Iron limitation triggers roseoceramide biosynthesis and membrane remodeling in marine roseobacter.

Chemical communication between marine bacteria and their algal hosts drives population dynamics and ultimately determines the fate of major biogeochemical cycles in the ocean. To gain deeper insights into this small molecule exchange, we screened niche-specific metabolites as potential modulators of the secondary metabolome of the roseobacter, . Metabolomic analysis led to the identification of a group of cryptic lipids that we have termed roseoceramides.

Expedited Aminoglutarimide C-N Cross-Coupling Enabled by High-Throughput Experimentation.

A simple protocol for the Buchwald-Hartwig cross-coupling of (hetero)aryl halides with unprotected aminoglutarimide to afford diverse cereblon binding motifs is disclosed. The development of this C-N cross-coupling method was enabled by high-throughput combinatory screening of solvents, bases, temperatures, and ligands. Scope studies revealed generality across various heteroaryl and aryl halides with the reaction proceeding under mild conditions.

Anhydrous and Stereoretentive Fluoride-Enhanced Suzuki-Miyaura Coupling of Immunomodulatory Imide Drug Derivatives.

Immunomodulatory imide drugs form the core of many pharmaceutically relevant structures, but C-C bond formation via metal-catalyzed cross coupling is difficult due to the sensitivity of the glutarimide ring ubiquitous in these structures. We report that replacement of the traditional alkali base with a fluoride source enhances a previously challenging Suzuki-Miyaura coupling on glutarimide-containing compounds with trifluoroborates. These enabling conditions are reactive enough to generate these derivatives in high yields but mild enough to preserve both the glutarimide and its sensitive stereocenter.

N-Cα Bond Cleavage Catalyzed by a Multinuclear Iron Oxygenase from a Divergent Methanobactin-like RiPP Gene Cluster.

DUF692 multinuclear iron oxygenases (MNIOs) are an emerging family of tailoring enzymes involved in the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs). Three members, MbnB, TglH, and ChrH, have been characterized to date and shown to catalyze unusual and complex transformations. Using a co-occurrence-based bioinformatic search strategy, we recently generated a sequence similarity network of MNIO-RiPP operons that encode one or more MNIOs adjacent to a transporter.

Catalytic Asymmetric Hydrogen Atom Transfer: Enantioselective Hydroamination of Alkenes.

We report a highly enantioselective radical-based hydroamination of enol esters with sulfonamides jointly catalyzed by an Ir photocatalyst, Brønsted base, and tetrapeptide thiol. This method is demonstrated for the formation of 23 protected β-amino-alcohol products, achieving selectivities up to 97:3 er. The stereochemistry of the product is set through selective hydrogen atom transfer from the chiral thiol catalyst to a prochiral -centered radical.

Characterization of Unexpected Self-Acylation Activity of Acyl Carrier Proteins in a Modular Type I Apicomplexan Polyketide Synthase.

Natural products play critical roles as antibiotics, anticancer therapeutics, and biofuels. Polyketides are a distinct natural product class of structurally diverse secondary metabolites that are synthesized by polyketide synthases (PKSs). The biosynthetic gene clusters that encode PKSs have been found across nearly all realms of life, but those from eukaryotic organisms are relatively understudied.

A single amino acid residue controls acyltransferase activity in a polyketide synthase from .

Type I polyketide synthases (PKSs) are multidomain, multimodule enzymes capable of producing complex polyketide metabolites. These modules contain an acyltransferase (AT) domain, which selects acyl-CoA substrates to be incorporated into the metabolite scaffold. Herein, we reveal the sequences of three AT domains from a polyketide synthase (PKS2) from the apicomplexan parasite .

Erratum: A single amino acid residue controls acyltransferase activity in a polyketide synthase from .

[This corrects the article DOI: 10.1016/j.isci.

Photochemical and Electrochemical Applications of Proton-Coupled Electron Transfer in Organic Synthesis.

We present here a review of the photochemical and electrochemical applications of multi-site proton-coupled electron transfer (MS-PCET) in organic synthesis. MS-PCETs are redox mechanisms in which both an electron and a proton are exchanged together, often in a concerted elementary step. As such, MS-PCET can function as a non-classical mechanism for homolytic bond activation, providing opportunities to generate synthetically useful free radical intermediates directly from a wide variety of common organic functional groups.

Mechanistic Investigation and Optimization of Photoredox Anti-Markovnikov Hydroamination.

The reaction mechanism and the origin of the selectivity for the photocatalytic intermolecular anti-Markovnikov hydroamination of unactivated alkenes with primary amines to furnish secondary amines have been revealed by time-resolved laser kinetics measurements of the key reaction intermediates. We show that back-electron transfer (BET) between the photogenerated aminium radical cation (ARC) and reduced photocatalyst complex (Ir(II)) is nearly absent due to rapid deprotonation of the ARC on the sub-100 ns time scale. The selectivity for primary amine alkylation is derived from the faster addition of the primary ARCs (as compared to secondary ARCs) to alkenes.

Expeditious synthesis of aromatic-free piperidinium-functionalized polyethylene as alkaline anion exchange membranes.

Alkaline anion exchange membranes (AAEMs) with high hydroxide conductivity and good alkaline stability are essential for the development of anion exchange membrane fuel cells to generate clean energy by converting renewable fuels to electricity. Polyethylene-based AAEMs with excellent properties can be prepared sequential ring-opening metathesis polymerization (ROMP) and hydrogenation of cyclooctene derivatives. However, one of the major limitations of this approach is the complicated multi-step synthesis of functionalized cyclooctene monomers.

Photocatalytic Generation of Aminium Radical Cations for C─N Bond Formation.

Aminium radical cations have been extensively studied as electrophilic aminating species that readily participate in C─N bond forming processes with alkenes and arenes. However, their utility in synthesis has been limited, as their generation required unstable, reactive starting materials and harsh reaction conditions. Visible-light photoredox catalysis has emerged as a platform for the mild production of aminium radical cations from either unfunctionalized or -functionalized amines.

A Systematic Analysis of Mosquito-Microbiome Biosynthetic Gene Clusters Reveals Antimalarial Siderophores that Reduce Mosquito Reproduction Capacity.

Advances in infectious disease control strategies through genetic manipulation of insect microbiomes have heightened interest in microbially produced small molecules within mosquitoes. Herein, 33 mosquito-associated bacterial genomes were mined and over 700 putative biosynthetic gene clusters (BGCs) were identified, 135 of which belong to known classes of BGCs. After an in-depth analysis of the 135 BGCs, iron-binding siderophores were chosen for further investigation due to their high abundance and well-characterized bioactivities.

Linking Genes to Molecules in Eukaryotic Sources: An Endeavor to Expand Our Biosynthetic Repertoire.

The discovery of natural products continues to interest chemists and biologists for their utility in medicine as well as facilitating our understanding of signaling, pathogenesis, and evolution. Despite an attenuation in the discovery rate of new molecules, the current genomics and transcriptomics revolution has illuminated the untapped biosynthetic potential of many diverse organisms. Today, natural product discovery can be driven by biosynthetic gene cluster (BGC) analysis, which is capable of predicting enzymes that catalyze novel reactions and organisms that synthesize new chemical structures.

Coculturing of Mosquito-Microbiome Bacteria Promotes Heme Degradation in Elizabethkingia anophelis.

Anopheles mosquito microbiomes are intriguing ecological niches. Within the gut, microbes adapt to oxidative stress due to heme and iron after blood meals. Although metagenomic sequencing has illuminated spatial and temporal fluxes of microbiome populations, limited data exist on microbial growth dynamics.

Anti-Markovnikov Hydroamination of Unactivated Alkenes with Primary Alkyl Amines.

We report here a photocatalytic method for the intermolecular anti-Markovnikov hydroamination of unactivated olefins with primary alkyl amines to selectively furnish secondary amine products. These reactions proceed through aminium radical cation (ARC) intermediates and occur at room temperature under visible light irradiation in the presence of an iridium photocatalyst and an aryl thiol hydrogen atom donor. Despite the presence of excess olefin, high selectivities are observed for secondary over tertiary amine products, even though the secondary amines are established substrates for ARC-based olefin amination under similar conditions.

In silico Screening and Evaluation of Plasmodium falciparum Protein Kinase 5 (PK5) Inhibitors.

An in silico screen of 350 000 commercially available compounds was conducted with an unbiased approach to identify potential malaria inhibitors that bind to the Plasmodium falciparum protein kinase 5 (PfPK5) ATP-binding site. PfPK5 is a cyclin-dependent kinase-like protein with high sequence similarity to human cyclin-dependent kinase 2 (HsCDK2), but its precise role in cell-cycle regulation remains unclear. After two-dimensional fingerprinting of the top scoring compounds, 182 candidates were prioritized for biochemical testing based on their structural diversity.

Metal- and Acid-Free C-H Formylation of Nitrogen Heterocycles: Using Trioxane as an Aldehyde Equivalent Enabled by an Organic-Soluble Oxidant.

A metal-free, innate, and practical C-H formylation of nitrogen heterocycles using trioxane as a formyl equivalent is reported. This reaction provides a mild and robust method for modifying medicinally relevant heterocycles with an aldehyde handle. The use of an organic soluble oxidant, tetrabutylammonium persulfate, is critical in promoting the desired coupling.

Plasmodium parasite exploits host aquaporin-3 during liver stage malaria infection.

Within the liver a single Plasmodium parasite transforms into thousands of blood-infective forms to cause malaria. Here, we use RNA-sequencing to identify host genes that are upregulated upon Plasmodium berghei infection of hepatocytes with the hypothesis that host pathways are hijacked to benefit parasite development. We found that expression of aquaporin-3 (AQP3), a water and glycerol channel, is significantly induced in Plasmodium-infected hepatocytes compared to uninfected cells.

Discovery of Antimicrobial Lipodepsipeptides Produced by a Serratia sp. within Mosquito Microbiomes.

The Anopheles mosquito that harbors the Plasmodium parasite contains a microbiota that can influence both the vector and the parasite. In recent years, insect-associated microbes have highlighted the untapped potential of exploiting interspecies interactions to discover bioactive compounds. In this study, we report the discovery of nonribosomal lipodepsipeptides that are produced by a Serratia sp.

Therapists' and clients' ratings of real relationship, attachment, therapist self-disclosure, and treatment progress.

Objective: While there has been much research on the role of the working alliance in psychotherapy, researchers only recently began investigating the role of the real relationship in treatment.

Methods: In the current study on therapist and client dyads, we used actor-partner interdependence modeling (APIM) to examine associations between therapists' and clients' ratings of the real relationship, therapist self-disclosure, attachment, and treatment progress. APIM analyses allowed for an examination into how therapists' and clients' views of a particular phenomenon might affect their own ratings (actor), as well as the others' (partner) ratings of that same phenomenon.

Unprotected Indazoles Are Resilient to Ring-Opening Isomerization: A Case Study on Catalytic C-S Couplings in the Presence of Strong Base.

Indazoles represent a privileged scaffold in medicinal chemistry. In the presence of strong base, however, N-protected indazoles are prone to an undesirable ring-opening reaction to liberate o-aminobenzonitriles. By employing unprotected indazoles with a free N-H bond, isomerization is averted because the heterocycle is deprotonated in situ.

Synthesis of Furo[2,3-c]pyridazines via Tandem Transition-Metal Catalysis.

A general and efficient catalytic approach to synthesis of the furo[2,3-c]pyridazine ring system is reported. Building on the easily accessible 2-bromo-3-aminopyridizinone skeleton, a tandem Sonogashira coupling-cycloisomerization provides ready access to functionalized furopyridazines. A wide functional group tolerance was observed in the tandem reaction, which proceeds in high yield in 1-3 h.

Exploring the Untapped Biosynthetic Potential of Apicomplexan Parasites.

Apicomplexan parasites encompass a diverse group of eukaryotic intracellular pathogens that infect various animal hosts to cause disease. Intriguingly, apicomplexans possess a unique organelle of algal origin, the apicoplast, which phylogenetically links these parasites to dinoflagellates and photosynthetic, coral-associated organisms. While production of secondary metabolites in closely related organisms has been thoroughly examined, it remains widely unexplored in apicomplexans.

Ethanolamine Catabolism in Pseudomonas aeruginosa PAO1 Is Regulated by the Enhancer-Binding Protein EatR (PA4021) and the Alternative Sigma Factor RpoN.

Unlabelled: Although genes encoding enzymes and proteins related to ethanolamine catabolism are widely distributed in the genomes of Pseudomonas spp., ethanolamine catabolism has received little attention among this metabolically versatile group of bacteria. In an attempt to shed light on this subject, this study focused on defining the key regulatory factors that govern the expression of the central ethanolamine catabolic pathway in Pseudomonas aeruginosa PAO1.