Decorating pradimicin : Three tailoring enzymes in the pradimicin biosynthetic pathway have been investigated. PdmN and PdmJ were identified as a D ‐amino acid ligase and a C‐5 P450 hydroxylase, respectively, whereas PdmW was deduced to be the C‐6 P450 hydroxylase.
Site‐specific immobilization of peptides and proteins is crucial to ensure their functionality in surface‐based assays. We report the use of aniline‐catalyzed oxime ligations as a very efficient and broadly applicable method to covalently attach the N terminus of proteins and peptides to a surface functionalized with alkoxy‐amine groups.
The big screen : We have devised a high‐throughput screening method for organic peroxide‐dependent P450 reactivity by taking advantage of a previously undescribed activity of catalase, which was used as reporter enzyme. This two‐step assay, followed by liquid chromatography/mass spectrometry analyses, allowed the facile identification of several new substrates for bacterial P450 enzymes.
Oxidation of a specific cysteine residue to Cα‐formylglycine is a novel post‐translational modification that is directed by a short recognition motif commonly found in pro‐ and eukaryotic sulfatases. As recently shown by C. Bertozzi and co‐workers, this system can be employed in protein engineering to equip proteins with genetically encoded aldehyde tags for site‐specific labeling, conjugation and immobilization.
The Great White Plague : Mycobacterium tuberculosis, the bacteria causing tuberculosis, is a continuing threat to global health through the emergence of resistant strains and the lack of novel therapeutic agents. Recently reported results on this important work are highlighted.
Not just another P450 : Shown here is a model of the overall structure of CYP74C3 with the putative membrane‐binding region that is required for enzyme activation. Members of the CYP74 family of cytochrome P450 enzymes are specialised in the metabolism of hydroperoxides and play an important role in oxylipin metabolism, which is one of the main defence mechanisms employed by plants.
Caught in a trap . In this study trapped polyketide species (see figure) were off‐loaded from a type III PKS by novel nonhydrolyzable malonyl coenzyme A analogues in which a methylene group or an oxygen atom replaces the sulfur atom of malonyl‐CoA. This strategy allows the straightforward characterisation of intermediates of polyketide biosynthesis by LC‐HR‐ESI‐MS/MS and provides valuable insights on the mechanism and timing of polyketide formation.
CypScore predicts the reactivity of competing positions in the same and different molecules to a variety of cytochrome P450 metabolic reactions on a single reactivity scale.
A series of DNA methyltransferase 1 (DNMT1) inhibitors were modeled by docking and molecular dynamics studies to rationalize their activity. Our findings will be valuable in guiding research efforts toward the rational design and virtual screening of novel DNMT inhibitors.
Playing polo : Small‐molecule inhibitors of polo‐like kinase 1 are mostly ATP‐competitive, and thus face enormous specificity hurdles. This communication explores the concept of inhibiting Plk1 with a small‐molecule inhibitor of the protein–protein interactions required for Plk1 function.
Novel angular and branched ellipticine‐correlated anticancer agents were developed. In particular, compound 24 , with two basic side chains on opposite sides of the molecule, exhibits cytotoxicity in the nanomolar range, acting as a DNA intercalator and topoisomerase II inhibitor. SAR studies with pyridocarbazole derivatives in comparison with corresponding smaller pyrroloquinolines are discussed.
Happy tree‐like friends . Using trypsin and α‐chymotrypsin cleavage sites as models, we show that the protease reactivity of peptide dendrimers, such as the structure illustrated in the figure, can be controlled by the degree of branching. Such a control provides a novel possibility to tune the biological properties of peptide dendrimers, and should be generally useful for their employment as functional biomolecule analogues, for example, in drug delivery applications.
Setting the right target : Most researchers who use small RNAs in mammalian cells assume that mRNA will be the target. Recent studies suggest that small RNAs can also target chromosomal DNA.
An iterative analogue library synthesis strategy rapidly developed comprehensive SAR for the mGluR5 ago‐potentiator ADX‐47273. This effort identified key substituents in the 3‐position of oxadiazole that engendered either mGluR5 ago‐potentiation or pure mGluR5 positive allosteric modulation. The mGluR5 positive allosteric modulators identified possessed the largest fold shifts (up to 27.9‐fold) of the glutamate CRC reported to date as well as providing improved physiochemical properties.
Come together right now with L ‐DOPA : Chemical cross‐linking is widely used to study protein–protein interactions. However, many cross‐linking agents suffer from low reactivity or selectivity. An efficient and selective reaction of site‐specific protein cross‐linking was achieved using genetically incorporated 3,4‐dihydroxy‐L ‐phenylalanine.
The power of proline : Bold amino acid substitutions in sensitive protein regions are frequently unproductive, while more subtle mutations can be sufficient to bring about dramatic changes. But introducing proline at the residue next to the sulfur ligand in P450BM3 (CYP102A1) has the unexpected and desirable effect of enhancing the activity of this fatty acid hydroxylase with a broad range of non‐natural substrates, as illustrated by the figure.
Powerful pyrene probes : Two kinds of pyrene‐labeled oligonucleotides (HNA‐ and RNA‐skeleton probes) were explored. The enhanced fluorescence intensity in the monomer region and the disappearance of aggregate/excimer emission in duplexes has been successfully used to detect the hybridization of oligonucleotides.
Unsaturated Mannich bases with potent antitrypanosomal action against multidrug‐resistant strains of T. brucei brucei were identified. Their observed activities correlated well with their high Michael acceptor properties but not with their affinities to the P2 purine transporter.
Fragment formal concept analysis (FragFCA) for compound classification: Signature fragment combinations for compound classes with closely related biological activity were identified using FragFCA. These combinations are used to accurately classify active test compounds on the basis of fragment mapping. FragFCA can extract class‐specific fragment combinations from compounds active against different target families that have signature character and practical utility in compound classification and database searching.
Illuminating glucosidases : The shown photoaffinity probe for endoplasmic reticulum (ER) α‐glucosidases was found to be a highly potent inhibitor of α‐glucosidase I in vitro and equally effective at inhibiting cellular ER glucosidases, as determined by a free oligosaccharide (FOS) analysis.
