In This Issue pubs.acs.org/acschemicalbiology
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TROLLING FOR ANTIBIOTIC TARGETS
conformational change. Obligate anaerobes depend upon O2 sensing to induce chemotaxis and move away from the oxygenrich environment. Understanding how anaerobe H-NOX proteins distinguish between the diatomic gases and modulate downstream physiology remains a fundamental mystery. In this issue, Hespen et al. (DOI: 10.1021/acschembio.6b00431) solve a new set of X-ray crystal structures and perform functional assays to gain deeper understanding of HNOX biology. They choose an H-NOX from a thermophilic obligate anaerobe, Caldanaerobacter subterraneus, and present structures of the Fe(II)-unliganded form along with the NO and CO complexed forms. After demonstrating that an intermediate conformational change occurs upon NO or CO binding compared to prior structures with O2, the researchers move to a heterologous functional assay pairing their characterized H-NOX with Vibrio cholerae histidine kinase. This kinase is autophosphorylated in response to an H-NOX signal and their assay demonstrates that O2, but not CO or NO, can induce strong kinase activity.
Pathogenic bacterial strains pose a significant public health threat when they are resistant to conventional antibiotics. To uncover new antimicrobials, researchers can go fishing with clever screens of natural product or small molecule libraries, but bridging growth inhibition hits into drugs in the clinic is especially difficult. Identifying the mechanism of action (MOA) for a putative hit is a helpful step, guiding chemical modifications and structure−function studies, but pinning down the molecular target is also a tough task. Here, Lamsa et al. (DOI: 10.1021/acschembio.5b01050) demonstrate a useful system to uncover an antimicrobial compound’s MOA. Their method is based on a prior observation that antibiotic-treated microbes have different cytological characteristics under a fluorescent microscope depending on the target of the antibiotic. Inspired by this observation, the researchers engineer B. subtilis strains harboring inducible destruction constructs aimed at several key cellular pathways including DNA replication and fatty acid biosynthesis. They show that antibiotics of a known cellular target display similar cytological characteristics when compared to engineered strains that destroy that same cellular pathway. They go on to use their system, which they dub rapid inhibition profiling or RIP, to probe the antimicrobial mechanism for nonsteroidal anti-inflammatory drugs.
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Cancer cells are known to be extra hungry for glucose, fueling a higher glycolytic burn rate and providing the cell with precursor molecules for tumorigenesis. This is known as the Warburg effect, and a number of downstream mechanisms have been uncovered that lead to selective advantage for cells that produce their energy primarily through glycolysis. Here, Kohnz et al. (DOI: 10.1021/acschembio.6b00433) investigate this phenomenon by using metabolomics to study individual breast cancer lines mutated in 11 common human oncogenes. In an effort to find shared metabolic pathways, the researchers feed carbon isotope-labeled glucose to the cells, providing a mass spectrometry handle to see where carbon is trafficked through glycolysis and connected metabolic pathways. Their profiling uncovers heightened sialic acid, a precursor for protein sialylation, in many cancer lines. To investigate how extra sialic acid affects the cells, the researchers go on to characterize cells depleted of the enzyme that converts sialic acid to the cytidine monophosphate-activated form, the precursor for protein sialylation. Taken together, their results are consistent with a new role for increased sialic acid in breast cancer pathogenicity.
SENSING OXYGEN FOR ANAEROBES 101
Diatomic gas molecules like O2 and NO can act as biological signals in both eukaryotes and prokaryotes. The heme nitric oxide−oxygen binding (H-NOX) proteins sense gases by coupling Fe(II) coordination of the gas molecule with a © 2016 American Chemical Society
SUGAR INTO SIALIC ACID
Published: August 19, 2016 2072
DOI: 10.1021/acschembio.6b00686 ACS Chem. Biol. 2016, 11, 2072−2072
