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In most archaea, the enzyme TiaS post-transcriptionally modifies a cytidine in the anticodon of tRNAIle, converting it to agmatidine (agm2C or C+). This unique nucleoside allows translation at the AUA isoleucine codon and prevents misreading of the AUG methionine codon.
The final steps in the biosynthetic pathway to the morphine alkaloids have been revealed with the characterization of two key enzymes. In addition to the widely exploited parent compound, these new O-demethylases control metabolic flux to pharmaceutically useful opioid precursors.
Many kinase inhibitors for cancer therapy are rather nonselective, and their cellular mechanisms of action are incompletely understood. A nested chemical proteomics and chemical genetics strategy reveals which cellular targets of the clinical kinase inhibitor dasatinib functionally relate to its anti-oncogenic activity.
Elongation factor G (EF-G) is an essential GTPase involved in translation, but how the translocating ribosome activates EF-G remains an open question. Nucleotide functional group mutagenesis implicates A2660 of 23S rRNA as the trigger of GTPase hydrolysis by EF-G.
GlgE is identified as a maltosyltransferase that catalyzes the polymerization step in a previously undescribed pathway in Mycobacterium tuberculosis for converting trehalose to α-glucan. A combination of traditional and chemical genetic strategies suggest GlgE to be a viable therapeutic target.
Glycosylation can affect biological targets transiently and at low levels, making the development of diagnostic tools of critical importance. The application of a new series of antibodies raised against GlcNAc-modified substrates identifies a host of protein targets in normal and traumatized cells.
A plant mutant that fails to accumulate morphine provides a genetic clue to identifying the last two enzymes in this alkaloid biosynthetic pathway. Surprisingly, the proteins are non-heme dioxygenases, thus expanding the range of this versatile class of catalysts.
Ru(II)(tris-bipyridyl)2+ derivatives photocatalytically generate singlet oxygen. Attaching these ruthenium conjugates to small-molecule inhibitors of intracellular or integral membrane proteins turned modest-potency compounds into chemical knockout reagents that potently inactivated targets in response to light.
Asymmetric ADP affinities and dissociation rates as well as optimization of subunit coordination through the long lever arm ensure high processivity under the intramolecular and external off-axis loads that myosin V experiences in vivo.
Simple and robust methods to access ubiquitin conjugates are needed to probe the role of this prevalent protein. A new intein-mediated disulfide crosslinking strategy now demonstrates a surprising lack of specificity for the site of ubiquitin labeling in DNA repair.
Semisynthetic methods to make ubiquitin conjugates have yielded broad conclusions for epigenetics. A robust intein-mediated chemical crosslinking strategy now expands our understanding by showing that a methyltransferase is surprisingly tolerant of changes to ubiquitin location and composition.
Organic synthesis plays a leading role in the discovery of small molecules for the exploration of biological systems. Therefore, the development of efficient strategies for the preparation of these molecules is a necessary aspect of the small-molecule approach to chemical biology.
A high-throughput phenotypic screen in zebrafish embryos provides distinctive signatures by which neuroactive chemicals can be classified. These “behavioral barcodes” provide a systems approach to elucidating the mechanistic neuropharmacology of drugs and novel compounds.
A reverse genetic engineering approach identifies metabolic enzymes and their cellular pathways as potential regulators of myoblast differentiation. Targeting these metabolic nodes has provocative implications for drug discovery and therapeutic efficacy.