, effectively making the thioesterase a final proofreader for the complex synthesis of this glycopeptide antibiotic.

The proteins of extremophiles, Earth’s microbes thriving in extreme conditions, have evolved to maintain their structure and activity under harsh conditions. With the advent of high throughput DNA sequencing, the proteomic secrets of previously unculturable species can be unlocked by reading genomics fragments obtained in nature. The heightened sensitivity has expanded our knowledge of the bacterial and archaeal kingdoms, in addition to providing new opportunities to uncover enzymes with novel activities or improved stability. In this issue, Grötzinger et al. (DOI: 10.1021/acschembio.7b00792) take advantage of modern technologies to go from sea to structure, starting with single microbial cells isolated from brine pools deep in the Red Sea and ending with a new structure in the Protein Data Bank. The Red Sea environment harbors microbes growing at higher temperatures and salinity, conditions that could be useful for research or industrial applications. After amplifying and sequencing individual genomes, they hone in on an alcohol dehydrogenase (ADH) encoded by a previously uncharacterized archaeon. Through a combination of biochemical experiments and high resolution structure determination, the study shows how the ADH enzyme has adapted to its halo-thermophilic environment.

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Millions of diabetics are dependent on insulin injections to help regulate the body’s response to blood glucose changes. Through recombinant DNA technologies, this peptide hormone can be produced in bacteria, but as cases of diabetes continue to rise, formulations with improved stability or more simple delivery would be a welcome innovation, especially in developing nations. To date, no orally available insulin analog has been approved for human use, but advances in this direction could be highly impactful for global health. Now, Guan et al. (DOI: 10.1021/acschembio.7b00794) take a stab at a stable version by chemically synthesizing new insulin analogs decorated by glycosylation at one of five different amino acid residues. They reasoned that glycosylation could alter the peptide’s stability or shift the balance between the active monomeric form and the less efficiently absorbed multimeric forms. After demonstrating a synthetic route for these tricky insulin analogs, they test the products for proper folding by circular dichroism and for activity by a cellular assay in which insulin triggers glucose intake. The study hones in on one threonine residue in the B-chain of insulin. When glycosylated by various sugars, the Thr-B27-modified insulins are still biologically active but are less prone to multimerization and proteolysis.

THIOESTERASE: QC FOR ANTIBIOTICS

Glycopeptide antibiotics such as vancomycin are produced in bacteria through a combination of nonribosomal peptide synthesis (NRPS) and a cyclization cascade that is critical for activity. The maturing antibiotic remains covalently attached to © 2018 American Chemical Society

SEARCHING FOR THE INSULIN OF THE FUTURE

Published: January 19, 2018 4

DOI: 10.1021/acschembio.8b00013 ACS Chem. Biol. 2018, 13, 4−4