ChemBioChem

The cover picture shows the human blood group B galactosyltransferase that resides in the Golgi apparatus. Design and synthesis of inhibitors of glycosyltransferases is still challenging. Here, the binding site of the enzyme is occupied by a pentityl conjugate of uric acid. Structure-based design and synthesis led to nonionic UDP mimics that act as enzyme inhibitors. For more information, see the Full Paper by B. Meyer et al. on p. 443 ff. The illustration of the Golgi apparatus is taken from U. Lüttge, M. Kluge, G. Thiel, Botanik–Die umfassende Biologie der Pflanzen, Wiley-VCH, Weinheim, 2010.

The serine protease plasmin plays a pivotal role in a variety of processes including fibrinolysis, degradation of the extracellular matrix and cell migration. This review focuses on naturally occurring and engineered inhibitors of this important enzyme.

(R)evolution of protein-based calcium sensors: Expanding the toolbox of genetically encoded calcium sensors with new colors and traits is important for understanding calcium signaling and its relation to other intracellular pathways. Campbell and co-workers have used a new directed-evolution strategy to develop a rich palette of new sensors, including the first red-shifted, genetically encoded calcium sensor.

The sialome comprises sialylated glycoproteins and glycolipids that play essential roles in cell–cell communication. Using azide-modified molecular precursors of sialic acids and copper-free click chemistry, we visualized the spatiotemporal dynamics of the sialome in live zebrafish embryos.

Needles and noodles: Studying amyloid toxicity is important for understanding protein misfolding diseases. Using a luminescent conjugated polythiophene, we found that cell binding of nontoxic filamentous amyloids of insulin and β2-microglobulin was less efficient than that of toxic fibrillar amyloids; this suggests a correlation between amyloid toxicity and cell binding.

Sticky residue: Pyrroline-carboxy-lysine (Pcl) can be readily incorporated into proteins expressed in E. coli and mammalian cells by using the pyrrolysyl tRNA/tRNA synthetase pair. Pcl can be used as a single amino acid purification tag and can be site-specifically modified with functional probes during the elution process (see scheme).

Roped in: The lasso peptide microcin J25 (MccJ25) is matured by two enzymes and is exported by a putative ABC transporter (see graphic). We probed the function of the maturation enzymes using mutagenesis. We demonstrate that fusions of the enzymes with intervening linkers can produce MccJ25. Even a 151 kDa tripartite fusion between the ABC transporter and the two enzymes is capable of producing and exporting MccJ25.

Rope tricks: Our comprehensive structure–activity analysis of the antimicrobial lasso peptide microcin J25 shows which sequence elements govern 1) the stabilization of the lasso fold and 2) the antibacterial activity of the peptide.

Peripheral sequences change DNAzyme selectivity: A stem loop and nucleotides within peripheral sequences influence the Co²⁺ selectivity of the clone 11 DNAzyme. An alternative truncation approach provides insights into structure function relationships of metal-dependent DNAzymes.

It's own sweet ways: Disaccharide analogues containing nonreducing 5-thiomannose moieties (see structures) have recently been shown to affect the N-glycosylation and activity of proprotein convertases. We have discovered that these compounds inhibit the early steps of dolichol-linked oligosaccharide biosynthesis, and thereby reduce protein N-glycosylation in a manner that resembles congenital disorders of glycosylation.

Turning Tsp ON: Chemical biology approaches have revealed that the quality control protease Tsp is triggered into an active state via interactions with various activating clues.

The screening of heterogeneous compound libraries identified the myxobacterial compound spirangien A and its derivate spirangien M522 as potent inhibitors of IL-8 expression. Both compounds decelerate the phosphorylation and degradation of IκBα, the key regulator of the IL-1-stimulated NF-κB signaling pathway.

New methodologies for efficient genome mining of secondary metabolites are of the utmost importance to tap the full potential revealed by the ever-expanding sequence data. Targeted gene inactivation combined with sophisticated analytical and statistical tools has led to the identification and characterisation of the rhizopodin biosynthetic gene cluster.

Stereoselectivity and concerted transfers: Enantioselective hydride abstraction from alcohol substrates in a member of the GMC superfamily is reported. We suggest that this is due to oxidation by aryl-alcohol oxidase; in contrast to other GMCs, this involves hydride abstraction by flavin N5 with concerted proton abstraction by catalytic His502, as shown by KIEs and QM/MM calculations.

Purine nucleosides bind to the AP site in DNA duplexes carrying complementary nucleosides opposite the AP site, whereas pyrimidine nucleosides do not show noticeable binding. By using this characteristic binding feature, aptasensing of adenosine is attained by competitive binding between adenosine and riboflavin bound to the AP site in a DNA duplex.

Inhibitors of glycosyltransferases are important tools for studying sugar transfer to a variety of natural product based acceptors. We present a new concept for specific inhibitors of glycosyltransferases. As a first step we present an inhibitor for the UDP binding site of the human blood group B galactosyltransferase (see graphic).

Glycotyping of KO mice: Glycotyping analysis of serum N-glycomes from gene-knockout mice that show no significant phenotype or abnormality can provide highly informative data to facilitate further comprehensive discussion of functions of cell surface C-type lectins in the maintenance of homeostatic balance of general immune system.

From primary screening for anti-breast-cancer agents, a neglected RAL, monocllin II, was found to have extraordinary activity both in vitro and in vivo. Its underlying mechanisms of action were investigated, and some interesting results were discovered. The high activity of monocillin II was assumed to derive from its chemical structure when compared with its anologue, radicicol.

Decommissioning the powerhouse: Mitochondrial-targeting agents have the capacity to be both vehicles for the delivery of bioactive agents and mitochondrial disrupters and show promise for the treatment of various diseases. Here, we assess the physicochemical properties governing mitochondrial matrix accumulation or membrane disruption caused by mitochondria-penetrating peptides (see graphic).