Tailor made : We report the rational biosynthesis of C15 hydroxylated non‐quinone geldanamycin analogues by site‐directed mutagenesis of the geldanamycin polyketide synthase (PKS), together with a combination of post‐PKS tailoring genes. Rational biosynthetic engineering allowed the generation of geldanamycin derivatives, such as DHQ3 illustrated in the figure, which had superior pharmacological properties in comparison to the parent compound.
Into neutral : We demonstrate the unique features of a pH click peptide based on an O‐acyl isopeptide method. Under acidic conditions, the click peptide remains in a monomeric form. Upon increase of the pH to 7.4, the click peptide is quickly able to convert into Aβ1–42 through an O‐to‐N intramolecular acyl migration. Further study using this pH click peptide would elucidate the pathological role of Aβ1–42 in Alzheimer's disease.
New and improved : The incorporation of a 6‐chlorotryptophan (6‐Cl‐Trp) into a β‐peptide (M)‐314 helix leads to a high‐affinity hDM2 inhibitor, as demonstrated by fluorescence fluctuation analysis at single molecule resolution. When conjugated to penetratin, the newly derived hDM2 binder specifically inhibits tumour cell growth in vitro.
Two steps to click iodine : We have developed a two‐step reaction for protein iodination using click chemistry. With this method, which is summarized in the scheme, covalent attachment of a stable iodine‐containing aromatic azide moiety to an alkyne‐containing protein was achieved.
Out of the green! Precursor‐directed biosynthesis allowed for the production of new nostocarboline derivatives that display phytotoxic and algicidal properties—in a phototrophic organism. The mechanism of action includes downregulation of photosynthesis, as demonstrated by chlorophyll‐a fluorescence imaging.
Saghatelian and colleagues recently introduced a global metabolite‐profiling approach that allows protein–metabolite interactions (PMI) to be identified. This approach represents an excellent strategy and valuable tool for unraveling the many secrets of the metabolome. The key features of the methodology will be summarized here.
Probing the sheet : The network of hydrogen bonds formed in the outer β sheet of the nicotinic acetylcholine receptor (nAChR; see figure) is fairly robust and tolerates single amide‐to‐ester mutations throughout. However, eliminating two proximal hydrogen bonds completely destroys receptor function; this adds further support to gating models that ascribe important roles to these β strands of the nAChR extracellular domain.
N‐Acylhomoserine lactones (AHLs) are used by a wide variety of bacteria for cell–cell communication in “quorum‐sensing”. These compounds are derived from L ‐homoserine lactone and a fatty acid, which varies in chain‐length, degree of saturation, and the presence or absence of an oxygen atom at C‐3. In this study we describe for the first time the occurrence of acyl chains carrying a methyl branch, and present a GC‐MS‐based method that can be used to distinguish these compounds from unbranched isomers. The bacterium Aeromonas culicicola produces several methyl branched AHLs. In Jannaschia helgolandensis—a marine bacterium of the Roseobacter clade—a doubly unsaturated AHL, (2E,9Z)‐N‐(2,9‐hexadecadienoyl)‐L ‐homoserine lactone, occurs. The location and configuration of the double bonds was proven by spectrometric investigation and synthesis. Finally, a method was developed to establish the absolute configuration of 3‐hydroxyalkanoyl‐HSLs by mild cleavage and chiral gas chromatography. The AHLs synthesized during this study were tested in sensor systems specific for certain AHL types. The results show that these compounds display varying responses to the respective sensors; this underlines the importance of determining the whole bouquet of AHLs and its function to fully understand their importance for regulatory functions in bacteria.相似文献
Antifolate labels : Molecules that bind specifically and with high affinity to proteins can be developed into powerful tools for chemical biology. The interaction between substituted 5‐benzyl pyrimidines and dihydrofolate reductase can be exploited for chemically labeling fusion proteins in mammalian cells.
Reversible mitochondrial shuttle : A novel concept in mitochondrial pharmacology allows the transport of bioactive compounds into the mitochondrial compartment and their subsequent release. A lipoic acid derivative containing a cleavable (“reversible”) triphenylphosphonium tag is endogenously cleaved by the mitochondrial aldehyde dehydrogenase (ALDH‐2) after mitochondrial accumulation.
