ChemBioChem

Both embryonic development and the onset of diseases are significantly influenced by apoptosis (also known as “programmed cell death”). The apoptosis signaling pathways have partially been elucidated, with CD95 being the best characterized death receptor (see schematic picture of the death-inducing signaling complex, DISC). This knowledge is the basis for the development of new therapeutic strategies for the modulation of apoptosis.

“The ribosome is a ribozyme”—there is no peptidyl transferase enzyme! This remarkable feature was revealed by the high-resolution crystal structure of the large subunit of the ribosome, which shows that peptidyl transfer, the reaction by which peptide bonds are made, is RNA-catalysed. (The picture shows active-site nucleotides and the tetrahedral carbon atom of a proposed reaction intermediate.) This finding elevates ribozyme catalysis to central importance in the cell, performing one of the main reactions of life processes, and may represent a kind of “molecular fossil” of an earlier RNA world.

Biochemically and phylogenetically unrelated to the well-characterized microbial polyketide synthases (PKSs), which are responsible for the biosynthesis of many clinically important natural products, is a new family of PKSs recently discovered in bacteria. These new enzymes, termed type III PKSs, may be the predecessors to the plant PKSs, and their study promises insights into a new condensing reaction towards small aromatic metabolites in bacteria (see scheme).

Irrespective of the position of the photoresponsive unit, the formation and dissociation of duplexes between azobenzene-modified oligonucleotides and their unmodified counterparts with complementary sequence was successfully regulated. This was achieved by irradiation with either UV or visible light, effecting the cis–trans isomerization of the azobenzene unit (see picture) while other parameters such as temperature, pH, and ionic strength were kept constant.

Affinity chromatography on immobilized methylchymotrypsin in the presence of 5 M NaCl was a key step in the purification of LUTI (Linum usitatissimum trypsin inhibitor), a member of the potato inhibitor I family of serine proteinases. The two protein peaks obtained upon elution with water and 0.1 n HCl (I and II, see picture) were shown to have identical properties. The primary structure of LUTI (69 amino acids, M_r=7655 Da) and its association constants (K_a) with some serine proteinases were determined.

Bridging the gap between photolabelled membrane proteins (such as glucose transporters) and biotin detection systems used in intact cells there need to be 60–70 spacer atoms (see schematic picture). A suitably long bridge can be synthesised with a combination of polyethylene glycol and tartarate groups. Introduction of these spacers generates hydrophilic products that can be cleaved by periodate.

The effect of nonylprodigiosin (1) on T-cell proliferation is independent of vacuolar acidification and likely mediated through distinct cellular targets. This has been shown for the first time by synthesizing 1, a macrocyclic alkaloid with immunosuppressive properties and a yet unknown mechanism of action, as well as several of its analogues and evaluating their biological activities.

An unambiguous chemical synthesis and biological evaluation of the title compounds revealed their comparable potencies to natural epothilone A (1) against tumor cell lines, shedding further light on structure–activity relationships within the epothilone class. The picture shows a superposition of molecular models of 1 and 12,13-cyclopropyl epothilone A (2) (C atoms in magenta and white, respectively) in the tubulin binding site. A water molecule hydrogen-bonded to 1 (H atoms in magenta) is displaced upon binding of 2 (H atoms in white) which makes hydrophobic interactions with the side chain of Leu 273.

The self-initiated structural transition from an initially formed α-helix structure to a β-sheet structure is the prerequisite for the spontaneous assembly of complementary peptide pairs into amyloid fibrils. The heterogeneous assembly is accomplished by favorable electrostatic interactions between pairs of designed peptide species that contain positively charged lysine (K) residues and negatively charged glutamate (E) residues (see picture).

Sensitivity to the presence of noncanonical base pairs and dependence on the bond angles around the hydrolyzable phosphodiester linkage was demonstrated for the cleavage of RNAs by tyrosine–cyclen derivatives (cyclen = 1,4,7,10-tetraazacyclododecane). From a small library of these conjugates compound 1 was identified to cleave preferentially at the 3′ end of unpaired uridines. To evaluate the general potential of this compound two additional aptamer RNAs (see picture) were used in the cleavage experiments. By incorporating unnatural nucleosides such as deoxyuridine and ribothymidine a more detailed picture of the cleavage mechanism was obtained.