Relevant bibliographies by topics / Metabolites – Identification

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Academic literature on the topic 'Metabolites – Identification'

Author: Grafiati
Published: 4 June 2021
Last updated: 19 October 2024

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Journal articles on the topic "Metabolites – Identification"

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Wu, Yali, Lulu Pan, Zhendong Chen, Yuandong Zheng, Xingxing Diao, and Dafang Zhong. "Metabolite Identification in the Preclinical and Clinical Phase of Drug Development." Current Drug Metabolism 22, no. 11 (September 2021): 838–57. http://dx.doi.org/10.2174/1389200222666211006104502.

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Metabolite identification plays a critical role in the phases during drug development. Drug metabolites can contribute to efficacy, toxicity, and drug-drug interaction. Thus, the correct identification of metabolites is essential to understand the behavior of drugs in humans. Drug administration authorities (e.g., FDA, EMA, and NMPA) emphasize evaluating the safety of human metabolites with exposure higher than 10% of the total drugrelated components. Many previous reviews have summarized the various methods, tools, and strategies for the appropriate and comprehensive identification of metabolites. In this review, we focus on summarizing the importance of identifying metabolites in the preclinical and clinical phases of drug development. Summarized scenarios include the role of metabolites in pharmacokinetics/pharmacodynamics (PK/PD) analysis, disproportional exposure of metabolites that contribute to drug toxicity, changes in metabolite exposure in renal-impaired patients, covalent tyrosine kinase inhibitors (anticancer drugs), and metabolite identification of drug candidates from natural medicines. This review is aimed to provide meaningful insight into the significant role of metabolite identification in drug development.
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Tabrez, Shams, Mohammed Razeeth Shait Mohammed, Nasimudeen R. Jabir, and Mohammad Imran Khan. "Identification of novel cardiovascular disease associated metabolites using untargeted metabolomics." Biological Chemistry 402, no. 6 (January 20, 2021): 749–57. http://dx.doi.org/10.1515/hsz-2020-0331.

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Abstract Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality around the world. Early diagnosis of CVD could provide the opportunity for sensible management and better clinical outcome along with the prevention of further progression of the disease. In the current study, we used an untargeted metabolomic approach to identify possible metabolite(s) that associate well with the CVD and could serve either as therapeutic target or disease-associated metabolite. We identified 26 rationally adjusted unique metabolites that were differentially present in the serum of CVD patients compared with healthy individuals, among them 15 were found to be statistically significant. Out of these metabolites, we identified some novel metabolites like UDP-l-rhamnose and N1-acetylspermidine that have not been reported to be linked with CVD directly. Further, we also found that some metabolites like ethanolamide, solanidine, dimethylarginine, N-acetyl-l-tyrosine, can act as a discriminator of CVD. Metabolites integrating pathway enrichment analysis showed enrichment of various important metabolic pathways like histidine metabolism, methyl histidine metabolism, carnitine synthesis, along with arginine and proline metabolism in CVD patients. Our study provides a great opportunity to understand the pathophysiological role and impact of the identified unique metabolites and can be extrapolated as specific CVD specific metabolites.
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Lake, Juniper A., Yiren Yan, Jack C. M. Dekkers, Jing Qiu, Erin M. Brannick, and Behnam Abasht. "Identification of circulating metabolites associated with wooden breast and white striping." PLOS ONE 17, no. 9 (September 26, 2022): e0274208. http://dx.doi.org/10.1371/journal.pone.0274208.

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Current diagnostic methods for wooden breast and white striping, common breast muscle myopathies of modern commercial broiler chickens, rely on subjective examinations of the pectoralis major muscle, time-consuming microscopy, or expensive imaging technologies. Further research on these disorders would benefit from more quantitative and objective measures of disease severity that can be used in live birds. To this end, we utilized untargeted metabolomics alongside two statistical approaches to evaluate plasma metabolites associated with wooden breast and white striping in 250 male commercial broiler chickens. First, mixed linear modeling was employed to identify metabolites with a significant association with these muscle disorders and found 98 metabolites associated with wooden breast and 44 metabolites associated with white striping (q-value < 0.05). Second, a support vector machine was constructed using stepwise feature selection to determine the smallest subset of metabolites with the highest categorization accuracy for wooden breast. The final support vector machine achieved 94% accuracy using only 6 metabolites. The metabolite 3-methylhistidine, which is often used as an index of myofibrillar breakdown in skeletal muscle, was the top metabolite for both wooden breast and white striping in our mixed linear model and was also the metabolite with highest marginal prediction accuracy (82%) for wooden breast in our support vector machine. Overall, this study identified a candidate set of metabolites for an objective measure of wooden breast or white striping severity in live birds and expanded our understanding of these muscle disorders.
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Otter, Don, Mingshu Cao, Hui-Ming Lin, Karl Fraser, Shelley Edmunds, Geoff Lane, and Daryl Rowan. "Identification of Urinary Biomarkers of Colon Inflammation in IL10-/-Mice Using Short-Column LCMS Metabolomics." Journal of Biomedicine and Biotechnology 2011 (2011): 1–12. http://dx.doi.org/10.1155/2011/974701.

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The interleukin-10-deficient (IL10-/-) mouse develops colon inflammation in response to normal intestinal microflora and has been used as a model of Crohn's disease. Short-Column LCMS metabolite profiling of urine from IL10-/-and wild-type (WT) mice was used, in two independent experiments, to identify mass spectral ions differing in intensity between these two genotypes. Three differential metabolites were identified as xanthurenic acid and as the glucuronides of xanthurenic acid and of α-CEHC (2,5,7,8-tetramethyl-2-(2′-carboxyethyl)-6-hydroxychroman). The significance of several differential metabolites as potential biomarkers of colon inflammation was evaluated in an experiment which compared metabolite concentrations in IL10-/-and WT mice housed, either under conventional conditions and dosed with intestinal microflora, or maintained under specific pathogen-free (SPF) conditions. Concentrations of xanthurenic acid, α-CEHC glucuronide, and an unidentified metabolitem/z495-/497+were associated with the degree of inflammation in IL10-/-mice and may prove useful as biomarkers of colon inflammation.
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Sun, Jiahong, Min Zhao, Liu Yang, Xue Liu, Lucia Pacifico, Claudio Chiesa, and Bo Xi. "Identification of Potential Metabolic Markers of Hypertension in Chinese Children." International Journal of Hypertension 2021 (August 24, 2021): 1–8. http://dx.doi.org/10.1155/2021/6691734.

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Background. Studies in adults have shown that several metabolites across multiple pathways are strongly associated with hypertension. However, as yet, to our knowledge, no study has investigated such association in childhood. We, therefore, compared the serum metabolite profile of children with normal and elevated blood pressure (BP) to identify potential metabolic markers and pathways that could be useful for the assessment of pediatric hypertension. Methods. The study included 26 hypertensive children (age range, 6–11 years) and 26 age- and sex-matched ones with normal BP, who were recruited from the baseline survey of the Huantai Childhood Cardiovascular Health Cohort Study. Ultrahigh-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry was performed to assess the serum metabolite profile. Logistic regression analysis was used to select significant metabolites associated with hypertension after adjustment for body mass index, waist circumference, and lipid profile. Kyoto Encyclopedia of Genes and Genomes (KEGG) and MetaboAnalyst were utilized to search for the potential pathways of metabolites. Results. A total of 45 and 34 metabolites were preliminarily screened in positive and negative modes, respectively (variable importance in the projection (VIP) > 1.0 and P < 0.05 ). After adjustment for the false discovery rate, 7 and 1 differential metabolites in the positive and negative modes, respectively, remained significant (VIP > 1.0 and q < 0.05). These metabolites were mainly involved in amino acid metabolism and glycerophospholipid metabolism. Among these, two significant metabolites including ethanolamine and 2-methyl-3-hydroxy-5-formylpyridine-4-carboxylate displayed an area under the curve value of 0.820 (95% confidence interval, 0.688–0.951), with a sensitivity of 0.846 and a specificity of 0.769. Conclusion. The untargeted metabolomics approach effectively identified the differential serum metabolite profile in children with and without hypertension. Notably, two metabolites including ethanolamine and 2-methyl-3-hydroxy-5-formylpyridine-4-carboxylate exhibited a good discriminative ability to identify children with hypertension, providing new insights into potential mechanisms of pediatric hypertension.
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Liu, Rui, Zheng-Xue Bao, Guo-Hong Li, Chun-Qiang Li, Shao-Lin Wang, Xue-Rong Pan, Ke-Qin Zhang, and Pei-Ji Zhao. "Identification of Nematicidal Metabolites from Purpureocillium lavendulum." Microorganisms 10, no. 7 (July 2, 2022): 1343. http://dx.doi.org/10.3390/microorganisms10071343.

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Purpureocillium lavendulum is a fungus with promising biocontrol applications. Here, transcriptome data acquired during the infection of Caenorhabditis elegans by Purpureocillium lavendulum showed that the transcription of metabolite synthesis genes was significantly up-regulated after 24 and 48 h of the fungus-nematode interaction. Then, the up-regulated transcription level of lipoxygenase was confirmed by RT-qPCR. The ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) analysis of differential metabolites revealed that this interaction resulted in the emergence of new metabolites or enhanced the production of metabolites. The results of the UPLC-MS analysis and the nematicidal assay were used to establish optimal culturing conditions under which 12 metabolites, including 3 hydroxylated C18 fatty acids and 9 steroids, were isolated and identified. Among them, hydroxylated fatty acids showed pronounced nematicidal activity against Meloidogyne incognita, and two degradative sterols showed chemotaxis activity to M. incognita. This study lays a foundation for the function of lipoxygenase and its products during the infection of Purpureocillium lavendulum.
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Srivastava, Nidhi, Vishal Dubey, Madhumita Sengar, and Rastogi Sameer. "Identification and Characterization of Metabolites of Irinotecan in-vivo and in-vitro matrixes by HPLC/LC-MS." Research in Pharmacy and Health Sciences 2, no. 3 (August 15, 2016): 211–18. http://dx.doi.org/10.32463/rphs.2016.v02i03.42.

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In the present study metabolite identification and characterization has done by using HPLC and LC-MS. During method development various mobile phases have tried for identification of metabolites. The matrixes selected for in- vivo study were urine because nearly all the metabolites of irinotecan were obtained in it. The extraction mixtures have selected to retain maximum amount of analyte with less effort. During experiment four extraction solvents were used in six different concentrations out of which TBME suit our method. In-vitro study done by Human Liver microsomes by using Phosphate buffer (pH 7.4) and NADPH as co-factors for initiation of enzymatic reaction. Irinotecan is a prodrug that is converted in the liver to an active metabolite, SN-38. It is eliminate in Bile and Faeces and thus its dose reduced in Hepatic Failure. Irinotecan act by inhibiting Topoisomerase-1.It is the enzyme which nicks, introduces negative supercoils and reseals the DNA strand. Conventionally, drug metabolite identification in the past has usually been based on the comparison of ultraviolet (UV) spectral data and high-performance liquid chromatography (HPLC) retention times of isolated ‘unknown’ metabolites with those of synthesised standards. Such a method of detecting and characterising drug metabolites is an uncertain, time-consuming and expensive process, as well as affording very limited structural information. Furthermore, Phase I metabolism of a drug candidate often results in only minor structural modification of the parent compound; these minor changes can make it particularly difficult to determine suitable chromatographic conditions to effect HPLC separation of metabolites. This study describes contemporary approach to identification and characterization of xenobiotic metabolites in complex biological fluids derived from drug metabolism studies.
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Vikingsson, Svante, Tobias Rautio, Jakob Wallgren, Anna Åstrand, Shimpei Watanabe, Johan Dahlén, Ariane Wohlfarth, et al. "LC-QTOF-MS Identification of Major Urinary Cyclopropylfentanyl Metabolites Using Synthesized Standards." Journal of Analytical Toxicology 43, no. 8 (August 23, 2019): 607–14. http://dx.doi.org/10.1093/jat/bkz057.

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Abstract Cyclopropylfentanyl is a fentanyl analog implicated in 78 deaths in Europe and over 100 deaths in the United States, but toxicological information including metabolism data about this drug is scarce. The aim of this study was to provide the exact structure of abundant and unique metabolites of cyclopropylfentanyl along with synthesis routes. In this study, metabolites were identified in 13 post-mortem urine samples using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Samples were analyzed with and without enzymatic hydrolysis, and seven potential metabolites were synthesized in-house to provide the identity of major metabolites. Cyclopropylfentanyl was detected in all samples, and the most abundant metabolite was norcyclopropylfentanyl (M1) that was detected in 12 out of 13 samples. Reference materials were synthesized (synthesis routes provided) to identify the exact structure of the major metabolites 4-hydroxyphenethyl cyclopropylfentanyl (M8), 3,4-dihydroxyphenethyl cyclopropylfentanyl (M5) and 4-hydroxy-3-methoxyphenethyl cyclopropylfentanyl (M9). These metabolites are suitable urinary markers of cyclopropylfentanyl intake as they are unique and detected in a majority of hydrolyzed urine samples. Minor metabolites included two quinone metabolites (M6 and M7), not previously reported for fentanyl analogs. Interestingly, with the exception of norcyclopropylfentanyl (M1), the metabolites appeared to be between 40% and 90% conjugated in urine. In total, 11 metabolites of cyclopropylfentanyl were identified, including most metabolites previously reported after hepatocyte incubation.
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Peng, Hongquan, Xun Liu, Chiwa Aoieong, Tou Tou, Tsungyang Tsai, Kamleong Ngai, Hao I. Cheang, Zhi Liu, Peijia Liu, and Haibin Zhu. "Identification of Metabolite Markers Associated with Kidney Function." Journal of Immunology Research 2022 (July 26, 2022): 1–9. http://dx.doi.org/10.1155/2022/6190333.

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Background. Chronic kidney disease (CKD) is a global public health problem. Identifying new biomarkers that can be used to calculate the glomerular filtration rate (GFR) would greatly improve the diagnosis and understanding of CKD at the molecular level. A metabolomics study of blood samples derived from patients with widely divergent glomerular filtration rates could potentially discover small molecule metabolites associated with varying kidney function. Methods. Using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), serum was analyzed from 53 participants with a spectrum of measured GFR (by iohexol plasma clearance) ranging from normal to severe renal insufficiency. An untargeted metabolomics assay (N ¼ 214) was conducted at the Calibra-Metabolon Joint Laboratory. Results. From a large number of metabolomics-derived metabolites, the top 30 metabolites correlated to increasing renal insufficiency according to mGFR were selected by the random forest method. Significant differences in metabolite profiles with increasing stages of CKD were observed. Combining candidate lists from six other unique statistical analyses, six novel, potential metabolites that were reproducibly strongly associated with mGFR were selected, including erythronate, gulonate, C-glycosyltryptophan, N-acetylserine, N6-carbamoylthreonyladenosine, and pseudouridine. In addition, hydroxyasparagine were strongly associated with mGFR and CKD, which were unique to this study. Conclusions. Global metabolite profiling of serum yielded potentially valuable biomarkers of different stages of CKD. Additionally, these potential biomarkers might provide insight into the underlying pathophysiologic processes that contribute to the progression of CKD as well as improve GFR estimation.
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Karlsson, Therese, Anna Winkvist, Millie Rådjursöga, Lars Ellegård, Anders Pedersen, and Helen M. Lindqvist. "Identification of Single and Combined Serum Metabolites Associated with Food Intake." Metabolites 12, no. 10 (September 27, 2022): 908. http://dx.doi.org/10.3390/metabo12100908.

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Assessment of dietary intake is challenging. Traditional methods suffer from both random and systematic errors; thus objective measures are important complements in monitoring dietary exposure. The study presented here aims to identify serum metabolites associated with reported food intake and to explore whether combinations of metabolites may improve predictive models. Fasting blood samples and a 4-day weighed food diary were collected from healthy Swedish subjects (n = 119) self-defined as having habitual vegan, vegetarian, vegetarian + fish, or omnivore diets. Serum was analyzed for metabolites by 1H-nuclear magnetic resonance spectroscopy. Associations between single and combined metabolites and 39 foods and food groups were explored. Area under the curve (AUC) was calculated for prediction models. In total, 24 foods or food groups associated with serum metabolites using the criteria of rho > 0.2, p < 0.01 and AUC ≥ 0.7 were identified. For the consumption of soybeans, citrus fruits and marmalade, nuts and almonds, green tea, red meat, poultry, total fish and shellfish, dairy, fermented dairy, cheese, eggs, and beer the final models included two or more metabolites. Our results indicate that a combination of metabolites improve the possibilities to use metabolites to identify several foods included in the current diet. Combined metabolite models should be confirmed in dose–response intervention studies.
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Dissertations / Theses on the topic "Metabolites – Identification"

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Long, Cai. "Identification of essential metabolites in metabolite networks." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/43554.

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Metabolite essentiality is an important topic in systems biology and as such there has been increased focus on their prediction in metabolic networks. Specifically, two related questions have become the focus of this field: how do we decrease the amount of gene knock-out workloads and is it possible to predict essential metabolites in different growth conditions? Two different approaches to these questions: interaction-based method and constraints-based method, are conducted in this study to gain in depth understanding of metabolite essentiality in complex metabolic networks. In the interaction-based approach, the correlations between metabolite essentiality and the metabolite network topology are studied. With the idea of predicting essential metabolites, the topological properties of the metabolite network are studied for the Mycobacterium tuberculosis model. It is found that there is strong correlation between metabolite essentiality and the degree and the number of shortest paths through the metabolite. Welch’s two sample T-test is performed to help identify the statistical significance of the differences between groups of essential metabolites and non-essential metabolites. In the constraint-based approach, essential metabolites are identified in-silico. Flux Balance Analysis (known as FBA), is implemented with the most advanced in-silico model of Chlamydomonas Reinhardtii, which contains light usage information in 3 different growth environments: autotrophic, mixotrophic, and heterotrophic. Essential metabolites are predicted by metabolite knock out analysis, which is to set the flux of a certain metabolite to zero, and categorized into 3 types through Flux Sum Analysis. The basal flux-sum for metabolites is found to follow a exponential distribution, it is also found that essential metabolites tend to have larger basal flux-sum.
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Bi, Honggang. "Urinary metabolites of anabolic steroids : identification and synthesis." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=70304.

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The metabolism of several anabolic 17$ alpha$-methyl steroids, namely formebolone, mestanolone, methandienone, methyltestosterone, oxandrolone, oxymetholone and stanozolol, were investigated. The identification of metabolites was based on GC/MS analysis of different derivatives, and chemical synthesis of corresponding reference steroids. Common metabolic reactions have been studied and structure-metabolism relationships were discussed. New biotransformation routes, such as oxidative pathways of 2-formyl and 2-hydroxymethylene steroids, have been unveiled. The mechanism of 17-epimerization of these 17$ beta$-hydroxy-17$ alpha$-methyl steroids in vivo has also been clarified.
A simple and convenient method for the preparation of 17$ beta$-tertiary sulfate derivatives of these steroids has been developed. A stereoselective approach was used for the partial synthesis of reference steroids in order to confirm the stereochemical features of an acidic metabolite of oxymetholone.
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Gough, A. J. E. "The isolation and identification of metabolites of interest from heteroptera." Thesis, Bucks New University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.371221.

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Williams, David Ellis. "Novel secondary metabolites from selected cold water marine invertebrates." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/29175.

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A study of the secondary metabolism of two nudibranchs and one soft coral has led to the isolation of eighteen new and two known secondary metabolites. The structures of all compounds were determined by a combination of the interpretation of spectral data, chemical degradations and interconversions, and single crystal x-ray diffraction analysis. The British Columbian dorid nudibranch Diaulula sandiegensis yielded two new steroidal metabolites, diaulusterols A (41) and B (42). The 25-(3-hydroxybutanoate) residue of diaulusterol A (41) and the 2α,3α-diol array of both 41 and 42 are not commonly encountered in naturally occurring steroids. Both metabolites exhibited considerable antibacterial and antifungal activity. Steroid 41 exhibited fish antifeedant activity. The relative concentration of 4.1 and 42 in the skin extracts of D. sandiegensis appears to be related to the animals' seasonal abundance. Extracts of the British Columbian soft coral Gersemia rubiformis yielded a series of ten diterpenes possessing cembrane (170-175), pseudopterane (167-169) and gersolane (176) carbon skeletons. The structure of an eleventh diterpene remains unresolved. In addition, the structure of a degraded diterpene possessing a 13-membered ring (177) is tentatively proposed. G. rubiformis represents the first example of a soft coral to yield pseudopterane diterpenes. The organism is the first to contain cembrane, pseudopterane and gersolane metabolites, a fact which has biogenetic implications. Two new sesquiterpenes were also isolated. Tochuinyl acetate (165) and dihydrotochuinyl acetate (166) represent the first examples of cuparane sesquiterpenes to be isolated from a soft coral. A biogenesis is proposed. Metabolite 166 exhibited fish antifeedant activity. Investigations of Gersemia rubiformis collected in Newfoundland waters revealed that the secondary metabolism differed from west coast specimens. The isolation of the new unstable sesquiterpene (+)-β-cubebene-3-acetate (178) resulted. Skin extracts of the dendronotoid nudibranch Toquina tetraquetra were examined in an attempt to correlate its feeding dependency and lack of predation to the presence of allomones. Metabolites 165, 166, 170, 179 and the new butanoate diterpene 180 could be traced to the coelenterates which make up the animal's diet. Tochuinyl acetate (165), dihydrotochuinyl acetate (166) and rubifolide (170) were previously found in extracts of Gersemia rubiformis. Ptilosarcenone (179) has been reported as one of the major metabolites of the sea pen Ptilosarcus gurneyi²¹³. The exact origin of a sixth metabolite, pukalide (63), remains unknown. It is proposed that Tochuina tetraquetra selectively sequesters dietary metabolites for defensive purposes.
Science, Faculty of
Chemistry, Department of
Graduate
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Rashash, Diana M. C. "Identification and characterization of odorous metabolites produced by selected freshwater algae." Diss., This resource online, 1994. http://scholar.lib.vt.edu/theses/available/etd-06062008-164628/.

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Lundahl, Anna. "In vivo Pharmacokinetic Interactions of Finasteride and Identification of Novel Metabolites." Doctoral thesis, Uppsala universitet, Institutionen för farmaci, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-129362.

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The general aim of this thesis was to improve the understanding of the in vivo pharmacokinetics and, in particular, the metabolism of finasteride, a 5α-reductase inhibitor used in the treatment of enlarged prostate glands and male pattern baldness. CYP3A4 has been identified as the major enzyme involved in the sequential metabolism of finasteride to ω-OH finasteride (M1) and ω-COOH finasteride (M3). The consequences of induced and inhibited metabolism on the pharmacokinetics of finasteride and its metabolites were investigated in humans and pigs. Both studies included bile collection. The collected human and pig samples were used for the metabolite identification. As expected, induced metabolism led to reduced plasma exposure of finasteride and inhibited metabolism had the opposite effect. The interactions were investigated in detail and included examination of the biliary pharmacokinetics of finasteride and its metabolites. In pigs, the study included monitoring of the hepatic extraction over time, deconvolution and the development of a semi-physiological model for comparison of the effects on the gut wall and liver metabolism. For M3, the concentration ratios of bile to plasma and the renal clearance indicated that carrier-mediated processes are involved in the biliary and urinary excretion. This was not, however, the case for finasteride. The metabolite, M1, could not be quantified either in humans or pigs. Instead, two other OH metabolites, M1 isomers, were identified in humans. These metabolites were found to undergo glucuronide conjugation. In humans, one glucuronide was identified intact and in pigs, both glucuronides were identified intact in bile and in urine. In addition, a glucuronide of M3 was identified in human bile. In conclusion, advances have been made in the understanding of the pharmacokinetics of finasteride, in particular in relation to the metabolism. Hopefully, the findings of this comprehensive investigation can be applied to other drugs and novel chemical entities.
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Martin, Scott. "Identification and mechanistic study of novel drug metabolites by LC-MS." Thesis, Sheffield Hallam University, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.713505.

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Understanding the metabolic fate of drug candidates in vitro and in vivo is a key component of drug development. Structural characterisation of drug candidate metabolites is important early in drug discovery to identify unwanted metabolic liabilities such as reactive, active, toxic or human specific metabolites. Reactive metabolite (RM) liability is a major concern for pharmaceutical companies during drug design, with most of the industry running primary RM trapping screens. This thesis investigates Fenclozic acid, homopiperazine reactivity, homomorphyline reactive aldehyde and methanol adduct formation, where RMs were not detected through routine glutathione/cyanide trapping assays. Fenclozic acid was withdrawn from clinical development due to hepatotoxicity; the mechanism of hepatotoxicity was never determined. In vitro covalent binding studies indicated phase I bioactivation in human liver microsomes, however no RMs were identified from in vitro experiments. As a part of this PhD thesis the metabolism of Fenclozic acid was investigated in bile duct cannulated rats using modern analytical techniques. Several new metabolites including glutathione related adducts formed through an epoxide RM were identified. A series of homopiperazine compounds were found to react with endogenous formaldehyde during rat in vivo studies. This thesis describes a detailed investigation into the identification and mechanism of formation of the resulting product, a bridged homopiperazine formed through a reactive Schiff base intermediate. A cysteineglycine conjugate observed for a series of homomorpholine compounds trapped by glutathione in human liver microsomes has been investigated in this thesis. NMR, detailed MS and methoxyamine trapping confirmed formation of a thiazolidine glycine product via a reactive aldehyde and subsequent glutathione rearrangement. A compound series in an early drug discovery programme formed unusual methanol adducts post incubation in human liver microsomes. The work undertaken in this thesis revealed the generation of a reactive aldehyde metabolite that did not form an adduct with glutathione, but reacted with the methanol mobile phase to form a pair of hemiacetal diastereoisomers. These examples would not have been detected using routine glutathione RM screening assays, this thesis highlights limitations of a screening approach, and where detailed metabolite identification studies employing modern LC-MS techniques are critical in understanding RM formation.
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Jones, Donald J. L. "The identification and characterisation of quercetin metabolites in humans and rats." Thesis, University of Leicester, 2001. http://hdl.handle.net/2381/30754.

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Quercetin is a dietary flavonoid, known to possess a range of biological properties of in in vitro systems. These properties may be of potential therapeutic benefit against certain diseases. Considerable work has focused on its antioxidant capability, which has been shown to be more powerful than that of vitamin E. Quercetin also has antineoplastic activity, and at 10M it inhibits the proliferation of malignant cell lines derived from breast, ovarian and gastrointestinal tumours and leukaemias. Therefore, a phase I clinical trial on cancer patients was conducted at the Queen Elizabeth Hospital in Birmingham, UK, in which quercetin was administered intravenously. One patient received quercetin p.o. In parallel to this clinical trial, blood and urine, derived from rats, were analysed in order to study the metabolism of quercetin, and the elucidate its bioavailability in vivo. The results show that metabolism by F344 rats, which received quercetin i.v., reflected adequately the metabolism seen in humans. Furthermore, analysis of both human and rat samples demonstrated that quercetin is rapidly metabolised via phase II biotransformation pathways to methyl, sulphate and glucuronide conjugates, thus eliminating quercetin efficiently from the body. The study shows that quercetin undergoes extensive first pass hepatic metabolism which in addition to the poor adsorption, means that quercetin has low bioavailability. Consequently, quercetin might be of limited therapeutic value, especially when taken orally. Whether or not the constant intake of quercetin via the diet may be beneficial to buttress the antioxidant defence system within the body remains to be elucidated. The existence of GSH-conjugates of quercetin was investigated as a possible explanation for the nephrotoxicity exhibited in rats and the clinical trial. GSH-conjugates of quercetin were not found in vivo, although they could be synthesised in vitro. Quercetin and isorhamnetin, although not quercetin sulphate nor glycosidic quercetin, exhibited potent COX-2 inhibition as demonstrated by reduced levels of PGE2 in HCA-7 cells.
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Holman, Stephen William. "Rapid and definitive identification of pharmaceutical drug metabolites using mass spectrometry." Thesis, University of Southampton, 2010. https://eprints.soton.ac.uk/72950/.

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Low-energy collision-induced dissociation-tandem mass spectrometry (CIDMS/ MS) is a well-established approach for identifying pharmaceutical drug metabolites. The technique fulfils many necessary requirements for this task, such as a low limit of detection, simple interfacing to chromatographic techniques, capability of fast analyses and automation, and high sensitivity, selectivity and accuracy. However, one of the main limitations of low-energy CID-MS/MS is that unambiguous assignment of the site of metabolism is often not possible, particularly for oxidised metabolites. Further, data interpretation can be time-consuming, thus producing a bottleneck to high-throughput analyses. The aim of the presented study was to identify structurally dependent dissociation pathways using low-energy CID-MS/MS that could facilitate rapid and definitive assignment of the sites of metabolism of new chemical entities. Chapter 4 details a specific loss of 50 m/z units in a model S-oxide that arises due to an ortho-effect. This loss could be used to definitively assign the site of oxidation and discriminate between multiple sulfur atoms in a parent compound. The 50 m/z unit loss was also shown to be a two-step process involving sequential radical losses; a rare observation for even-electron precursor ions under low-energy CID conditions. Chapter 5 discusses the experimental investigation of two unexpected rearrangements during the dissociation of a model S-oxide that could prevent correct assignment of the site of metabolism. Chapter 6 presents a rapid and definitive approach to the characterisation of dialkyl tertiary amine-N-oxides. The work also elucidated generic dissociation behaviour under low-energy CID conditions. Finally, chapter 7 considers an observation of site-specific intra-ionic hydrogen/deuterium exchange in the gas phase. Seven sets of compounds were analysed to investigate the substructures that facilitate the exchange. The work demonstrates a method by which a deuterium label can be inserted into the carbon skeleton of a small molecule without having to synthetically produce the compound, which could be useful in performing timely and cost-effective structural elucidation studies. In summary, the presented study provides two potentially useful approaches for the rapid and definitive identification of oxidised metabolites, as well as increasing the body of knowledge relating to ion-chemistry under low-energy CID conditions.
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Hoang, Tiffany Truc. "Speciation and identification of low molecular weight organoselenium metabolites in human urine." Diss., Georgia Institute of Technology, 2003. http://hdl.handle.net/1853/30671.

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Books on the topic "Metabolites – Identification"

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C, Rashash Diana M., and AWWA Research Foundation, eds. Identification and control of odorous algal metabolites. Denver, CO: AWWA Research Foundation and American Water Works Association, 1996.

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Faddin, Jean F. Mac. Biochemical tests for identification of medical bacteria. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 1999.

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Indriani, Ine Dewi. Biodiversity of marine-derived fungi and identification of their metabolites: = Biodiversität von Pilzen mariner Herkunft und Identifizierung ihrer Sekundärstoffe. Göttingen: Cuvillier, 2008.

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McClean, Stephen. An investigation of modern analytical techniques for the identification and determination of selected drugs and pollutants, their degradation products and metabolites. [S.l: The Author], 1999.

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Skirycz, Aleksandra, Marcin Luzarowski, and Jennifer C. Ewald, eds. Cell-Wide Identification of Metabolite-Protein Interactions. New York, NY: Springer US, 2023. http://dx.doi.org/10.1007/978-1-0716-2624-5.

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Seca, Ana Maria Loureiro da, and Antoaneta Trendafilova, eds. Isolation and Identification of Bioactive Secondary Metabolites. MDPI, 2022. http://dx.doi.org/10.3390/books978-3-0365-3766-5.

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Seca, Ana M. L., and Antoaneta Trendafilova. Isolation and Identification of Bioactive Secondary Metabolites. Mdpi AG, 2022.

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Identification and Quantification of Drugs, Metabolites, Drug Metabolizing Enzymes, and Transporters. Elsevier, 2020. http://dx.doi.org/10.1016/c2018-0-03355-1.

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Nassar, Ala F. Biotransformation and Metabolite Elucidation of Xenobiotics: Characterization and Identification. Wiley & Sons, Incorporated, John, 2010.

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Nassar, Ala F. Biotransformation and Metabolite Elucidation of Xenobiotics: Characterization and Identification. Wiley & Sons, Incorporated, John, 2011.

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Book chapters on the topic "Metabolites – Identification"

1

Thrane, Ulf. "Identification of Fungi by Secondary Metabolites." In Developments in Plant Pathology, 91–98. Dordrecht: Springer Netherlands, 1996. http://dx.doi.org/10.1007/978-94-009-1698-2_13.

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Dobo, Krista, Don Walker, and Andrew Teasdale. "Human Genotoxic Metabolites: Identification and Risk Management." In Genotoxic Impurities, 151–67. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2011. http://dx.doi.org/10.1002/9780470929377.ch6.

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Ogra, Yasumitsu. "Speciation and Identification of Chalcogen-Containing Metabolites." In Metallomics, 43–61. Tokyo: Springer Japan, 2017. http://dx.doi.org/10.1007/978-4-431-56463-8_2.

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Novák, Ondřej, Aleš Pěnčík, and Karin Ljung. "Identification and Profiling of Auxin and Auxin Metabolites." In Auxin and Its Role in Plant Development, 39–60. Vienna: Springer Vienna, 2014. http://dx.doi.org/10.1007/978-3-7091-1526-8_3.

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Cruz-Morató, C., C. E. Rodríguez-Rodríguez, E. Marco-Urrea, M. Sarrà, G. Caminal, T. Vicent, A. Jelić, et al. "Biodegradation of Pharmaceuticals by Fungi and Metabolites Identification." In The Handbook of Environmental Chemistry, 165–213. Berlin, Heidelberg: Springer Berlin Heidelberg, 2012. http://dx.doi.org/10.1007/698_2012_158.

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Halder, Mihir, Anirban Kundu, and Sumita Jha. "Secondary Metabolites Identification Techniques of the Current Era." In Reference Series in Phytochemistry, 1–41. Cham: Springer Nature Switzerland, 2024. http://dx.doi.org/10.1007/978-3-031-30037-0_31-1.

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Patil, Ravindra H., Mohini P. Patil, and Vijay L. Maheshwari. "Identification of Bioactive Secondary Metabolites of Apocynaceae Members." In Apocynaceae Plants, 67–81. Singapore: Springer Nature Singapore, 2023. http://dx.doi.org/10.1007/978-981-99-5406-3_6.

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Surendran, Karuna, R. Aswati Nair, and Padmesh P. Pillai. "Molecular Markers and Their Application in the Identification of Elite Germplasm." In Plant Metabolites: Methods, Applications and Prospects, 57–70. Singapore: Springer Singapore, 2020. http://dx.doi.org/10.1007/978-981-15-5136-9_3.

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Akgün, İsmail Hakkı, and Fazilet Vardar-Sukan. "Identification Strategies for Bioactive Secondary Metabolites of Fungal Origin." In Medicinal and Aromatic Plants of the World, 511–47. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-5978-0_16.

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Dharumadurai, Dhanasekaran, Karthikeyan Saravanan, Chandraleka Saravanan, Sivaranjani Govindhan, and Latha Selvanathan. "Extraction, Characterization, and Identification of Odorous Metabolites from Streptomyces." In Methods in Actinobacteriology, 629–40. New York, NY: Springer US, 2022. http://dx.doi.org/10.1007/978-1-0716-1728-1_94.

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Conference papers on the topic "Metabolites – Identification"

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Braga, Jose Renato G., Alexandre Carlos B. Ramos, and Alvaro Antonio A. Queiroz. "Using artificial neural nets to Hemo metabolites identification." In 2012 IEEE 14th International Conference on e-Health Networking, Applications and Services (Healthcom 2012). IEEE, 2012. http://dx.doi.org/10.1109/healthcom.2012.6379374.

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Christodoulou, Christiana C., George Minadakis, Christiana Demetriou, Eleni Zamba-Papanicolaou, and George Spyrou. "Computational Identification of Metabolites for Pathways Related to Huntington's Disease." In 2019 IEEE 19th International Conference on Bioinformatics and Bioengineering (BIBE). IEEE, 2019. http://dx.doi.org/10.1109/bibe.2019.00155.

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Manninen, M., M. Karonen, and J.-P. Salminen. "Mass spectrometric tools for species identification from leaf bud metabolites." In GA – 70th Annual Meeting 2022. Georg Thieme Verlag KG, 2022. http://dx.doi.org/10.1055/s-0042-1759035.

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Donovan, B., K. N. Turi, T. Gebretsadik, S. L. Havstad, J. E. Gern, D. J. Jackson, C. Ober, et al. "Identification of Newborn Screening Metabolites and Associated Risk of Infant Bronchiolitis." In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a1188.

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Kalampokis, Evangelos, Theodora Nikou, Dimitrios Michailidis, Christina Fytili, Nikolaos Tentolouris, and Maria Halabalaki. "Isolation and identification of urine metabolites after hydroxytyrosol supplementation in humans." In GA – 69th Annual Meeting 2021, Virtual conference. Georg Thieme Verlag, 2021. http://dx.doi.org/10.1055/s-0041-1736850.

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Sousa, Matheus Henrique Oliveira de, Gilvan de Oliveira Costa Dias, and Joselene Ribeiro de Jesus Santos. "Phytochemical prospecting, identification and evaluation of the microbiological activity of secondary metabolites of Annona mucosa Jacq." In V Seven International Multidisciplinary Congress. Seven Congress, 2024. http://dx.doi.org/10.56238/sevenvmulti2024-049.

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The present work describes the results obtained for the phytochemical and microbiological studies of the 70% hydroethanolic extract, its fractions and metabolites isolated from the leaves of Biribazeiro ( Annona mucosa Jacq.). Initially, the hydroethanolic extract (70%) of the vegetable leaves was prepared and a phytochemical screening was carried out in search of the secondary metabolites of study. The tests confirmed the presence of tannins, flavonols, flavanones, flavanonols, xanthones, leucoanthocyanidins, anthocyanidins, free steroids,
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"Rapid Identification of Cunninghamella bertholletiae’s Toxins/Secondary Metabolites via a Fermentation Technique." In Nov. 19-20 2018 Cape Town (South Africa). Eminent Association of Pioneers, 2018. http://dx.doi.org/10.17758/eares4.eap1118110.

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Wang, Mengyuan, Huiru Zheng, Haiying Wang, Richard J. Dewhurst, and Rainer Roehe. "A knowledge driven mutual information-based analytical framework for the identification of rumen metabolites." In 2019 IEEE International Conference on Bioinformatics and Biomedicine (BIBM). IEEE, 2019. http://dx.doi.org/10.1109/bibm47256.2019.8983182.

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Rivera, Katya P. Vazquez, Ana Maria Gallego, José M. Hernández, Adriana Monroy-Guzmán, Yolanda Mares-Gutiérrez, José A. Christen, Luis G. Ruiz-Suárez, Silvestre Alavez, and Antonio M. Juárez. "Identification and quantification of metabolites in exhaled breath in a sample population in México." In MEDICAL PHYSICS: Fourteenth Mexican Symposium on Medical Physics. Author(s), 2016. http://dx.doi.org/10.1063/1.4954094.

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Grafakou, M. E., C. Barda, E. Skaltsa, and J. Heilmann. "Identification of parthenolide metabolites in human liver microsomes by LC-Q-TOF-MS/MS." In GA – 69th Annual Meeting 2021, Virtual conference. Georg Thieme Verlag, 2021. http://dx.doi.org/10.1055/s-0041-1736874.

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Reports on the topic "Metabolites – Identification"

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Powell, Samantha, Daisy Herrera, Irina El Khoury, Cayden Perdue, Natalie Sadler, John Cort, Grace Robinson, Pubudu Handakumbura, James Evans, and Vivian Lin. Accelerating the identification of novel secondary metabolites in bioenergy plant root exudates using MicroED. Office of Scientific and Technical Information (OSTI), September 2024. http://dx.doi.org/10.2172/2452767.

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Ginzberg, Idit, Richard E. Veilleux, and James G. Tokuhisa. Identification and Allelic Variation of Genes Involved in the Potato Glycoalkaloid Biosynthetic Pathway. United States Department of Agriculture, August 2012. http://dx.doi.org/10.32747/2012.7593386.bard.

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Steroidal glycoalkaloids (SGAs) are secondary metabolites being part of the plant defense response. The two major SGAs in cultivated potato (Solanum tuberosum) are α-chaconine and α-solanine, which exhibit strong cellular lytic properties and inhibit acetylcholinesterase activity, and are poisonous at high concentrations for humans. As SGAs are not destroyed during cooking and frying commercial cultivars have been bred to contain low levels, and their content in tubers should not exceed 20 mg/100 g fresh weight. However, environmental factors can increase tuber SGA content above the safe level. The focus of the proposed research was to apply genomic approaches to identify candidate genes that control potato SGA content in order to develop tools for potato improvement by marker-assisted selection and/or transgenic approaches. To this end, the objectives of the proposal included identification of genes, metabolic intermediates and allelic variations in the potato SGAbiosynthetic pathway. The SGAs are biosynthesized by the sterol branch of the mevalonic acid/isoprenoid pathway. Transgenic potato plants that overexpress 3-hydroxy-3-methylglutaryl-CoA reductase 1 (HMG1) or squalene synthase 1 (SQS1), key enzymes of the mevalonic acid/isoprenoid pathway, exhibited elevated levels of solanine and chaconine as well as induced expression of genes downstream the pathway. These results suggest of coordinated regulation of isoprenoid (primary) metabolism and SGA secondary metabolism. The transgenic plants were further used to identify new SGA-related candidate genes by cDNA-AFLP approach and a novel glycosyltransferase was isolated. In addition, genes involved in phytosterol biosynthesis may have dual role and synthesize defense-related steroidal metabolites, such as SGAs, via lanosterol pathway. Potato lanosterol synthase sequence (LAS) was isolated and used to prepare transgenic plants with overexpressing and silencing constructs. Plants are currently being analyzed for SGA content. The dynamics of SGA accumulation in the various organs of a potato species with high SGA content gave insights into the general regulation of SGA abundance. Leaf SGA levels in S. chacoense were 10 to 20-fold greater than those of S. tuberosum. The leptines, SGAs with strong antifeedant properties against Colorado potato beetles, were present in all aerial tissues except for early and mid-developmental stages of above ground stolons, and accounted for the high SGA content of S. chacoense. These results indicate the presence of regulatory mechanisms in most tissues except in stolons that limit the levels of α-solanine and α-chaconine and confine leptine accumulation to the aerial tissues. The genomes of cultivated and wild potato contain a 4-member gene family coding for SQS. Three orthologs were cloned as cDNAs from S. chacoense and heterologously expressed in E. coli. Squalene accumulated in all E. coli lines transformed with each of the three gene constructs. Differential transcript abundance in various organs and amino acid sequence differences in the conserved domains of three isoenzymes indicate subfunctionalization of SQS activity and triterpene/sterol metabolism. Because S. chacoense and S. phureja differ so greatly for presence and accumulation of SGAs, we selected four candidate genes from different points along the biosynthetic pathway to determine if chcor phuspecific alleles were associated with SGA expression in a segregating interspecific diploid population. For two of the four genes (HMG2 and SGT2) F2 plants with chcalleles expressed significantly greater total SGAs compared with heterozygotes and those with phualleles. Although there are other determinants of SGA biosynthesis and composition in potato, the ability of allelic states at two genes to affect SGA levels confirms some of the above transgenic work where chcalleles at two other loci altered SGA expression in Desiree. Present results reveal new opportunities to manipulate triterpene/sterol biosynthesis in more targeted ways with the objective of altering SGA content for both human health concerns and natural pesticide content without disrupting the essential metabolism and function of the phytosterol component of the membranes and the growth regulating brassinosteroids.
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Horwitz, Benjamin, and Barbara Gillian Turgeon. Secondary Metabolites, Stress, and Signaling: Roles and Regulation of Peptides Produced by Non-ribosomal Peptide Synthetases. United States Department of Agriculture, 2005. http://dx.doi.org/10.32747/2005.7696522.bard.

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Fungal pathogens of plants produce a diverse array of small molecules. Often referred to as secondary metabolites because they were thought to be dispensable for basic functions, they may indeed have central roles as signals for the fungal cell, and in interactions with the host. We have identified more than a dozen genes encoding nonribosomal peptide synthetases (NPS) in Cochliobolusheterostrophus, the agent of southern corn leaf blight. The aim of this project was to identify roles of these genes in stress responses and signaling. The first objective was to test a complete collection of C. heterostrophus nonribosomal peptide synthetase (NRPS)-encoding gene deletion mutant and wildtype (WT) strains for sensitivity to various agents of oxidative (ROS) and nitrosative (RNOS) stress, in vitro. The second objective and next step in this part of the project was to study the relevance of sensitivity to ROS and RNOS in the host pathogen interaction, by measuring the production of ROS and RNOS in planta, when plants are inoculated with wild type and mutant strains. A third objective was to study expression of any genes shown to be involved in sensitivity to ROS or RNOS, in vitro and in planta. Another objective was to determine if any of the genes involved in oxidative or nitrosative stress responses are regulated by components of signal transduction pathways (STP) that we have identified and to determine where mechanisms overlap. Study of the collection of nps mutants identified phenotypes relevant for virulence, development and oxidative stress resistance for two of the genes, NPS2 and NPS6. Mutants in genes related to RNOS stress have no virulence phenotypes, while some of those related to ROS stress have reduced virulence as well as developmental phenotypes, so we focused primarily on ROS stress pathways. Furthermore, the identification of NPS2 and NPS6 as encoding for NRPS responsible for siderophore biosynthesis lent a new focus to the project, regulation by Fe. We have not yet developed good methods to image ROS in planta and work in this direction is continuing. We found that NPS6 expression is repressed by Fe, responding over the physiological Fe concentration range. Studying our collection of mutants, we found that conserved MAPK and G protein signal transduction pathways are dispensable for Fe regulation of NPS6, and initiated work to identify other pathways. The transcription factor SreA is one candidate, and is responsible for part, but not all, of the control of NPS6 expression. The results of this project show that the pathogen contends with oxidative stress through several signaling pathways. Loss of the siderophore produced by Nps6 makes the fungus sensitive to oxidative stress, and decreases virulence, suggesting a central role of the ability to sequester and take up extracellular iron in the host-pathogen interaction. Siderophores, and manipulation of Fe levels, could be targets for new strategies to deal with fungal pathogens of maize and other plants.
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Sharon, Amir, and Maor Bar-Peled. Identification of new glycan metabolic pathways in the fungal pathogen Botrytis cinerea and their role in fungus-plant interactions. United States Department of Agriculture, 2012. http://dx.doi.org/10.32747/2012.7597916.bard.

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The involvement of glycans in microbial adherence, recognition and signaling is often a critical determinant of pathogenesis. Although the major glycan components of fungal cell walls have been identified there is limited information available on its ‘minor sugar components’ and how these change during different stages of fungal development. Our aim was to define the role of Rhacontaining-glycans in the gray mold disease caused by the necrotrophic fungus B. cinerea. The research was built on the discovery of two genes, Bcdhand bcer, that are involved in formation of UDP-KDG and UDP-Rha, two UDP- sugars that may serve as donors for the synthesis of cell surface glycans. Objectives of the proposed research included: 1) To determine the function of B. cinereaBcDh and BcEr in glycan biosynthesis and in pathogenesis, 2) To determine the expression pattern of BcDH and BcERand cellular localization of their encoded proteins, 3) Characterize the structure and distribution of Rha- containing glycans, 4) Characterization of the UDP-sugar enzymes and potential of GTs involved in glycanrhamnosylation. To address these objectives we generated a series of B. cinereamutants with modifications in the bchdhand bcergenes and the phenotype and sugar metabolism in the resulting strains were characterized. Analysis of sugar metabolites showed that changes in the genes caused changes in primary and secondary sugars, including abolishment of rhamnose, however abolishment of rhamnose synthesis did not cause changes in the fungal phenotype. In contrast, we found that deletion of the second gene, bcer, leads to accumulation of the intermediate sugar – UDP- KDG, and that such mutants suffer from a range of defects including reduced virulence. Further analyses confirmed that UDP-KDG is toxic to the fungus. Studies on mode of action suggested that UDP-KDG might affect integrity of the fungal cell wall, possibly by inhibiting UDP-sugars metabolic enzymes. Our results confirm that bcdhand bcerrepresent a single pathway of rhamnose synthesis in B. cinerea, that rhamnose does not affect in vitro development or virulence of the fungus. We also concluded that UDP-KDG is toxic to B. cinereaand hence UDP-KDG or compounds that inhibit Er enzymes and lead to accumulation of UDP-KDG might have antifungal activity. This toxicity is likely the case with other fungi, this became apparent in a collaborative work with Prof. Bart Thomma of Wageningen University, NETHERLANDS . We have shown the deletion of ER mutant in Verticillium dahlia gave plants resistance to the fungal infection.
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Blumwald, Eduardo, and Avi Sadka. Sugar and Acid Homeostasis in Citrus Fruit. United States Department of Agriculture, January 2012. http://dx.doi.org/10.32747/2012.7697109.bard.

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Citrus fruit quality standards have been determined empirically, depending on species and on the particular growing regions. In general, the TSS (total soluble solids) to total acidity (TA) ratio determines whether citrus fruit can be marketed. Soluble sugars account for most of the TSS during harvest while TA is determined almost solely by the citric acid content, which reaches levels of 1-5% by weight in many cultivated varieties. Acid and sugar homeostasis in the fruit is critical for the management of existing cultivars, the development of new cultivars, the improvement of pre- and post-harvest strategies and the control of fruit quality and disorders. The current proposal (a continuation of a previous proposal) aimed at: (1) completing the citrus fruit proteome and metabolome, and establish a citrus fruit functional database, (2) further characterization of the control of fruit acidity by studying the regulation of key steps affecting citrate metabolism, and determine the fate of citrate during acid decline stage, and (3) Studying acid and sugar homeostasis in citrus fruits by characterizing transport mechanisms across membranes. These aims were completed as the following: (1) Our initial efforts were aimed at the characterization and identification of citric acid transporters in citrus juice cells. The identification of citrate transporters at the vacuole of the citrus juice cell indicated that the steady-state citrate cytosolic concentration and the action of the cytosolic aconitase were key elements in establishing the pH homeostat in the cell that regulates the metabolic shift towards carbon usage in the fruit during the later stages of fruit development. We focused on the action of aconitase, the enzyme mediating the metabolic use of citric acid in the cells, and identified processes that control carbon fluxes in developing citrus fruits that control the fruit acid load; (2) The regulation of aconitase, catalyzing a key step in citrate metabolism, was further characterized by using two inhibitors, citramalte and oxalomalte. These compounds significantly increased citrate content and reduced the enzyme’s activity. Metabolite profiling and changes of amino-acid metabolizing enzymes in oxalomalate- treated cells suggested that the increase in citrate, caused by aconitase inhibition, induces amino acid synthesis and the GABA shunt, in accordance with the suggested fate of citrate during the acid decline stage in citrus fruit. (3) We have placed a considerable amount of time on the development of a citrus fruit proteome that will serve to identify all of the proteins in the juice cells and will also serve as an aid to the genomics efforts of the citrus research community (validating the annotation of the fruit genes and the different ESTs). Initially, we identified more than 2,500 specific fruit proteins and were able to assign a function to more than 2,100 proteins (Katz et al., 2007). We have now developed a novel Differential Quantitative LC-MS/MS Proteomics Methodology for the identification and quantitation of key biochemical pathways in fruits (Katz et al., 2010) and applied this methodology to identify determinants of key traits for fruit quality (Katz et al., 2011). We built “biosynthesis maps” that will aid in defining key pathways associated with the development of key fruit quality traits. In addition, we constructed iCitrus (http://wiki.bioinformatics.ucdavis.edu/index.php/ICitrus), a “functional database” that is essentially a web interface to a look-up table that allows users to use functional annotations in the web to identify poorly annotated citrus proteins. This resource will serve as a tool for growers and field extension specialists.
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Ron, Eliora, and Eugene Eugene Nester. Global functional genomics of plant cell transformation by agrobacterium. United States Department of Agriculture, March 2009. http://dx.doi.org/10.32747/2009.7695860.bard.

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The aim of this study was to carry out a global functional genomics analysis of plant cell transformation by Agrobacterium in order to define and characterize the physiology of Agrobacterium in the acidic environment of a wounded plant. We planed to study the proteome and transcriptome of Agrobacterium in response to a change in pH, from 7.2 to 5.5 and identify genes and circuits directly involved in this change. Bacteria-plant interactions involve a large number of global regulatory systems, which are essential for protection against new stressful conditions. The interaction of bacteria with their hosts has been previously studied by genetic-physiological methods. We wanted to make use of the new capabilities to study these interactions on a global scale, using transcription analysis (transcriptomics, microarrays) and proteomics (2D gel electrophoresis and mass spectrometry). The results provided extensive data on the functional genomics under conditions that partially mimic plant infection and – in addition - revealed some surprising and significant data. Thus, we identified the genes whose expression is modulated when Agrobacterium is grown under the acidic conditions found in the rhizosphere (pH 5.5), an essential environmental factor in Agrobacterium – plant interactions essential for induction of the virulence program by plant signal molecules. Among the 45 genes whose expression was significantly elevated, of special interest is the two-component chromosomally encoded system, ChvG/I which is involved in regulating acid inducible genes. A second exciting system under acid and ChvG/Icontrol is a secretion system for proteins, T6SS, encoded by 14 genes which appears to be important for Rhizobium leguminosarum nodule formation and nitrogen fixation and for virulence of Agrobacterium. The proteome analysis revealed that gamma aminobutyric acid (GABA), a metabolite secreted by wounded plants, induces the synthesis of an Agrobacterium lactonase which degrades the quorum sensing signal, N-acyl homoserine lactone (AHL), resulting in attenuation of virulence. In addition, through a transcriptomic analysis of Agrobacterium growing at the pH of the rhizosphere (pH=5.5), we demonstrated that salicylic acid (SA) a well-studied plant signal molecule important in plant defense, attenuates Agrobacterium virulence in two distinct ways - by down regulating the synthesis of the virulence (vir) genes required for the processing and transfer of the T-DNA and by inducing the same lactonase, which in turn degrades the AHL. Thus, GABA and SA with different molecular structures, induce the expression of these same genes. The identification of genes whose expression is modulated by conditions that mimic plant infection, as well as the identification of regulatory molecules that help control the early stages of infection, advance our understanding of this complex bacterial-plant interaction and has immediate potential applications to modify it. We expect that the data generated by our research will be used to develop novel strategies for the control of crown gall disease. Moreover, these results will also provide the basis for future biotechnological approaches that will use genetic manipulations to improve bacterial-plant interactions, leading to more efficient DNA transfer to recalcitrant plants and robust symbiosis. These advances will, in turn, contribute to plant protection by introducing genes for resistance against other bacteria, pests and environmental stress.
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