An ongoing challenge in chemical research is to design catalysts that select the outcomes of the reactions of complex molecules. Chemists rely on organo- or transition metal catalysts to control stereo-, regio-, and periselectivity (selectivity among possible pericyclic reactions). Nature achieves these types of selectivity with a variety of enzymes such as the recently discovered pericyclases – a family of enzymes that catalyze pericyclic reactions. 1 To date, the majority of characterized enzymatic pericyclic reactions are cycloadditions and it has been difficult to rationalize how observed selectivities are achieved. 2 - 13 We report here the discovery of two homologous groups of pericyclases that catalyze distinct reactions: one group catalyzes an Alder-ene reaction, previously unknown in biology; the second catalyzes a stereoselective hetero-Diels–Alder reaction. Guided by computational studies, we rationalized the observed differences in reactivities and designed mutants that reverse periselectivities from Alder-ene to hetero-Diels–Alder and vice versa . A combination of in vitro biochemical characterizations, computational studies, enzyme co-crystal structures, and mutational studies provide a picture of how high regio- and periselectivities are achieved in nearly identical active sites.

Fungal highly reducing polyketide synthases (HRPKSs) biosynthesize polyketides using a single set of domains iteratively. Product release is a critical step in HRPKS function to ensure timely termination and enzyme turnover. Nearly all of the HRPKSs characterized to date employ a separate thioesterase (TE) or acyltransferase enzyme for product release. In this study, we characterized two fungal HRPKSs that have fused C-terminal TE domains, a new domain architecture for fungal HRPKSs. We showed that both HRPKS-TEs synthesize aminoacylated polyketides in an ATP-independent fashion. The KU42 TE domain selects cysteine and homocysteine, and catalyzes transthioesterification using the side chain thiol group as the nucleophile. In contrast, the KU43 TE domain selects leucine methyl ester and performs a direct amidation of the polyketide, a reaction typically catalyzed by nonribosomal peptide synthetase (NRPS) domains. The characterization of these HRPKS-TE enzymes showcase the functional diversity of HRPKS enzymes, and provides potential TE domains as biocatalytic tools to diversify HRPKS structures.

Sarcophyton glaucum is one of the most abundant and chemically studied soft corals with over 100 natural products reported in the literature, primarily cembrane diterpenoids. Yet, wide variation in the chemistry observed from S. glaucum over the past 50 years has led to its reputation as a capricious producer of bioactive metabolites. Recent molecular phylogenetic analysis revealed that S. glaucum is not a single species but a complex of at least seven genetically distinct species not distinguishable using traditional taxonomic criteria. We hypothesized that perceived intraspecific chemical variation observed in S. glaucum was actually due to differences between cryptic species (interspecific variation). To test this hypothesis, we collected Sarcophyton samples in Palau, performed molecular phylogenetic analysis, and prepared chemical profiles of sample extracts using gas chromatography-flame ionization detection. Both unsupervised (principal component analysis) and supervised (linear discriminant analysis) statistical analyses of these profiles revealed a strong relationship between cryptic species membership and chemical profiles. Liquid chromatography with tandem mass spectrometry-based analysis using feature-based molecular networking permitted identification of the chemical drivers of this difference between clades, including cembranoid diterpenes (2R,11R,12R)-isosarcophytoxide (5), (2S,11R,12R)-isosarcophytoxide (6), and isosarcophine (7). Our results suggest that early chemical studies of Sarcophyton may have unknowingly conflated different cryptic species of S. glaucum, leading to apparently idiosyncratic chemical variation.

We report the annulation of heterocyclic building blocks to access pi-extended polycyclic aromatic hydrocarbons (PAHs). The method involves the trapping of short-lived hetarynes with catalytically-generated biaryl palladium intermediates and allows...

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