Reactive Azlactone Intermediate Drives Fungal Secondary Metabolite Cross-Pathway Generation.

Pathogenic fungi of Aspergillus section Fumigati are known to produce various secondary metabolites. A reported isolation of a compound with an atypical carbon skeleton called fumimycin from A. fumisynnematus prompted us to examine a related fungus, A. lentulus, for production of similar products. Here we report the isolation of fumimycin and a related new racemic compound we named lentofuranine. Detailed analyses revealed that both compounds were assembled by a nonenzymatic condensation of a polyketide intermediate from the terrein biosynthetic pathway and a highly reactive azlactone intermediate produced by an unrelated nonribosomal peptide synthetase carrying a terminal condensation-like domain. While highly reactive azlactone is commonly used in chemical synthesis, its production by a conventional non-metalloenzyme and employment as a biosynthetic pathway intermediate is unprecedented. The observed unusual carbon skeleton formation is likely due to the reactivity of azlactone. Our finding provides another example of a chemical principle being aptly exploited by a biological system.

Alkaloid Biosynthetic Enzyme Generates Diastereomeric Pair via Two Distinct Mechanisms.

Ergopeptines constitute one of the representative classes of ergoline alkaloids and carry a tripeptide extension on the lysergic acid core. In the current study, we discovered and structurally characterized newly isolated ergopeptine-like compounds named lentopeptins from a filamentous fungus Aspergillus lentulus, a close relative of A. fumigatus. Interestingly, in lentopeptins, the common lysergic acid moiety of ergopeptines is replaced by a cinnamic acid moiety at the N-terminus of the peptide segment. Moreover, lentopeptins lack the C-terminal proline residue necessary for the spontaneous cyclization of the peptide extension. Herein, we report the atypical lentopeptin biosynthetic pathway identified through targeted deletion of the len cluster biosynthetic genes predicted from the genome sequence. Further in vitro characterizations of the thiolation-terminal condensation-like (T-CT) didomain of the nonribosomal peptide synthetase LenA and its site-specific mutants revealed the mechanism of peptide release via diketopiperazine formation, an activity previously unreported for CT domains. Most intriguingly, in vitro assays of the cytochrome P450 LenC illuminated the unique mechanisms to generate two diastereomeric products. Lentopeptin A forms via a stereospecific hydroxylation, followed by a spontaneous bicyclic lactam core formation, while lentopeptin B is produced through an initial dehydrogenation, followed by a bicyclic lactam core formation and stereospecific hydration. Our results showcase how nature exploits common biosynthetic enzymes to forge new complex natural products effectively (213/250).

Full determination of individual reconstructed atomic columns in intermixed heterojunctions.

Heterojunctions offer a tremendous opportunity for fundamental as well as applied research, ranging from the unique electronic phases in between oxides to the contact issues in semiconductor devices. Despite their pivotal roles, determining individual building atom of matter in heterojunctions is still challenging, especially for those between highly dissimilar structures, in which breaking of symmetry, chemistry, and bonds may give rise to complex reconstruction and intermixing at the junction. Here, we combine electron microscopy, spectroscopy, and first-principles calculations to determine individual reconstructed atomic columns and their charge states in a complex, multicomponent heterojunction between the delafossite CuScO2 and spinel MgAl2O4. The high resolution enables us to demonstrate that the reconstructed region can accommodate a highly selective intermixing of Cu cations at specific Sc cation sites with half atomic density, forming a complex ordered superstructure. Such ability to resolve reconstructed heterojunctions to the atomic dimensions helps elucidate atomistic mechanisms and discover novel properties with applications in a diverse range of scientific disciplines.