International Journal of Tryptophan Research最新文献

{"title":"Cerebrospinal Fluid, Plasma Tryptophan, Kynurenine, and Kynurenate with Sleep Phenotypes: A Bidirectional Mendelian Randomization Analysis.","authors":"Qin Xie, Guangya Liu, Xiaolan Liu","doi":"10.1177/11786469261441903","DOIUrl":"https://doi.org/10.1177/11786469261441903","url":null,"abstract":"<p><p>Sleep is crucial for physiological regulation in humans and essential for sustaining life. Although melatonin, an intermediate in the tryptophan (TRP)-serotonin pathway, is widely explored as a modulator of the sleep-wake cycle, the association of TRP-kynurenine (KYN) pathway with sleep or circadian timing remains poorly understood. This work employed Mendelian randomization (MR) to examine possible causal links between sleep-associated phenotypes and metabolites in the TRP-KYN pathway. We applied data derived from genome-wide association research of TRP, KYN, and kynurenate (KYNA), the key metabolites in this pathway, and investigated sleep-related phenotypes extensively, including both self-reported phenotypes and those objectively estimated with an accelerometer. We evaluated the associations between 11 sleep-related phenotypes and plasma and cerebrospinal fluid (CSF) metabolites via two-sample bidirectional MR analysis. The forward MR analysis revealed a positive association between genetically predicted plasma KYN levels and L5 timing, with an OR of 1.194 (95% CI: 1.025-1.389; <i>P</i> = .022) utilizing the inverse variance weighted (IVW) approach. This effect direction was consistent across all MR methods, without evident horizontal pleiotropy or heterogeneity. However, this association was no longer significant after false discovery rate (FDR) correction and should therefore be interpreted as suggestive. In reverse MR analysis, sleep-related phenotypes showed no significant causal effects on CSF and plasma metabolites. To complement the population-level MR analyses, we performed an exploratory, hypothesis-generating in vitro experiment in Rat-1 fibroblasts and found that 200 μM L-kynurenine continuously upregulated <i>Bmal1</i> mRNA at several circadian time points. Overall, our findings provide suggestive evidence that genetically predicted higher plasma kynurenine are associated with delayed L5 timing, which requires confirmation through replication and mechanistic studies.</p>","PeriodicalId":46603,"journal":{"name":"International Journal of Tryptophan Research","volume":"19 ","pages":"11786469261441903"},"PeriodicalIF":4.1,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147785250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effect of L-Tryptophan Intake on Dynamic Strength in Paralympic Powerlifting.","authors":"Márcio Getirana-Mota, Felipe J Aidar, Raphael Fabricio de Souza, Ciro José Brito, Taísa Pereira Santos, Jonason Espínola Lacerda, Lúcio Marques Vieira-Souza, Georgian Badicu","doi":"10.1177/11786469261420614","DOIUrl":"10.1177/11786469261420614","url":null,"abstract":"<p><strong>Introduction: </strong>L-tryptophan supplementation has been studied in endurance sports with controversial results, and its influence on maximal strength sports remains largely unexplored. This study investigated whether L-tryptophan supplementation improves dynamic strength indicators in Paralympic powerlifting athletes.</p><p><strong>Methodology: </strong>A randomized, double-blind, crossover clinical trial was conducted with 13 paralympic powerlifting athletes. The athletes were supplemented with L-tryptophan or placebo for 72 hours before training. Strength was assessed using an encoder, measuring mean propulsive velocity (MPV), maximal velocity (<i>V</i> _max), and power (PO) at different time points (pre, post, 24, and 48 hours) and loads (45% and 80% of 1 RM).</p><p><strong>Results: </strong>L-tryptophan supplementation resulted in higher MPV, <i>V</i> _max, and PO values at the pre-exercise time point compared to placebo. However, after exercise, this difference diminished, and the benefits of supplementation were not sustained after 48 hours.</p><p><strong>Conclusion: </strong>L-tryptophan supplementation appears to temporarily improve pre-exercise strength performance in Paralympic powerlifting athletes, possibly by influencing neuromuscular relaxation.</p>","PeriodicalId":46603,"journal":{"name":"International Journal of Tryptophan Research","volume":"19 ","pages":"11786469261420614"},"PeriodicalIF":4.1,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12961097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147379014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Ecofriendly L-Tryptophan Containing UVA-1 Permissive Sunscreen Formulation: A Novel Approach for Inflammatory and Fibrosing Skin Diseases.","authors":"Rowland Noakes","doi":"10.1177/11786469261416785","DOIUrl":"https://doi.org/10.1177/11786469261416785","url":null,"abstract":"<p><p>UVA-1 phototherapy, used in the management of psoriasis, atopic dermatitis and fibrosing skin disorders has been reported to mediate part of its therapeutic benefit via aryl hydrocarbon receptor (AHR) signalling. Accessibility to therapy remains limited and a cost-effective topical preparation permissive of UVA-1 transmission at therapeutic doses whilst offering photoprotection in the UVB and UVA-2 spectra and activity at the AHR would represent a notable therapeutic advance. The amino acid L-tryptophan absorbs maximally at 280 nm with absorbance falling rapidly to 310 nm potentially providing photoprotection in the UVB spectrum. In addition, this amino acid is photo-oxidized to 6-formylindolo[3,2-b] carbazole (FICZ), a potent endogenous ligand of the AHR and is thus a potential candidate for inclusion. Lecithin absorbs UV light in a broad band from 200 to 380 nm with peak absorbance at 235, 271 and 355 nm and has potential as a biodegradable and ecofriendly sunscreen with an efficacy equivalent to traditional sunscreens. A proof-of-concept study was performed to assess whether a topical solution of L-tryptophan formulated to favour the generation of FICZ on photoactivation demonstrated activity at the aryl hydrocarbon receptor (AHR) as assessed by the intensity of cytochrome P450 1A2 staining. Ten participants applied a trial agent consisting of 2% L-tryptophan, 30% sunflower lecithin, 3% polyvinyl alcohol, 20% ethanol, pH 5.8 followed by 36 sessions of progressively graduated sun exposure increasing to a total of 20 J/cm² as determined by UV integrator over a period 12 weeks. At the end of the trial, biopsies were taken from treated sites and assessed by the intensity of cytochrome P450 1A2 staining. Photo protected skin from the buttock was used as a control. An average baseline value of 53 488 923 units was obtained at the control site and 972 214 294 at the treatment site supporting the concept that this preparation displays activity at the AHR.</p>","PeriodicalId":46603,"journal":{"name":"International Journal of Tryptophan Research","volume":"19 ","pages":"11786469261416785"},"PeriodicalIF":4.1,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12949794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147345218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accumulation of Quinolinic Acid Modulates the Pulmonary Immune Response During Influenza Infection.","authors":"Guillaume Pamart, Benjamin Hennart, Anaïs Ollivier, Gwenola Kervoaze, Muriel Pichavant, Philippe Gosset, Olivier Le Rouzic, Odile Poulain-Godefroy","doi":"10.1177/11786469261423809","DOIUrl":"https://doi.org/10.1177/11786469261423809","url":null,"abstract":"<p><p>Influenza viruses cause a highly contagious, acute pulmonary disease that results in significant mortality each year. These infections trigger the production of interferons, known to induce the expression of the rate-limiting enzyme in the kynurenine degradation pathway in the lungs. As some kynurenine pathway metabolites are biologically active, we aimed to gain a better understanding of their role in influenza A virus infection. The expression of kynurenine pathway enzymes and the levels of their metabolites were quantified in the lungs of C57BL/6 mice 7 days after infection with an H3N2 influenza A virus (IAV). Furthermore, the impact of quinolinic acid supplementation was evaluated on IAV-infected mice and in vitro, in human monocyte-derived macrophages. The expression of key enzymes (IDO1, KMO, and KYNU) increased in mice in the airways of IAV infected mice. High levels of quinolinic acid were produced in the lungs, as revealed by immunohistochemistry in both epithelial cells and immune cells. Oral quinolinic acid supplementation resulted in higher levels of viral mRNA in the lungs and modulated cytokine production, leading to an increased number of neutrophils and interstitial macrophages in lung tissue. In IAV-infected macrophages, the addition of quinolinic acid was associated with higher levels of viral RNA and protein and in increased antiviral and proinflammatory responses (IFN-β, CXCL-1, and TNF-α). These increases were further reduced by memantine, an NMDA receptor antagonist, suggesting that quinolinic acid may modulate the macrophage immune response via NMDA receptors. A deeper understanding of these mechanisms could lead to new therapeutic strategies for influenza infections.</p>","PeriodicalId":46603,"journal":{"name":"International Journal of Tryptophan Research","volume":"19 ","pages":"11786469261423809"},"PeriodicalIF":4.1,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12929833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147291330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered Tryptophan-Kynurenine Pathway and Low-Grade Inflammation in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Insights from LC-MS/MS-Based Metabolite Profiling.","authors":"Kübranur Ünal, Leyla İbrahimkhanlı, Mehmet Emre Erol, Nemat İbrahimkhanlı, Sabri Engin Altıntop, Mahi Nur Cerit, Ethem Turgay Cerit, Halit Nahit Şendur","doi":"10.1177/11786469261423510","DOIUrl":"https://doi.org/10.1177/11786469261423510","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multisystem disorder characterized by hepatic lipid accumulation, low-grade inflammation, and metabolic dysregulation. Although the kynurenine pathway has been implicated in the pathogenesis of metabolic and inflammatory diseases, its contribution to MASLD remains unclear. This study aimed to evaluate tryptophan (TRP) metabolism and its relationship with inflammatory biomarkers and lipid parameters across different grades of steatosis. A total of 88 adults (62 MASLD, 26 healthy controls; aged 20-69 years) were enrolled in this study. Serum concentrations of inflammatory markers (CRP, IL-6, and TNF-α) were determined using immunoassay-based methods, and TRP metabolites (TRP, KYN, KYNA, 3-HK, 3-HAA, QA, PIC) were quantified using validated LC-MS/MS. Steatosis grades (0-3) were assessed via ultrasonography. Statistical analyses included the Mann-Whitney <i>U</i> test, the Kruskal-Wallis test, and the Spearman correlation test. MASLD subjects showed significantly higher BMI, triglycerides, AST, ALT, GGT, CRP, TNF-α, and KYNA levels compared with controls (all <i>P</i> < .05), while HDL-C levels were lower (<i>P</i> = .014). Across steatosis grades, BMI, TG, and CRP increased progressively (<i>P</i> < .001), and IL-6 showed a positive correlation with steatosis severity (<i>r</i> = .280, <i>P</i> < .05). KYNA levels were elevated in early steatosis (Grade 1, <i>P</i> = .008) and inversely correlated with TC and LDL-C (<i>r</i> = -.393 and <i>r</i> = -.384, respectively). The elevation of KYNA may reflect an early compensatory mechanism imitigating hepatic and metabolic stress. Integrating inflammatory and kynurenine pathway biomarkers could improve disease stratification and therapeutic targeting in MASLD.</p>","PeriodicalId":46603,"journal":{"name":"International Journal of Tryptophan Research","volume":"19 ","pages":"11786469261423510"},"PeriodicalIF":4.1,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12929866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147291275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucocorticoid Treatment Dampens Kynurenine Pathway Activation and Cytokine Release in Immune Stimulated Human Microglia.","authors":"Martina Esposito Soccoio, Robert P Mason, Julien Devilliers, Roberto Feuda, Mary E W Collier, Flaviano Giorgini","doi":"10.1177/11786469261416782","DOIUrl":"10.1177/11786469261416782","url":null,"abstract":"<p><p>As a first line of defence for the central nervous system (CNS), microglia play a critical role in maintaining homeostasis within the brain. Upon detection of damage or threats, activated cells release factors to communicate and potentiate immune responses. This activation also increases activity of the kynurenine pathway (KP) and alters expression of key KP enzymes such as indoleamine 2,3-dioxygenase (IDO-1) and kynurenine 3-monooxygenase (KMO), both major contributors in the pathology of several neurodegenerative and psychiatric disorders. This study investigated the impact of pro-inflammatory stimuli on the C20 human microglial cell line, focussing on the regulation of <i>KMO</i> and <i>IDO-1</i> expression, and the production of cytokines. Additionally, we explored whether the anti-inflammatory effects of dexamethasone (DEXA) influenced these outcomes. This additional characterisation of a physiologically relevant human microglial cell line offers a novel and reliable platform for investigating human-specific microglial biology and function. C20 were challenged for 24 hours with cytokines or lipopolysaccharide (LPS). Gene expression was measured by RT-qPCR and excreted cytokines were quantified using a multiplex array. Our results showed up-regulation of <i>IDO-1</i> and <i>KMO</i> transcripts, and increased release of pro- and anti-inflammatory cytokines. Notably, these effects were significantly dampened by pre-incubation with DEXA. Furthermore, transcriptomic analyses supported these data by highlighting TNF-α-activated enriched pathways, as well as those down-regulated in samples co-treated with DEXA. This study contributes to the understanding of key mechanisms regulated in human microglia by immune challenges and supports the crucial role of synthetic glucocorticoids (GCs) in moderating the microglial immune response induced by pro-inflammatory signals. These data support the use of GCs as possible therapeutic interventions for diseases associated with neuroinflammation, particularly those with altered KP metabolism.</p>","PeriodicalId":46603,"journal":{"name":"International Journal of Tryptophan Research","volume":"19 ","pages":"11786469261416782"},"PeriodicalIF":4.1,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12833124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146067643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kynurenine Pathway Dysregulation in Parkinson's Disease: Insights for Disease Modulation and Therapy.","authors":"Vaibhav A Chakkarwar, Yogesh A Kulkarni","doi":"10.1177/11786469251401459","DOIUrl":"10.1177/11786469251401459","url":null,"abstract":"<p><p>Parkinson's disease (PD) is identified as the most common neurodegenerative disorder of the central nervous system. Around 8.5 million individuals suffer from PD globally. Neuroinflammation triggers the activation of microglia, resulting in the release of numerous proinflammatory mediators. A major modulator of immune response in Parkinsonism is the kynurenine pathway (KP), probably linked to neurotoxic and inflammatory processes. Two types of compounds are produced by this pathway that act as neurotoxic and neuroprotective. Among these, kynurenic acid released by astrocytes acts as neuroprotective, and quinolinic acid released by microglia acts as neurotoxic by various mechanisms. Previous studies have shown that modulation of enzymes in this pathway can be a therapeutic approach for treating PD. Studies were performed to determine the effect of various drug treatments in inhibiting the enzymes of KP and preventing neurodegeneration. Pharmacological modulators of the KP enzymes will likely be a novel therapeutic approach for PD, and some of the KP metabolites may serve as predictive biomarkers.</p>","PeriodicalId":46603,"journal":{"name":"International Journal of Tryptophan Research","volume":"18 ","pages":"11786469251401459"},"PeriodicalIF":4.1,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12708996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Novel Method to Quantify Quinolinic Acid in Biological Samples.","authors":"Masatsuna Tasaka, Hidetsugu Fujigaki, Sayaka Sugiura, Suwako Fujigaki, Akihiro Ikuno, Yasuko Yamamoto, Masao Takemura, Akio Kimura, Kuniaki Saito","doi":"10.1177/11786469251390415","DOIUrl":"10.1177/11786469251390415","url":null,"abstract":"<p><strong>Background: </strong>The accumulation of quinolinic acid (QUIN) in cerebrospinal fluid and serum may be used as a biomarker for various neuropsychiatric and inflammatory diseases. In this study, we developed a highly sensitive method to measure QUIN.</p><p><strong>Methods: </strong>A reverse-phase high-performance liquid chromatography (HPLC) with fluorescence detection was established based on the enzymatic conversion of QUIN to nicotinic acid mononucleotide by recombinant quinolinic acid phosphoribosyltransferase, followed by the formation of fluorescent (BODIPY)-labeled deamido-NAD by recombinant nicotinic acid mononucleotide adenyltransferase.</p><p><strong>Results: </strong>BODIPY-deamido-NAD was isocratically eluted within 6 minutes using reverse-phase chromatography and its chromatographic peak was resolved. The calibration range, precision, and analytical recovery of the QUIN assay are suitable for the analysis of biological fluids. Compared with published quantitation limits for QUIN measurement by HPLC, this method is at least 30-fold more sensitive and has a lower limit of detection of 5.0 nmol/L. The sensitivity was comparable to that previously reported for gas chromatography/mass spectrometry (GC/MS) and the quantitation results of QUIN from samples of cerebrospinal fluid correlated well with that of the GC/MS method.</p><p><strong>Conclusions: </strong>We established a novel method to quantify QUIN in biological samples. Due to its high sensitivity and the fact that it does not rely on MS instrumentation, this method has the potential for widespread adoption in research laboratories.</p>","PeriodicalId":46603,"journal":{"name":"International Journal of Tryptophan Research","volume":"18 ","pages":"11786469251390415"},"PeriodicalIF":4.1,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12579120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145432586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroactive Kynurenine Metabolite Alterations Unveil Novel Association to Locomotor Deterioration in Diabetic Neuropathy.","authors":"Alejandra Perez-Alvarez, Victor Salazar, Gustavo Bruges, Eva Vonasek, Antonio Eblen-Zajjur","doi":"10.1177/11786469251372797","DOIUrl":"10.1177/11786469251372797","url":null,"abstract":"<p><strong>Background: </strong>The effect of prolonged hyperglycemia on the sensory pathway of the nervous system has been the focus of numerous diabetes studies that aim at understanding the pathophysiology of the underlying inflammatory condition and neuropathy. In this study, we investigate the effects of prolonged hyperglycemia on the motoneurons of the ventral horn of the spinal cord, a lesser-studied area of the nervous system, with a focus on alterations in the Kynurenine Pathway (KP) as potential factors contributing to the induction, progression, and/or chronicity of diabetic neuropathy.</p><p><strong>Methods: </strong>KP metabolites were identified and assessed by immunohistochemistry in cross-sections of the lumbar spinal cord of type 2 diabetes (T2D) streptozotocin-induced (STZ) adult Sprague-Dawley rats.</p><p><strong>Results: </strong>Neuropathy, hyperglycemia, and gait alterations were associated to myelin loss in the spinal cord. KP metabolites were identified in glia, motoneuron, and non-motoneuron. The KP induction, as evidenced by enhanced L-kynurenine (L-KYN) fluorescence, appears to be associated with increased levels of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Notable differences in fluorescence merging of L-KYN with IFN-γ and TNF-α, of Quinolinic acid (QUIN) with 3-Hydroxykynurenine (3-HK), and of QUIN with advanced glycation end products (AGEs) were observed in the T2D group, contrasting with the control (<i>P</i> < .05). Additionally, in ventral horn cells, AGEs emerged as an added pro-inflammatory factor.</p><p><strong>Conclusions: </strong>The KP is activated during diabetic neuropathy, and it displays divergent metabolic profiles in glia, motoneuron, and non-motoneuron, which differ from the controls. Their presence also evolves with time, indicating the dynamic nature of the process.</p>","PeriodicalId":46603,"journal":{"name":"International Journal of Tryptophan Research","volume":"18 ","pages":"11786469251372797"},"PeriodicalIF":4.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12480792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Insights Into the Interaction of Tryptophan Metabolites With Tryptophan and Indoleamine 2,3-Dioxygenases: Nitric Oxide a New Effector of Tryptophan 2,3-Dioxygenase and Their Roles in Infection.","authors":"Abdulla A-B Badawy, Shazia Dawood","doi":"10.1177/11786469251372339","DOIUrl":"10.1177/11786469251372339","url":null,"abstract":"<p><p>Feedback and other negative controls are important determinants of metabolic pathway activities. Other than inhibition of indoleamine 2,3-dioxygenase (IDO) by tryptophan (Trp) and nitric oxide (NO) and feedback inhibition of Trp 2,3-dioxygenase (TDO) by NAD(P)H, little is known of potential effects of Trp and kynurenine metabolites on the kynurenine (Kyn) pathway (KP). Whereas previous studies suggested that some Trp metabolites inhibit TDO activity in vitro, when administered in vivo to rats, inhibition is not always demonstrable, suggesting involvement of mitigating factors. To resolve this difference and provide indicators of likely interaction of Trp metabolites with TDO and IDO1, we performed molecular docking in silico of Trp and a range of its metabolites to these 2 KP enzymes. We found that Trp and many of its Kyn and 5-hydroxyindole metabolites docked to the active site of the TDO2 crystal structure, whereas no docking was observed with Kyn or kynurenic acid. Docking of NAD⁺(P⁺)H occurred at a different site, provisionally identified as the TDO allosteric site. By contrast, docking to IDO1 was limited to Trp, N'-formylkynurenine, 3-hydroxyanthranilic acid and picolinic acid. We conclude that bioinformatics can resolve controversial issues and identify amino acid residues at unexplored sites. The IDO1 effector nitric oxide (NO) docked to TDO as well as to IDO1. NO controls TDO2 and IDO1 activities in a dual fashion, through provision and limitation of the heme cofactor. We propose NO as a new TDO effector and discuss its role in control of TDO during acute inflammation. We propose TDO as an important player in the acute inflammatory responses in parallel with IDO1.</p>","PeriodicalId":46603,"journal":{"name":"International Journal of Tryptophan Research","volume":"18 ","pages":"11786469251372339"},"PeriodicalIF":4.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12441266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145087710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}