Asperustins K-P, Chlorinated Austocystins from NRRL 5856.

Asperustins K-P (-), six unreported chlorinated austocystins, were isolated from NRRL 5856. Their structures, including absolute configurations, were elucidated by extensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction. Asperustin K () features an unprecedented carbon skeleton with a 6/6/6/5/5/6/6/6 fused octacyclic ring system, while asperustin L () represents a distinctive carbon skeleton with a 6/6/6/5/5/5 hexacyclic ring system.

A unique three-enzyme cascade mediates efficient regioselective and stereospecific epoxytetrahydrofuran ring formation in deoxyverrucosidin biosynthesis.

The fungal octaketide deoxyverrucosidin shares the same α-pyrone core with several nonaketides, including aurovertins, citreoviridin, and asteltoxin. Deoxyverrucosidin features a unique epoxytetrahydrofuran ring. In this study, we demonstrate that this ring system is formed a flavin-containing monooxygenase-mediated epoxidation on the polyene chain, followed by rearrangement with an epoxide expandase and a second epoxidation on the resulting 2,5-dihydrofuran ring with a cytochrome P450 enzyme.

Phthalides and Norphthalides From the Ethyl Acetate Extracts of Ligusticum chuanxiong and Their Inhibitory Effects on Xanthine Oxidase In Vitro.

Four unreported compounds (1-4) and five known compounds (5-9) were isolated from ethyl acetate extracts of Ligusticum chuanxiong by a silica gel column chromatography, Sephadex LH-20 column chromatography, and semi-preparative HPLC. The planar structures of compounds 1-4 were confirmed by analyzing their HR-ESIMS, IR, and NMR spectra. Compounds 1 and 2 feature a norphthalide mono-ring skeleton derived from phthalide by the loss of one carbon atom.

Comparing Artificial Intelligence-Generated and Clinician-Created Personalized Self-Management Guidance for Patients With Knee Osteoarthritis: Blinded Observational Study.

Background: Knee osteoarthritis is a prevalent, chronic musculoskeletal disorder that impairs mobility and quality of life. Personalized patient education aims to improve self-management and adherence; yet, its delivery is often limited by time constraints, clinician workload, and the heterogeneity of patient needs. Recent advances in large language models offer potential solutions.

Unraveling new therapeutic targets in ankylosing spondylitis: Multi-omics Mendelian randomization on immune cells, metabolites, and inflammation proteins.

This study aims to identify novel immunological, metabolic, and inflammatory determinants of ankylosing spondylitis (AS) using Mendelian randomization (MR), offering new insights into its pathogenesis and potential therapeutic interventions. Employing a bidirectional, secondary validation two-sample MR, this study investigated causal associations among 1400 serum metabolites, 731 immune cell traits, and 91 circulating inflammatory proteins with AS. Instrumental variables were identified using PLINK for minimal linkage disequilibrium, applying strict significance thresholds.

The role of the hippocampus and SLC39A8 in chronic musculoskeletal pain-induced dementia: a Mendelian randomization study.

Despite observational studies suggesting a link between chronic musculoskeletal pain (CMP) and increased risk of cognitive decline and dementia, the causal nature of this relationship remains uncertain due to potential confounding factors and reverse causality. We employed two-sample Mendelian Randomization (TSMR), bidirectional MR, mediation MR, drug-target MR, and colocalization analysis, along with gene set enrichment and protein-protein interaction (PPI) analyses. TSMR assessed the causal associations between CMP and the risk of dementia and its subtypes, including Alzheimer's disease (AD), vascular dementia (VaD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and Parkinson's disease (PD).

Formation of -Hydroxyethylisoindolinone Derivatives in Fungi Requires Highly Coordinated Consecutive Oxidation Steps.

Gene duplication significantly contributes to the diversification of biosynthetic potential and increases the structural diversity of secondary metabolites. Here, we report the second alkyl salicylaldehyde derivative biosynthetic gene cluster in , being responsible for the formation of ethanolamine-containing derivatives. Heterologous expression and feeding experiments provided evidence for their formation via collaboration and modification with one cytochrome P450 and two flavin-containing monooxygenases in a highly ordered manner before and after ethanolamine incorporation.

Expression of a Colletotrichum polyketide synthase gene in Aspergillus nidulans leads to unexpected conjugates with a host metabolite.

Heterologous expression of the putative 1,3,6,8-tetrahydroxynaphthalene synthase gene ChPKS from Colletotrichum higginsianum in Aspergillus nidulans led to the formation of at least eight new compounds. LC-MS analysis proved them as coupling products of 1,3,6,8-tetrahydroxynaphthalene with an intermediate of the cichorine biosynthetic pathway. Comprehensive NMR analysis confirmed the structures of the two predominant products higginidulans A and B.

MIBiG 4.0: advancing biosynthetic gene cluster curation through global collaboration.

Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To share information about BGCs in a standardized and machine-readable way, the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard and repository was initiated in 2015.

Divergent Metabolism of -l-Trp-l-Leu in by Hydroxylation and Nucleobase Transfer with Two Cytochrome P450 Enzymes.

A three-gene cluster from was proven to be responsible for the formation of -l-Trp-l-Leu (cWL) derivatives. An strain harboring the cyclodipeptide synthase (CDPS) gene produced cWL. Expression of the whole cluster or genes of various combinations in revealed different metabolites of cWL by two cytochrome P450 enzymes.

Biosynthesis of Tetramate Derivatives in Reveals the Involvement of -Quinone Methide in Crosstalk of Multiple Pathways.

Genome mining and gene deletion experiments in proved the involvement of the PKS-NRPS PemA and the -enoyl reductase PemB in the formation of three enantiomeric clavatol-containing tetramate pairs. Overexpression of a transcription factor significantly improved the product yields. Feeding experiments provided evidence for their formation via 1,4-Michael addition of hydroxyclavatol to two tetramates from the Pem pathway.

Platelet-rich plasma: A bibliometric and visual analysis from 2000 to 2022.

Background: Platelet-rich plasma (PRP) is an integral biotherapeutic modality with evolving significance in the medical domain. Despite its expanding applications, a comprehensive bibliometric evaluation is essential to understand its development and impact.

Methods: The Web of Science core collection subject search identified articles pertinent to PRP applications.

Geranylation of Cyclic Dipeptides and Naphthols by the Fungal Prenyltransferase CdpC3PT_F253G.

Prenyl modification often improves the biological activities of compounds. Prenyltransferases have attracted attention as environmentally friendly biocatalysts for catalyzing prenyl modification of compounds. Compared to dimethylallyl modifications, research on geranyl modifications is relatively limited.

Cupin-domain containing protein is not essential for the alkyl salicylaldehyde formation in .

Previous studies demonstrated the requirement of four enzymes including a cupin-domain containing protein for the formation of alkyl salicylaldehydes and derivatives. Heterologous expression of three biosynthetic genes from resulted in the formation of such compounds in high-yields without involvement of a cupin analogue.

Biosynthesis of the Sesquiterpenoid Malfilanol D in Implies Alkyl and Hydride Migrations during the Bicyclo[5.4.0]undecane Skeleton Formation.

The great variety and fascinating complexity of terpenoid skeletons are achieved through different cyclizations catalyzed by terpene cyclases. Here, we report a sesquiterpene cyclase (MfdS) from for the formation of malfilanol D, a member of the group of biochemically less investigated sesquiterpenes with a bicyclo[5.4.

Construction of an expression platform for fungal secondary metabolite biosynthesis in Penicillium crustosum.

Filamentous fungi are prolific producers of bioactive natural products and play a vital role in drug discovery. Yet, their potential cannot be fully exploited since many biosynthetic genes are silent or cryptic under laboratory culture conditions. Several strategies have been applied to activate these genes, with heterologous expression as one of the most promising approaches.

Increasing structure diversity of farnesylated chalcones by a fungal aromatic prenyltransferase.

Farnesylated chalcones were favored by researchers due to their different biological activities. However, only five naturally occurring farnesylated chalcones were described in the literature until now. Here, the farnesylation of six chalcones by the Aspergillus terreus aromatic prenyltransferase AtaPT was reported.

Fungal Prenyltransferase AnaPT and Its F265 Mutants Catalyze the Dimethylallylation at the Nonaromatic Carbon of Phloretin.

Phloretin is widely found in fruit and shows various biological activities. Here, we demonstrate the dimethylallylation, geranylation, and farnesylation, particularly the first dimethylallylation at the nonaromatic carbon of phloretin () by the fungal prenyltransferase AnaPT and its mutants. F265 was identified as a key amino acid residue related to dimethylallylation at the nonaromatic carbon of phloretin.

The Promiscuous Flavin-Dependent Monooxygenase PboD from Increases the Structural Diversity of Hydroxylated Pyrroloindoline Diketopiperazines.

The potential of natural products as pharmaceutical and agricultural agents is based on their large structural diversity, resulting in part from modifications of the backbone structure by tailoring enzymes during biosynthesis. Flavin-dependent monooxygenases (FMOs), as one such group of enzymes, play an important role in the biosynthesis of diverse natural products, including cyclodipeptide (CDP) derivatives. The FMO PboD was shown to catalyze C-3 hydroxylation at the indole ring of -l-Trp-l-Leu in the biosynthesis of protubonines, accompanied by pyrrolidine ring formation.

Asperustins A-J: Austocystins with Immunosuppressive and Cytotoxic Activities from NRRL 5856.

Ten new (-) and nine known (-) austocystins, along with four known anthraquinones (-), were isolated from the culture of NRRL 5856 by bioactivity-guided fractionation. The structures of the new compounds were elucidated by spectroscopic data analysis, X-ray crystallographic study, the modified Mosher's method, [Rh(OCOCF3)]-induced ECD spectral analysis, and comparison of the experimental ECD spectra with those of the similar analogues. Compounds - represent the first examples of austocystins with a C-4' oxygenated substitution.

Biosynthesis of Epipyrone A Reveals a Highly Specific Membrane-Bound Fungal -Glycosyltransferase for Pyrone Galactosylation.

Epipyrone A is a unique -galactosylated 4-hydroxy-2-pyrone derivative with an antifungal potential from the fungus . We elucidated its biosynthesis via heterologous expression and characterized an unprecedented membrane-bound pyrone -glycosyltransferase biochemically. Molecular docking and mutagenesis experiments suggested a possible mechanism for the heterocyclic -glycosylation and the importance of a transmembrane helix for its catalysis.

Four new steroidal glycosides from Lilium lancifolium Thunb. and their antitumor activity.

Four new steroidal glycosides (1-4), including two steroidal saponins named lililancifoloside B and C (1-2), one pregnane glycoside named lililancifoloside D (3), and one C22-steroidal lactone glycoside named lililancifoloside E (4), together with five known ones (5-9), were isolated from the bulbs of Lilium lancifolium Thunb. By using spectroscopic analysis, including 1D, 2D NMR, and HR-ESI-MS, the structures of 1-4 were elucidated. All isolates were tested for their cytotoxic potential against the MCF-7, MDA-MB-231, HepG2, and A549 cell lines.

P450 in C-C coupling of cyclodipeptides with nucleobases.

Bacterial cytochrome P450 enzymes catalyze various and often intriguing tailoring reactions during the biosynthesis of natural products. In contrast to the majority of membrane-bound P450 enzymes from eukaryotes, bacterial P450 enzymes are soluble proteins and therefore represent excellent candidates for in vitro biochemical investigations. In particular, cyclodipeptide synthase-associated cytochrome P450 enzymes have recently gained attention due to the broad spectrum of reactions they catalyze, i.