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In this issue

O -GlcNAc on the brain

Much like phosphorylation, β-N-acetylglucosamine (O-GlcNAc) can modify serine and threonine residues of intracellular proteins. However, investigating the biological significance of this post-translational modification has been difficult owing to a lack of tools for its in vivo detection. Khidekel et al. have developed a new method, called QUIC-Tag, that combines chemoenzymatic and differential isotopic labeling of O-GlcNAc for quantitative mass spectrometry–based proteomics. With this approach, electron-transfer dissociation can be used to elucidate the exact sites of O-GlcNAc modification by mass spectrometry. Using QUIC-Tag, Khidekel et al. observed reversible O-GlcNAc glycosylation in neurons and found that excitatory stimulation of rat brains modulates O-GlcNAc glycosylation. These results suggest the importance of O-GlcNAc in regulating neuronal signaling and highlight the advantages of this method for investigating the physiological levels of O-GlcNAc modification. [Articles, p. 339 ; News & Views, p. 303 ] JK

Tagging made simple

Site-specific labeling of proteins is desirable for many protein engineering and protein tagging studies. Given that proteins contain numerous instances of the various 20 amino acids, simple substitution cannot be used to achieve site-specific labeling. Carrico et al. now demonstrate how FGE, the formylglycine (fGly)-generating enzyme, can help get around this problem. The enzyme oxidizes a cysteine residue within a six-amino-acid motif to generate fGly. By inserting this short motif into proteins of interest, unique fGly residues are generated by the action of either endogenous or exogenously expressed prokaryotic FGE. Because fGly contains a reactive aldehyde, simple chemistry can then be used to covalently modify proteins with various tags, including fluorophores and polyethylene glycol chains. This strategy can theoretically be applied to any protein and can be used with any aldehyde-specific reagent. [Brief Communications, p. 321 ] MB

Tuberculosis drug target

Diarylquinolines are promising candidates for antituberculosis drugs. The tuberculosis strains Mycobacterium tuberculosis and Mycobacterium smegmatis can be killed by diarylquinolines such as R207910. Mutations in the ATP synthase complex have been shown to cause resistance of these strains to R207910, which suggests that the synthase may be the target of R207910. Using biochemistry, Dendouga et al. now show that R207910 binds to the AtpE subunit of the synthase complex. This conclusive identification of a complex involved in energy metabolism as a diarylquinoline target represents a new strategy for development of drugs to treat tuberculosis infection. [Brief Communications, p. 323 ] MB

Yeast that smell

In mammals, odorant binding to an olfactory receptor stimulates a signaling cascade within a single neuron in the nose that is ultimately interpreted by the olfactory regions of the brain. Smells can often be recognized by multiple receptors, which results in a combinatorial array of signals that are responsible for the high sensitivity of the olfactory system. To capitalize on odorant receptors for biosensor development, Radhika et al. created a yeast strain that expresses the primary components of the mammalian olfactory signaling pathway. By screening a yeast library expressing the binding pocket of orphan olfactory receptors, the authors identified an olfactory receptor that is responsive to 2,4-dinitrotoluene. With these 'olfactory yeast', it may now be possible to gain a better understanding of the molecular basis of olfactory receptor chemical specificity. [Letters, p. 325 ; News & Views, p. 306 ] JK

Activating autophagy

Autophagy, a process for degrading cytoplasmic components, is an important clearance mechanism in eukaryotic cells. Autophagy is believed to have a role in preventing Huntington's disease and other neurodegenerative diseases by removing aggregation-prone proteins. Currently rapamycin is the only known small-molecule enhancer of autophagy. To identify additional small-molecule regulators of autophagy, Sarkar et al. screened a small-molecule library for compounds that modulate the effects of rapamycin on yeast growth. Three of the identified small-molecule enhancers of rapamycin (SMERs) activated autophagy in mammalian cells. Using models of Huntington's disease, the authors found that the SMERs reduce protein aggregation and cell death in mammalian cells and protect against neurodegeneration in Drosophila melanogaster. The SMERs seem to act independently of the rapamycin-inhibited mTOR kinase pathway, which suggests that these compounds may target currently unknown regulators of autophagy. [Letters, p. 331 ; News & Views, p. 304 ] JK

Just a trim, please

Proteins destined for the plasma membrane, the Golgi, or the endosome-lysosome system enter the endoplasmic reticulum (ER) immediately after translation, where they encounter various protein processing events. Glycosidases and glycanases add and subtract sugars to most proteins that enter the ER in a process called N-glycosylation. In addition, the ER is the home to molecular chaperones that assist in the folding of the newly synthesized proteins. If misfolding occurs, proteins are delivered by the ER-associated degradation system to the cytosol for degradation by proteasomes. To escape this fate by becoming properly folded and eventually released from the ER retention system, proteins must have specific N-glycan sugar chains associated with them so that they can recruit the proper chaperones. Molinari reviews the timing associated with N-glycan processing, and the importance of it and of sugar identity in determining folding and disposal. [Review, p. 313 ] MB

In This Issue written by Mirella Bucci and Joanne Kotz

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In this issue. Nat Chem Biol 3, v (2007).

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