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Many bacterial natural products contain C‐branched sugars, including components from the outer cell wall or antibiotically active metabolites. The enzymatic C‐branching of keto sugars leading to longer side chains (≥C2) is catalyzed by thiamine diphosphate (ThDP)‐dependent enzymes. Chiral tertiary α‐hydroxy ketones are formed in this process. The ThDP‐dependent enzymes that catalyze C‐branching reactions belong to one of three enzymatic superfamilies: decarboxylases, transketolases, and α‐ketoacid dehydrogenases 2, but branching of keto sugars has only been demonstrated for decarboxylases. In this study, we showed that an α‐ketoacid dehydrogenase is responsible for C‐branching of the deoxyketo sugar amycolose in the biosynthesis of kibdelomycin in Kibdelosporangium sp. MA7385. In addition, we characterized an amino transferase in the same biosynthetic gene cluster (BGC) that accepts a sterically demanding tertiary α‐hydroxy ketone in a downstream reaction. Subsequently, we identified approximately 400 similar BGCs in silico, suggesting that there is a large diversity of possible ThDP‐dependent enzymes catalyzing the C‐branching of keto sugars and subsequent modifications. [ABSTRACT FROM AUTHOR]

Sensory navigation results from coordinated transitions between distinct behavioral programs. During chemotaxis in the Drosophila melanogaster larva, the detection of positive odor gradients extends runs while negative gradients promote stops and turns. This algorithm represents a foundation for the control of sensory navigation across phyla. In the present work, we identified an olfactory descending neuron, PDM-DN, which plays a pivotal role in the organization of stops and turns in response to the detection of graded changes in odor concentrations. Artificial activation of this descending neuron induces deterministic stops followed by the initiation of turning maneuvers through head casts. Using electron microscopy, we reconstructed the main pathway that connects the PDM-DN neuron to the peripheral olfactory system and to the pre-motor circuit responsible for the actuation of forward peristalsis. Our results set the stage for a detailed mechanistic analysis of the sensorimotor conversion of graded olfactory inputs into action selection to perform goal-oriented navigation.

Scaling up biocatalytic reactions involving cytochrome P450 monooxygenases (P450s) is challenging due to their instability, low substrate loading, co‐factor, and oxygen requirements as well as the dependency on a reductase partner, which limits their integration into synthetic chemistry. Recently, a biocatalytic study investigated frequently used bacterial P450s to produce bioactive stilbenoids, extending the repertoire of sustainable synthetic strategies with remarkable success. This article explores the complementary application of less common eukaryotic P450s as a viable alternative for generating the same compounds when employed as a Pichia pastoris‐based whole‐cell biocatalyst. In a direct comparison to their bacterial equivalents, the recently discovered P450s CYP5035S7 and CYP5035S9 from the white‐rot fungus Polyporus arcularius are shown to be competitively efficient at synthesising stilbenoids at preparative‐scale. [ABSTRACT FROM AUTHOR]

Biocatalysis, early-stage functionalisation, enzyme kits, late-stage functionalisation, lead diversification Cover Feature: Enzyme Kits to Facilitate the Integration of Biocatalysis into Organic Chemistry - First Aid for Synthetic Chemists (ChemCatChem 11/2022) Keywords: biocatalysis; early-stage functionalisation; enzyme kits; late-stage functionalisation; lead diversification EN biocatalysis early-stage functionalisation enzyme kits late-stage functionalisation lead diversification 1 1 1 06/10/22 20220608 NES 220608 B The Cover Feature b illustrates how enzyme kits function as proficient and readily available "First Aid" for synthetic chemists, to simplify syntheses of complex molecules complementary to conventional chemical methods. [Extracted from the article]

Keywords: biocatalysis; cytochrome P450 enzymes; drug discovery; natural product diversification; P450 3A4 EN biocatalysis cytochrome P450 enzymes drug discovery natural product diversification P450 3A4 1 1 1 01/18/22 20220110 NES 220110 B The Cover Feature b shows cytochrome P450 3A4 revealing its magic ability to diversify natural products such as nootkatone to many functionalised metabolites in one step, as illustrated by a grey butterfly transforming into coloured butterflies. Biocatalysis, cytochrome P450 enzymes, drug discovery, natural product diversification, P450 3A4 Cover Feature: Natural Product Diversification by One-Step Biocatalysis using Human P450 3A4 (ChemCatChem 1/2022). [Extracted from the article]

The biological potency of natural products has been exploited for decades. Their inherent structural complexity and natural diversity might hold the key to efficiently address the urgent need for the development of novel pharmaceuticals. At the same time, it is that very complexity, which impedes necessary chemical modifications such as structural diversification, to improve the effectiveness of the drug. For this purpose, Cytochrome P450 enzymes, which possess unique abilities to activate inert sp 3 -hybridised C-H bonds in a late-stage fashion, offer an attractive synthetic tool. In this review the potential of cytochrome P450 enzymes in chemoenzymatic lead diversification is illustrated discussing studies reporting late-stage functionalisations of natural products and other high-value compounds. These enzymes were proven to extend the synthetic toolbox significantly by adding to the flexibility and efficacy of synthetic strategies of natural product chemists, and scientists of other related disciplines., Competing Interests: The authors declare no conflict of interest.