SynopsisThe 13C nmr chemical shifts of the common amino acid residues were measured in DzO solutions of the linear tetrapeptides H-Gly-Gly-X-L-Ala-OH. For Asp, Glu, Lys, Tyr, and His, the titration shifts arising from the ionization of the amino acid side chains were also ohtained. These data are compared with the corresponding chemical shifts in the pro-the linear pentapeptides H-Gly-Gly-X-Gly-Gly-OH, and the free amino acids. On this basis, the selection of suitable "random coil" chemical shifts for conformational studies of polypeptide chains is discussed.

The cyclic depsipeptide FR900359 (FR), isolated from the tropical plant Ardisia crenata, is a strong and selective inhibitor of Gq proteins, making it an indispensable pharmacological tool to study Gq-related processes, as well as a promising drug candidate. Gq inhibition is a novel mode of action for defense chemicals and crucial for the ecological function of FR, as shown by in vivo experiments in mice, its affinity to insect Gq proteins, and insect toxicity studies. The uncultured endosymbiont of A. crenata was sequenced, revealing the FR nonribosomal peptide synthetase (frs) gene cluster. We here provide a detailed model of FR biosynthesis, supported by in vitro enzymatic and bioinformatic studies, and the novel analogue AC-1, which demonstrates the flexibility of the FR starter condensation domains. Finally, expression of the frs genes in E. coli led to heterologous FR production in a cultivable, bacterial host for the first time.

The catalytic and selective construction of carbon-carbon bonds for the generation of complex molecules is one of the most important tasks in organic chemistry. This was clearly highlighted by the 2010 Nobel Prize in Chemistry, which was awarded for the development of Pd-catalyzed cross-coupling reactions. The underlying concept of cross-linking building blocks to generate molecular complexity can also be widely found in natural product biosynthesis. Impressive examples for such natural cross-coupling reactions are biosynthetic processes for the assembly of biaryl moieties in natural products--highly efficient enzymatic reactions that often achieve synthetically yet unmatched selectivities. This Minireview highlights selected examples that showcase these fascinating biotransformations.

The potent and selective Gq protein inhibitor depsipeptide FR900359 (FR), originally discovered as the product of an uncultivable plant endosymbiont, is synthesized by a complex biosynthetic system comprising two nonribosomal peptide synthetase (NRPS) assembly lines. Here we characterize a cultivable bacterial FR producer, enabling detailed investigations into biosynthesis and attachment of the functionally important FR side chain. We reconstitute side chain assembly by the monomodular NRPS FrsA and the non-heme monooxygenase FrsH, and characterize intermolecular side chain transesterification to the final macrocyclic intermediate FR-Core, mediated by the FrsA thioesterase domain. We harness FrsA substrate promiscuity to generate FR analogs with altered side chains and demonstrate indispensability of the FR side chain for efficient Gq inhibition by comparative bioactivity, toxicity and docking studies. Finally, evolution of FR and side chain biosynthesis is discussed based on bioinformatics analyses. Side chain transesterification boosts potency and target affinity of selective Gq inhibitor natural products.