Research articles

A chemical genetics approach identifies the Raf-MEK-ERK signaling system downstream of PKC in formation of the antimicrobial cell structures called neutrophil extracellular traps.

A potent hepatitis C virus protease protein inhibitor forms an irreversible covalent bond to a virally conserved noncatalytic cysteine in the protease substrate-binding pocket identified in a bioinformatic analysis.

In addition to its incorporation into proteins, phenylalanine serves as an important precursor for natural products and components of the plant cell wall. The identification of the last gene in phenylalanine biosynthesis explains why flux in this pathway traffics through an arogenate intermediate in plants.

The antiviral S-acyl-2-mercaptobenzamide thioester ejects an essential coordinated zinc ion from and induces aggregation and dysfunction of the HIV-1 nucleocapsid protein NCp7 via repetitive intracellular enzymatic acyl transfers, dependent on acetyl-CoA.

Some cyclodipeptides are unusual in that their cyclic scaffold is created from activated, amino-acid–loaded tRNA substrates. Structural and biochemical evidence now demonstrates that the enzymes that perform this reaction are homologous to tRNA synthetases and use a covalently bound intermediate.

A variety of natural C-nitroso compounds are known, but the path to these important functional groups has been a mystery. Elucidation of the biosynthetic route to an iron chelator now reveals a tyrosinase-like copper-containing monooxygenase as responsible for the transformation.

Coenzyme Q serves a number of important roles in cells, including as an electron shuttle and as an antioxidant, but the exact roles and specific details of these processes have been difficult to investigate. The discovery of a selective inhibitor for Coq2, a critical enzyme in the biosynthesis of coenzyme Q, now primes the field for new investigations.

The chemical synthesis of acylated dipeptide substrates for SfmC, a tetradomain NRPS enzyme, defines the mechanism of formation of two rings in saframycin and explains the unusual presence of a fatty acid loading system in this biosynthetic gene cluster.

A new NMR method—requiring only milligram quantities of substrates—uses isotopically labeled neighbor atoms to directly and continuously report on KIEs at the reaction center. Application of the methodology defines a reaction coordinate for sialidase hydrolysis.

Expression of vancomycin resistance genes is known to be controlled by the two-component regulatory system VanRS, but the identity of the VanS receptor ligand has been controversial. Synthesis of a vancomycin photoaffinity probe has now revealed that vancomycin directly binds VanS to induce the expression of resistance genes.

Glycosyltransferases transfer sugars from a donor to an acceptor, with current inhibitors directly competing with these substrates. Modification of the donor reveals a new mode of allosteric inhibition in which a bulky substituent prevents conformational changes and thus enzyme activation.

A membrane-permeant caged derivative of PtdIns(3)P induces EEA1-dependent endosomal fusion upon photoactivation in vivo, potentially with a time course close to that of the native process.

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.

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.

Beewolf digger wasps protect their larvae from microbial infestation by cultivating Streptomyces bacteria that produce antimicrobial compounds. A new study uses intact specimens to investigate the placement and production of nine antibiotics that combine to kill a wide range of pathogens.

Bacterial cultures can express proteins in high yields but cannot create mammalian N-glycoforms. Engineering of the glycosylation machinery of C. jejuni and its transfer into E. coli, combined with trimming and rebuilding of the N-linked glycan, now provides a robust route to glycoproteins.

A caged version of the neurotransmitter GABA can be activated by two-photon excitation to evoke small, fast GABAergic currents to allow functional mapping of GABA receptor distribution in living brain tissue with single-synapse resolution.

Pd-catalyzed domino reactions have been shown to stitch together chemical groups to form more complex scaffolds. Now these methods are used in a diversity-oriented synthesis approach to make intricate natural product–like structures using simple sugars as starting materials.