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Strychnine is a natural product that, through isolation, structural elucidation and synthetic efforts, shaped the field of organic chemistry. Currently, strychnine is used as a pesticide to control rodents 1 because of its potent neurotoxicity 2 , 3 . The polycyclic architecture of strychnine has inspired chemists to develop new synthetic transformations and strategies to access this molecular scaffold 4 , yet it is still unknown how plants create this complex structure. Here we report the biosynthetic pathway of strychnine, along with the related molecules brucine and diaboline. Moreover, we successfully recapitulate strychnine, brucine and diaboline biosynthesis in Nicotiana benthamiana from an upstream intermediate, thus demonstrating that this complex, pharmacologically active class of compounds can now be harnessed through metabolic engineering approaches. The biosynthetic pathway of strychnine, brucine and diaboline is described, and the biosynthesis of these complex, pharmacologically active compounds has been successfully recapitulated in Nicotiana benthamiana from an upstream intermediate.

The X-ray crystal structure of the human glycine receptor in the presence of strychnine, an antagonist, reveals how antagonist binding leads to closure of the channel pore. Structure of human GlyR The strychnine-sensitive glycine receptor (GlyR) mediates neurotransmission throughout the spinal cord and brainstem. These ligand-gated channels control a wide range of motor and sensory functions, including vision and audition, and their dysfunction is linked to multiple neurological disorders, including autism and hyperekplexia. In this manuscript, the authors report the X-ray crystal structure of human GlyR in the presence of the antagonist strychnine. The structure reveals how antagonist binding leads to closure of the channel pore. Also in this issue of Nature , Eric Gouaux and colleagues have determined the high-resolution electron cryo-microscopy structure of strychnine-sensitive glycine receptor (GlyR) from zebrafish in both agonist- and antagonist-bound forms. Neurotransmitter-gated ion channels of the Cys-loop receptor family are essential mediators of fast neurotransmission throughout the nervous system and are implicated in many neurological disorders. Available X-ray structures of prokaryotic and eukaryotic Cys-loop receptors provide tremendous insights into the binding of agonists, the subsequent opening of the ion channel, and the mechanism of channel activation 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Yet the mechanism of inactivation by antagonists remains unknown. Here we present a 3.0 Å X-ray structure of the human glycine receptor-α3 homopentamer in complex with a high affinity, high-specificity antagonist, strychnine. Our structure allows us to explore in detail the molecular recognition of antagonists. Comparisons with previous structures reveal a mechanism for antagonist-induced inactivation of Cys-loop receptors, involving an expansion of the orthosteric binding site in the extracellular domain that is coupled to closure of the ion pore in the transmembrane domain.

Ferroptotic cell death is characterized by iron-dependent lipid peroxidation that is initiated by ferrous iron and H 2 O 2 via Fenton reaction, in which the role of activating transcription factor 3 (ATF3) remains elusive. Brucine is a weak alkaline indole alkaloid extracted from the seeds of Strychnos nux-vomica , which has shown potent antitumor activity against various tumors, including glioma. In this study, we showed that brucine inhibited glioma cell growth in vitro and in vivo, which was paralleled by nuclear translocation of ATF3, lipid peroxidation, and increases of iron and H 2 O 2 . Furthermore, brucine-induced lipid peroxidation was inhibited or exacerbated when intracellular iron was chelated by deferoxamine (500 μM) or improved by ferric ammonium citrate (500 μM). Suppression of lipid peroxidation with lipophilic antioxidants ferrostatin-1 (50 μM) or liproxstatin-1 (30 μM) rescued brucine-induced glioma cell death. Moreover, knockdown of ATF3 prevented brucine-induced accumulation of iron and H 2 O 2 and glioma cell death. We revealed that brucine induced ATF3 upregulation and translocation into nuclei via activation of ER stress. ATF3 promoted brucine-induced H 2 O 2 accumulation via upregulating NOX4 and SOD1 to generate H 2 O 2 on one hand, and downregulating catalase and xCT to prevent H 2 O 2 degradation on the other hand. H 2 O 2 then contributed to brucine-triggered iron increase and transferrin receptor upregulation, as well as lipid peroxidation. This was further verified by treating glioma cells with exogenous H 2 O 2 alone. Moreover, H 2 O 2 reversely exacerbated brucine-induced ER stress. Taken together, ATF3 contributes to brucine-induced glioma cell ferroptosis via increasing H 2 O 2 and iron.

Background Drug metabolism va-specific dosing. Strychnine, the primary active compound in strychnine-based alkaloids, is used for treatment of hemiplegia or amblyopia. However, knowledge of sex-based difference in the pharmacokinetics of strychnine remains limited, increasing the risk of dosage error and potential toxicity in patient.ries between men and women derived from the difference in body fat distribution and hormone secretion, necessitating sex. Method Rats were divided into intact (possessing reproductive organ) and gonadectomized (GDX) groups, including 6 males and 6 females in each one. In the GDX rat group, testes were removed from male rat at 5 weeks of age, while ovaries were removed from female rat. The GDX rats were maintained for an additional 15 days. All intact and GDX rats were tested at 8 weeks of age. Both intact and GDX rats were subjected to acute strychnine exposure through an oral dose of 0.59 mg/kg aqueous strychnine nitrate solution. Blood sampleswere collected from orbital vein into a centrifuge tube containing sodium heparin at following time points: 5, 10, 15, 30, and 45 min, as well as 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h. In the metabolomics experiments, male and female rats were divided into experimental and control groups. Each group containing 10 males and 10 females. The experimental group was orally administered 0.59 mg/kg of aqueous strychnine nitrate, while the control group was given the same dose of ultrapure water. Blood samples were collected from the orbital vein at 30 min, 2 h, and 12 h following administration. The plasma concentration of strychnine was quantified using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), while the metabolic kinetics data was acquired via HPLC-time-of-flight mass spectrometry (HPLC-TOF-MS). These data was subsequently analyzed to elucidate the intrinsic sex-specific metabolic difference between male and female rats. Result Intact female rats metabolized strychnine more slowly than male rats, with significantly higher peak plasma concentrations. Moreover, the peak concentrations in both male and female rats decreased after gonadectomy, the plasma peak concentration in GDX female rats remained significantly higher than that in GDX male rats.The metabolic profile of the rat changed significantly after gonadectomy, suggesting that sex hormones may be involved in the metabolism of strychnine. Significant differences were also observed between the metabolomics of male and female rats, such as ABC transporter expression, pyrimidine metabolism, and linoleic acid metabolism pathways. Conclusion Significant sex-specific difference exists between strychnine pharmacokinetics and metabolomics of male and female rats, potentially due to the differential expression of ABC transporter expression, pyrimidine metabolism and linoleic acid metabolism. These findings provide an important reference for sex-specific clinical management of strychnine toxicity. Plain Language summary Strychnine is a medication used for the treatment of muscle weakness and visual issues. However, it affects males and females differently. If dosing is not customized according to sex, it may lead to toxicity. Therefore, we explored the mechanisms underlying the toxic effects of strychnine in male and female rats (both intact and gonadectomized). We found that female rats showed higher blood drug levels. Moreover, the peak blood drug concentrations of both male and female rats decreased after gonadectomy. Additionally, sex-specific differences were observed in the expression of ABC transporter expression, pyrimidine metabolism and linoleic acid metabolism. These differences may explain why strychnine affects male and female rats differently. Highlights The plasma concentration of strychnine is significantly lower in GDX rat than that in intact rat. The primary metabolites showing differences between male and female rats after strychnine exposure. Different expression of ABC transporters, pyrimidine metabolism and linoleic acid metabolism between sexes may be responsible for the difference of strychnine absorption and metabolism.

The strychnine-sensitive glycine receptor (GlyR) mediates inhibitory synaptic transmission in the spinal cord and brainstem and is linked to neurological disorders, including autism and hyperekplexia. Understanding of molecular mechanisms and pharmacology of glycine receptors has been hindered by a lack of high-resolution structures. Here we report electron cryo-microscopy structures of the zebrafish α1 GlyR with strychnine, glycine, or glycine and ivermectin (glycine/ivermectin). Strychnine arrests the receptor in an antagonist-bound closed ion channel state, glycine stabilizes the receptor in an agonist-bound open channel state, and the glycine/ivermectin complex adopts a potentially desensitized or partially open state. Relative to the glycine-bound state, strychnine expands the agonist-binding pocket via outward movement of the C loop, promotes rearrangement of the extracellular and transmembrane domain ‘wrist’ interface, and leads to rotation of the transmembrane domain towards the pore axis, occluding the ion conduction pathway. These structures illuminate the GlyR mechanism and define a rubric to interpret structures of Cys-loop receptors. A high-resolution electron cryo-microscopy structure of the zebrafish α1 glycine receptor bound to agonists or antagonists reveals the conformational changes that take place when the channel transitions from closed to open state. Glycine receptor mechanism Eric Gouaux and colleagues have determined the high-resolution electron cryo-microscopy structure of strychnine-sensitive glycine receptor (GlyR) from zebrafish, bound to agonists or antagonists to reveal the conformational changes that take place when the channel opens. GlyRs mediate neurotransmission throughout the spinal cord and brainstem and their dysfunction is linked to multiple neurological disorders, including autism and hyperekplexia. Also in this issue of Nature , Xin Huang et al . report the X-ray crystal structure of the human GlyR in the presence of the antagonist strychnine.

AKR1B1 and AKR1B10 are important members of aldo–keto reductase family which plays a significant role in cancer progression by modulating cellular metabolism. These enzymes are involved in various metabolic processes, including the synthesis and metabolism of hormones, detoxification of reactive aldehydes, and the reduction of various endogenous and exogenous compounds. This study aimed to explore the potential of strychnine as an anticancer agent by targeting AKR1B1 and AKR1B10 via drug repurposing approach. To assess the drug-like properties of strychnine, a physiologically based pharmacokinetic (PKPB) model and High Throughput Pharmacokinetics (HTPK) approach were employed. The obtained results fell within the expected range for drug molecules, confirming its suitability for further investigation. Additionally, density functional theory (DFT) studies were conducted to gain insight into the electronic properties contributing to the drug molecule’s reactivity. Building upon the promising DFT results, molecular docking analysis using the AutoDock tool was performed to examine the binding interactions between strychnine and the proposed targets, AKR1B1 and AKR1B10. Findings from the molecular docking studies suggested a higher probability of strychnine acting as an inhibitor of AKR1B1 and AKR1B10 with docking scores of − 30.84 and − 29.36 kJ/mol respectively. To validate the stability of the protein–ligand complex, Molecular Dynamic Simulation (MDS) studies were conducted, revealing the formation of a stable complex between the enzymes and strychnine. This comprehensive approach sheds light on the potential effectiveness of strychnine as a treatment for breast, lung, liver, and pancreatic cancers, as well as related malignancies. The novel insights gained from the physiologically based pharmacokinetic modeling, density functional theory, molecular docking, and molecular dynamics simulations collectively support the prospect of strychnine as a promising molecule for anticancer therapy. Further investigations are warranted to validate these findings and explore the therapeutic potential of strychnine in preclinical and clinical settings.

Vasculogenic mimicry (VM) with the pattern of endothelial independent tubular structure formation lined by aggressive tumor cells mimics regular tumor blood vessels to ensure robust blood supply and correlates with the proliferation, invasion, metastasis, and poor prognosis of malignant tumors, which was demonstrated to be a major obstacle for resistance to antiangiogenesis therapy. Therefore, it is urgent to discover methods to abrogate the VM formation of tumors, which possesses important practical significance for improving tumor therapy. Brucine is a traditional medicinal herb extracted from seeds of Strychnos nux-vomica L. (Loganiaceae) exhibiting antitumor activity in a variety of cancer models. In the present study, the effect of brucine on vasculogenic mimicry and the related mechanism are to be investigated. We demonstrated that, in a triple-negative breast cancer cell line MDA-MB-231, brucine induced a dose-dependent inhibitory effect on cell proliferation along with apoptosis induction at higher concentrations. The further study showed that brucine inhibited cell migration and invasion with a dose-dependent manner. Our results for the first time indicated that brucine could disrupt F-actin cytoskeleton and microtubule structure, thereby impairing hallmarks of aggressive tumors, like migration, invasion, and holding a possibility of suppressing vasculogenic mimicry. Hence, the inhibitory effect of brucine on vasculogenic mimicry was further verified. The results illustrated that brucine significantly suppressed vasculogenic mimicry tube formation with a dose-dependent effect indicated by the change of the number of tubules, intersections, and mean length of tubules. The in-depth molecular mechanism of vasculogenic mimicry suppression induced by brucine was finally suggested. It was demonstrated that brucine inhibited vasculogenic mimicry which might be through the downregulation of erythropoietin-producing hepatocellular carcinoma-A2 and matrix metalloproteinase-2 and metalloproteinase-9.

Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine. A natural approach to natural product synthesis By combining two biosynthetic principles that have evolved in the natural world, David MacMillan and colleagues at the Merck Center for Catalysis at Princeton University, New Jersey, have developed a powerful strategy for the production of a broad spectrum of natural products. The first technique is organocascade catalysis, in which a continuous catalytic cascade replaces the traditional stop-go method of synthesis. The second is collective synthesis, in which a general synthetic route is used to reach a common molecular scaffold that, with appropriate fine-tuning, serves as a conduit to other members of the same chemical family. The method is demonstrated with the asymmetric total syntheses of six high-profile alkaloids: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.

Strychnine (STN) and its major metabolite Strychnine N-Oxide (SNO) were examined electrochemically. Both parent compounds and its major metabolite showed electroactivity on glassy carbon electrodes using CV and DPV techniques. One oxidation peak at 1008 mV was observed for STN with the optimum peak intensity at pH 7. SNO produced two oxidation peaks, at 617 mV and 797 mV, at pH 5. The peaks demonstrated irreversible behaviour and the irreversibility of the system was confirmed at different scan rates. A calibration curve was produced for both CV and DPV measurements and the sensitivity of the proposed EC method was good compared with previous electrochemical and non-electrochemical methods. The precision of oxidation peak of STN using the STN-MIP method produced a maximum value of 11.5% and 2.32% for inter-day and intraday %RSD, respectively. The average% recovery was around 92%. The electrochemical method has been successfully applied to the determination of STN in spiked plasma and urine samples. For SNO, both anodic peaks of SNO demonstrated irreversible behaviour. A different sweep rate was used for calculating the number of ‘transfer electrons’ in the system; based on this, the mechanism of oxidation reaction was proposed. Calibration curves for both oxidative peaks were produced using DPV measurements. The second anodic peak demonstrated high linearity and precision with %RSD < 1.96%.

Glycine Receptors (GlyRs) provide inhibitory neuronal input in the spinal cord and brainstem, which is critical for muscle coordination and sensory perception. Synaptic GlyRs are a heteromeric assembly of α and β subunits. Here we present cryo-EM structures of full-length zebrafish α1β B GlyR in the presence of an antagonist (strychnine), agonist (glycine), or agonist with a positive allosteric modulator (glycine/ivermectin). Each structure shows a distinct pore conformation with varying degrees of asymmetry. Molecular dynamic simulations found the structures were in a closed (strychnine) and desensitized states (glycine and glycine/ivermectin). Ivermectin binds at all five interfaces, but in a distinct binding pose at the β-α interface. Subunit-specific features were sufficient to solve structures without a fiduciary marker and to confirm the 4α:1β stoichiometry recently observed. We also report features of the extracellular and intracellular domains. Together, our results show distinct compositional and conformational properties of α 1 βGlyR and provide a framework for further study of this physiologically important channel. Glycine receptors (GlyR) are a critical postsynaptic component of spinal neurons. Here, the auhtors present cryo-EM structures of a heteromeric GlyR in the presence of an antagonist, agonist and agonist with a positive allosteric modulator.