Jul 2026· International Journal of Biological Macromolecules· pp.
153783
· 0 citations· 33 references
Medicine
TL;DR
This study expands the enzymatic repertoire of licorice OMTs, provides new insights into the structure-function relationships underling multiple methylations, and establishes a foundation or sustainable biocatalytic production of highly bioactive methylated flavonoids in G. inflata and related species.
Abstract
Flavonoids are plant specialized metabolites widely distributed in plants with many health benefits. O-methyltransferases (OMTs) are pivotal in plant specialized metabolism by producing methylated derivatives with enhanced biological activity. In this study, we identified two novel flavonoid OMTs, GiOMT4 and GiOMT9, from Glycyrrhiza inflata, a medicinal licorice species commonly used in Chinese medicine. These enzymes could catalyze myricetin and dihydromyricetin to produce 3',4',5'-O-trimethyl derivatives in a reaction. Structural modeling and site-directed mutagenesis identified Trp193 as critical residue determining the specificity of trimethylation of GiOMT4. Notably, trimethylation markedly enhanced the antibacterial activity of flavonoids against Gram-positive bacteria, including Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococcus. Furthermore, trimethyl dihydromyricetin was identified as a novel compound with unexplored pharmacological potential. Collectively, this study expands the enzymatic repertoire of licorice OMTs, provides new insights into the structure-function relationships underling multiple methylations, and establishes a foundation or sustainable biocatalytic production of highly bioactive methylated flavonoids in G. inflata and related species.
Sour jujube (Ziziphus jujuba var. spinosa) is a valuable medicinal and edible fruit owing to its health-promoting properties. Methoxylated flavonoids enhance their value by improving stability and bioavailability. However, the cellular basis of their biosynthesis remains unclear. We constructed a single-nucleus transcriptomic atlas of sour jujube fruit. Parenchyma cells were identified as the primary sites for flavonoid biosynthesis and their O-methylation, characterized by high expression of phenylpropanoid pathway genes and O-methyltransferases (OMTs). Among the 48 identified OMTs, four (ZjOMT1–4) exhibited high expression, phylogenetically clustered with known functional OMTs, and localized to the cytoplasm; they were further characterized by enzyme activity assays. Notably, ZjOMT1 demonstrates moderate substrate promiscuity, catalyzing the methylation of various substrates, including quercetin, quercitrin, and rutin. Our findings reveal the cellular architecture of flavonoid metabolism in sour jujube fruit, providing genetic resources for breeding varieties with enhanced flavonoid profiles to develop functional foods and nutraceuticals.
Guo-Long Li, Hong-Hong Jiao, Wan-Li Zhao et al.· Journal of Agricultural and...· 0 citations
As part of our continuing search for antifungal natural products, we investigated the secondary metabolites of Streptomyces sp. SID10815, an actinomycete isolated from a ground-nesting bee-associated environment that exhibited notable antifungal activity in preliminary screenings. Herein, we report the discovery of four new N-acetylcysteine-modified ansamycins (1−4) and three new hydroxymycotrienin analogues (5−7), together with six known ansamycins (8−13), produced by this strain. These metabolites were detected and prioritized through a metabolomics-guided dereplication strategy integrating LC−MS profiling and bioactivity correlation. Their structures were elucidated by comprehensive spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (1H, 13C, COSY, HSQC, HMBC, and NOESY) in combination with high-resolution mass spectrometry. The newly identified metabolites expand the structural diversity of the ansamycin family and provide a basis for future structure−activity relationship studies of N-acetylcysteine-conjugated ansamycins. These findings define a distinctive ansamycin profile of Streptomyces sp. SID10815 that may serve as a useful chemical signature for future comparative studies of insect-associated actinomycetes.
Won Se Suh, Alexander J. Smith, Allan Artavia-León et al.· Journal of Natural Products· 0 citations
Jujubosides are the principal bioactive constituents of the traditional Chinese medicine Ziziphi Spinosae Semen and are well-known for their sedative, anxiolytic, and sleep-promoting activities. These compounds are dammarane-type triterpenoid saponins characterized by a unique aglycone, jujubogenin, featuring a 5,6-spiroketal moiety that forms a rigid D/E/F tricyclic scaffold. However, the enzymatic basis underlying the formation of this distinctive spiroketal structure remains elusive. In this study, we identified and functionally characterized three cytochrome P450 enzymes from wild jujubes and Bacopa monnieri. These enzymes cooperatively catalyze an oxidative cascade in which site-selective oxidations at C-16, C-23, and C-30 drive spiroketal formation, converting dammarenediol II into jujubogenin. We further reconstituted the complete biosynthetic pathway in engineered yeast, enabling the de novo production of jujubogenin. This study establishes a foundational platform for the complete biosynthesis of jujubosides in microbial cell factories.
Jun Tang, Wei Liu, Lin-Hua Zhao et al.· Journal of Agricultural and...· 0 citations
N-Acetylglucosamine (GlcNAc)-decorated natural products represent a structurally unique class of metabolites that possess diverse biological activities. Through the genome mining of Coccidioides sp. CMB-TN39F, we identified a GlcNAc transferase-encoding terpene synthase gene cluster brc. Heterologous expression of this cluster in Aspergillus nidulans enabled the characterization of seven GlcNAc-adorned brasilane-type sesquiterpene glycosides, including six previously undocumented compounds, brasilane G−L (1−6), and one known compound, brasilane A (7). Functional characterization revealed that the cytochrome P450 BrcC functions as an epoxidase, catalyzing a stereoselective epoxidation of 7 to form 1. Compound 1 can undergo non-enzymatic conversions to generate compounds 2−5 under mildly acidic conditions. Pharmacological evaluation demonstrated that compounds 1−6 effectively downregulate the expression of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in LPS/IFN-γ-stimulated THP-1-derived macrophages. Notably, 1, which features an epoxide moiety, exhibits superior anti-inflammatory activity compared to its biosynthetic precursor 7, with an IC50 value of 30.4 μM against IL-6. This study expands the chemical space of GlcNAc-conjugated terpenoids and showcases a biosynthetic logic in which enzymatic tailoring is coupled with nonenzymatic reactions to amplify both structural diversity and biological properties.
Ming-Min Wu, Yao-Hui Shi, Yu-Wei Lin et al.· Journal of Natural Products· 0 citations
The limited diversity of fungicide modes of action and rising resistance highlight the need for novel agrochemicals. Here, aminopyrimidine/pyridine hydrazones were rationally designed through bioisosteric modification of lead compound L. Twenty-five derivatives were synthesized and evaluated, yielding multiple candidates with strong activity against major phytopathogenic fungi. Compound 4b-8 showed the best performance, with an EC50 of 0.3 μg/mL against Monilinia fructicola and >90% in vivo control efficacy against peach brown rot at 50 μg/mL, outperforming chlorothalonil. Mechanistic studies suggested that 4b-8 induces extensive ultrastructural damage, mitochondrial dysfunction, ATP depletion, and antioxidant system collapse in fungal hyphae. Transcriptomic profiling indicated substantial disruption of carbohydrate metabolism, particularly glucan-associated processes, which was consistent with the marked reduction in total β-glucan content. Collectively, the data demonstrate that 4b-8 exerts fungicidal activity through interference with glucan-related cellular processes, providing a promising lead with a mode of action distinct from commercial standards.
Lei Zeng, Tuo-Tuo Zhang, Yuan Zhou et al.· Journal of Agricultural and...· 0 citations
The global health crisis driven by Antimicrobial Resistance (AMR) necessitates a pivot toward novel therapeutic agents, yet the Asteraceae genus Verbesina remains significantly under-characterized. Despite comprising over 300 species, early assessments indicated that only approximately 10% had been biologically investigated. This review provides a critical synthesis of the pharmacological landscape of Verbesina, focusing on the structural duality of its major specialized metabolites, the Sesquiterpene Lactones (SLs). The review systematically analyzes reported in vitro data, emphasizing high-potency scaffolds such as 6β-cinnamoyloxy-3β,4α-dihydroxyeudesmane (MIC = 3.9 μg/mL) and Verbesindiol (IC50 = 4.0 ± 0.6 μM) against prostate cancer cells. A core focus is placed on the Selectivity Index (SI = IC50/MIC); to address the translational challenge of non-selective toxicity. Notably, an Arbusculin derivative demonstrates a superior SI of up to 88.2, significantly outperforming standard drugs like meglumine antimoniate (SI = 40.0). Furthermore, the review evaluates the molecular mechanisms of action, such as the role of the α-methylene-γ-lactone moiety in alkylating cellular targets, while distinguishing structure-specific effects like mitochondrial uncoupling and respiratory chain inhibition. By bridging ethnopharmacology with modern mechanistic and quantitative data, this review critically assesses the translational potential of Verbesina metabolites, exposes current methodological limitations in the literature, and highlights clear directions for bioassay-guided isolation and chemical optimization as next-generation anti-resistance scaffolds.
Karla Irazú Ventura-Hernández, T. Pawar, F. R. Ramos-Morales et al.· Frontiers in Pharmacology· 0 citations
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