The thiodiketopiperazine derivatives shovelmycin A–B and ansamycin derivative divergolide X from the cold-seep-derived Streptomyces olivaceus HDN22-001
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A polyketide-based biosynthetic platform for diols, amino alcohols and hydroxy acids
Medium- and branched-chain diols and amino alcohols are important industrial solvents, polymer building blocks, cosmetics and pharmaceutical ingredients, yet biosynthetically challenging to produce. Here we present an approach that uses a modular polyketide synthase (PKS) platform for the efficient production of these compounds. This platform takes advantage of a versatile loading module from the rimocidin PKS and nicotinamide adenine dinucleotide phosphate-dependent terminal thioreductases. Reduction of the terminal aldehyde with alcohol dehydrogenases enables the production of diols, oxidation enables the production of hydroxy acids and specific transaminases allow the production of various amino alcohols. Furthermore, replacement of the malonyl-coenzyme A-specific acyltransferase in the extension module with methyl- or ethylmalonyl-coenzyme A-specific acyltransferase enables the production of branched-chain diols, amino alcohols and carboxylic acids in high titres. Use of our PKS platform in Streptomyces albus demonstrated the high tunability and efficiency of the platform.
Accurately adjusted phenothiazine conformations: reversible conformation transformation at room temperature and self-recoverable stimuli-responsive phosphorescence
Conformational flexibility is essential to the stimuli-responsive property of organic materials, but achieving the reversible molecular transformation is still challenging in functional materials for the high energy barriers and restriction by intermolecular interactions. Herein, through the incorporation of various steric hindrances into phenothiazine derivatives with different positions and quantities to tune the molecular conformations by adjustable repulsive forces, the folded angles gradually changed from 180° to 90° in 17 compounds. When the angle located at 112° with moderated steric effect, dynamic and reversible transformation of conformations under mechanical force has been achieved for the low energy barriers and mutually regulated molecular motions, resulting in both self-recoverable and stimuli-responsive phosphorescence properties for the first time. It opened up a new way to realize the self-recovery property of organic materials, which can facilitate the multi-functional property of smart materials with the opened avenue for other fields with inspiration.
Simultaneous entry as an adaptation to virulence in a novel satellite-helper system infecting Streptomyces species
Satellites are mobile genetic elements that are dependent upon the replication machinery of their helper viruses. Bacteriophages have provided many examples of satellite nucleic acids that utilize their helper morphogenic genes for propagation. Here we describe two novel satellite-helper phage systems, Mulch and Flayer, that infect Streptomyces species. The satellites in these systems encode for encapsidation machinery but have an absence of key replication genes, thus providing the first example of bacteriophage satellite viruses. We also show that codon usage of the satellites matches the tRNA gene content of the helpers. The satellite in one of these systems, Flayer, does not appear to integrate into the host genome, which represents the first example of a virulent satellite phage. The Flayer satellite has a unique tail adaptation that allows it to attach to its helper for simultaneous co-infection. These findings demonstrate an ever-increasing array of satellite strategies for genetic dependence on their helpers in the evolutionary arms race between satellite and helper phages.
Kdm2a inhibition in skeletal muscle improves metabolic flexibility in obesity
Skeletal muscle is a critical organ in maintaining homoeostasis against metabolic stress, and histone post-translational modifications are pivotal in those processes. However, the intricate nature of histone methylation in skeletal muscle and its impact on metabolic homoeostasis have yet to be elucidated. Here, we report that mitochondria-rich slow-twitch myofibers are characterized by significantly higher levels of H3K36me2 along with repressed expression of Kdm2a, an enzyme that specifically catalyses H3K36me2 demethylation. Deletion or inhibition of Kdm2a shifts fuel use from glucose under cold challenge to lipids under obese conditions by increasing the proportion of mitochondria-rich slow-twitch myofibers. This protects mice against cold insults and high-fat-diet-induced obesity and insulin resistance. Mechanistically, Kdm2a deficiency leads to a marked increase in H3K36me2 levels, which then promotes the recruitment of Mrg15 to the Esrrg locus to process its precursor messenger RNA splicing, thereby reshaping skeletal muscle metabolic profiles to induce slow-twitch myofiber transition. Collectively, our data support the role of Kdm2a as a viable target against metabolic stress.
Biomimetic 1,2-amino migration via photoredox catalysis
Synthetic organic chemists continually draw inspiration from biocatalytic processes to innovate synthetic methodologies beyond existing catalytic platforms. Within this context, although 1,2-amino migration represents a viable biochemical process, it remains underutilized within the synthetic organic chemistry community. Here we present a biomimetic 1,2-amino migration accomplished through the synergistic combination of biocatalytic mechanism and photoredox catalysis. This platform enables the modular synthesis of γ-substituted β-amino acids by utilizing abundant α-amino-acid derivatives and readily available organic molecules as coupling partners. This mild method features excellent substrate and functionality compatibility, affording a diverse range of γ-substituted β-amino acids (more than 80 examples) without the need for laborious multistep synthesis. Mechanistic studies, supported by both experimental observations and theoretical analysis, indicate that the 1,2-amino migration mechanism involves radical addition to α-vinyl-aldimine ester, 3-exo–trig cyclization and a subsequent rearrangement process. We anticipate that this transformation will serve as a versatile platform for the highly efficient construction of unnatural γ-substituted β-amino acids.
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