ChemBioChem

The cover picture shows a can of prebiotic soup for an improved “product”, thanks to the addition of UV photons. On p. 1240 ff., N. V. Hud, T. M. Orlando and co-workers demonstrate that model prebiotic reactions with formamide as a source material produce a greater yield and diversity of purine nucleobases when formamide is irradiated with UV photons during heating, in the presence and absence of inorganic catalysts. Guanine is also observed for the first time in model prebiotic formamide reactions, as emphasized by the pasta shape. The observation that purine nucleobases are still formed in UV-irradiated/heated formamide solutions in the absence of inorganic catalysts (i.e., with “100 % less salt”) further relaxes the requirements for obtaining nucleobases on the prebiotic Earth.

The inside cover picture shows solanapyrone A biosynthesis by a highly reducing iterative type I polyketide synthase, prosolanapyrone synthase (PSS), and a possible “Diels-Alderase”, solanapyrone synthase (SPS). PSS (top) produces desmethylprosolanapyrone I. In the catalytic cavity of SPS (center), prosolanapyrone II is oxidized to solanapyrone A, possibly by exo-selective Diels–Alder cyclization. For more information, see the paper by I. Fujii et al. on p. 1245 ff.

Bioorthogonal chemistry: Reactions of organic azides with designed probes proceed with ever increasing efficiency and form a cornerstone in the rapidly evolving field of bioorthogonal conjugation chemistry.

Enzyme of the rings: Vitamin B₆ biosynthesis through the DXP-independent route is catalyzed by PLP synthase. The enzyme utilizes ribose 5-phosphate, glyceraldehyde 3-phosphate and ammonia to synthesize the cofactor form of the vitamin, pyridoxal 5′-phosphate (PLP). This review provides the emerging mechanistic details of this remarkable Pdx1:Pdx2 glutamine amidotransferase complex.

Lipidating proteins: Protein prenylation is catalyzed by protein prenyltransferases, and enables proteins to reversibly associate with intracellular membranes. The mechanisms of protein prenylation and the recent developments in analysis and biotechnological exploitation of these modifications are reviewed.

To tag or not to tag: An oriented lectin microarray utilizing recombinant lectins with the standard prokaryotic expression tag glutathione S-transferase has been reported. The oriented lectin microarray improves the overall sensitivity and limits of detection by site-specific orientation of recombinant lectins. This continual improvement of the lectin microarray technology enables a deeper understanding of the biological function of glycans.

Hard core: We have analyzed the structural rearrangements of the urea-denatured state of recombinant prion protein by using liquid-state NMR spectroscopy. Our studies document that prion amyloid fibrils generated from monomeric, urea-unfolded human prion protein have a rigid core between residues 145–223.

Zinc sink: CCPGCC motifs added to a protein sequence provide a favorable environment for Zn^II coordination. This interaction reduces the binding of biarsenicals to the tetracysteine tag. Zinc's high affinity for this motif can affect the zinc pool in a eukaryotic system if a protein containing the motif is expressed at high concentration.

Protein arginine methyltransferases (PRMTs) catalyze the post-translational methylation of arginine residues. PRMT1 is the predominant mammalian isozyme and is responsible for generating the majority of the asymmetrically dimethylated arginine found in vivo. Herein, we describe the most potent PRMT1 inhibitor, C21, described to date.

Needle in a haystack: Synthesis of a high-purity, biogenic, heterocyclic, 936-member library enabled the identification of a small molecule, triazatricyclamide (1), that potently inhibited the proliferation of several cancer cell lines and induced rapid oxidative stress. Unusually, this agent caused cell death by activating both caspase-dependent and -independent pathways.

MAO enzymes: Demonstration of the presence of tyrosyl radicals in partially reduced monoamine oxidases (MAO) was achieved by a combination of specific isotopic labelling and pulsed ENDOR techniques. Comparative studies between human MAO A and MAO N indicate that the equilibrium distribution of the radical species is not localised to the active site residues near the flavin cofactor.

Triggering leucine: A new ligation strategy of using β-mercaptoleucine coupled with desulfurization at leucine sites was developed, and its applicability in protein synthesis is presented. The efficiency of our Leu-NCL was examined in several model peptides and utilized for the first total synthesis of HIV-1 Tat protein.

Pinning phosphines on proteins: A method for the cysteine-selective bioconjugation of phosphines has been developed. The photoactive yellow protein has been site-selectively functionalized with phosphine ligands and phosphine transition metal complexes to afford artificial metalloenzymes that are active in palladium-catalysed allylic nucleophilic substitution reactions.

Relaxed requirements: We demonstrate the formation of adenine, hypoxanthine, and guanine from heated (130 °C), UV-irradiated formamide solutions in the absence of an inorganic catalyst. Evidence is also provided that “classical” HCN pathways for purine nucleobase production are also active in heated and UV-irradiated formamide reactions.

Enzyme-catalyzed Diels–Alder cycloaddition: The biosynthetic gene cluster for solanapyrone has been cloned from Alternaria solani. The polyketide synthase product was identified as desmethylprosolanapyrone I. Expression and in vitro analysis indicated that Sol5—solanapyrone synthase—is a possible enzyme that catalyzes Diels–Alder cycloaddition.

Biosynthesis from two chains: Corallopyronin A is a potent antimicrobially active metabolite from Corallococcus coralloides. The putative biosynthetic genes belong to a trans-AT-type mixed PKS/NRPS cluster. One of the unusual features of the biosynthesis of corallopyronin A is its formation from two chains, which it is proposed are interconnected through the action of a trans-acting ketosynthase (CorB).

Feeling pK_ay: The title reaction demonstrates that the pK_a of the β-NH₂ group in 2,3-diaminopropionic acid (Dap) is significantly lowered when Dap is incorporated into peptides. The pK_a for Dap in a designed amphipathic peptide lends itself to applications requiring functional groups sensitive to pH changes. This is observed in mammalian cell endosomes, such as nonviral nucleic acid delivery.

Protein ligands for cellular receptors can be conveniently arrayed by click chemistry on biocompatible surfaces, as illustrated here with transferrin and the virus-like Qβ capsid particle. Binding of cell-surface receptors and internalization by clathrin-coated pits is aided by the polyvalent ligand display in a density-dependent fashion.

Membrane-permeant oligomers are the species responsible for human islet amyloid polypeptide (hIAPP) cytotoxicity because isolated oligomers showed the lowest cell survival rates in a WST-1 assay on INS-1E cells, whereas hIAPP fibrils exhibited no pronounced cytotoxicity. AFM and fluorescence microscopy experiments on model raft membranes confirmed the membrane-permeabilizing character of the species.

Mutant-specific transport inhibitors: A high-throughput screen identified novel small-molecule inhibitors of the exocytic pathway in yeast. The compounds are toxic specifically to cargo-sorting mutant strains and also block exocytosis specifically in these mutants. They are thus promising tools for identifying pathway-specific components and regulators of the exocytic transport machinery.