Further Insights into the Oxidative Pathway of Thiocarbonyl-Type Antitubercular Prodrugs: Ethionamide, Thioacetazone, and Isoxyl

Author(s):  
Tércio de Freitas Paulo ◽  
Carine Duhayon ◽  
Luiz Gonzaga de França Lopes ◽  
Eduardo Henrique Silva Sousa ◽  
Remi Chauvin ◽  
...  
Keyword(s):  
2021 ◽  
Author(s):  
Nathalie D Lackus ◽  
Axel Schmidt ◽  
Jonathan Gershenzon ◽  
Tobias G Köllner

AbstractBenzenoids (C6–C1 aromatic compounds) play important roles in plant defense and are often produced upon herbivory. Black cottonwood (Populus trichocarpa) produces a variety of volatile and nonvolatile benzenoids involved in various defense responses. However, their biosynthesis in poplar is mainly unresolved. We showed feeding of the poplar leaf beetle (Chrysomela populi) on P. trichocarpa leaves led to increased emission of the benzenoid volatiles benzaldehyde, benzylalcohol, and benzyl benzoate. The accumulation of salicinoids, a group of nonvolatile phenolic defense glycosides composed in part of benzenoid units, was hardly affected by beetle herbivory. In planta labeling experiments revealed that volatile and nonvolatile poplar benzenoids are produced from cinnamic acid (C6–C3). The biosynthesis of C6–C1 aromatic compounds from cinnamic acid has been described in petunia (Petunia hybrida) flowers where the pathway includes a peroxisomal-localized chain shortening sequence, involving cinnamate-CoA ligase (CNL), cinnamoyl-CoA hydratase/dehydrogenase (CHD), and 3-ketoacyl-CoA thiolase (KAT). Sequence and phylogenetic analysis enabled the identification of small CNL, CHD, and KAT gene families in P. trichocarpa. Heterologous expression of the candidate genes in Escherichia coli and characterization of purified proteins in vitro revealed enzymatic activities similar to those described in petunia flowers. RNA interference-mediated knockdown of the CNL subfamily in gray poplar (Populus x canescens) resulted in decreased emission of C6–C1 aromatic volatiles upon herbivory, while constitutively accumulating salicinoids were not affected. This indicates the peroxisomal β-oxidative pathway participates in the formation of volatile benzenoids. The chain shortening steps for salicinoids, however, likely employ an alternative pathway.


2009 ◽  
Vol 2009 ◽  
pp. 1-5 ◽  
Author(s):  
Shinichiro Kina ◽  
Toshiyuki Nakasone ◽  
Hiroyuki Takemoto ◽  
Akira Matayoshi ◽  
Shoko Makishi ◽  
...  

Inflammation is associated with disease progression and, by largely unknown mechanisms, has been said to drive oncogenesis. At inflamed sites, neutrophils deploy a potent antimicrobial arsenal that includes proteinases, antimicrobial peptides, and ROS. Reactive oxygen species (ROSs) induce chemokines. In the present study, the concentrations of IL-8 in culture supernatants of HeLa cells treated with ROS were determined by enzyme-linked immunosorbent assay. We used -phenanthroline to deplete in order to investigate the mechanisms through which ROSs induce IL-8 secretion in our system. The iron chelator -phenanthroline effectively inhibited -induced ERK2 activation. Enzyme-linked immunosorbent assays showed that IL-8 protein secretion was elevated in ROS-treated HeLa cells. When was removed from these cells, IL-8 secretion was inhibited. Collectively, these results indicate that -mediated Erk pathway activation is an important signal transduction pathway in ROS-induced IL-8 secretion in epithelial cells.


1965 ◽  
Vol 43 (2) ◽  
pp. 209-224 ◽  
Author(s):  
B. I. Uppin ◽  
P. G. Scholefield

Studies have been made of the effects of metabolic inhibitors on the oxidation and incorporation of radioactivity into nucleotides of glucose labelled in the 1, 2, and 6 positions. The results indicate that in Ehrlich ascites carcinoma cells the predominant oxidative pathway is the hexosemonophosphate shunt. Investigation of the time courses of oxidation of the labelled glucose molecules confirms this conclusion. The pattern of incorporation of radioactivity initially suggests that nucleotide ribose is not formed via this pathway. However, it is shown that the coupling of an active transketolase system with the other enzymes of the hexosemonophosphate shunt provides a sufficient explanation of all the experimental observations. The conclusion is reached that pentose is formed by oxidation of glucose through the shunt but that the labelling pattern is largely established as the result of the exchange reaction catalyzed by transketolase.


Processes ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 137 ◽  
Author(s):  
Erin E Johnson ◽  
Lars Rehmann

By monitoring the real-time gas production (CO2 and H2) and redox potential at high sampling frequency in continuous culture of Clostridium pasteurianum on glycerol as sole carbohydrate, the self-synchronized oscillatory metabolism was revealed and studied. The oscillations in CO2 and H2 production were in sync with each other and with both redox potential and glycerol in the continuous stirred tank reactor (CSTR). There is strong evidence that the mechanism for this is in the regulation of the oxidative pathway of glycerol metabolism, including glycolysis, and points toward complex, concerted cycles of enzyme inhibition and activation by pathway intermediates and/or redox equivalents. The importance of understanding such an “oscillatory metabolism” is for developing a stable and highly productive industrial fermentation process for butanol production, as unstable oscillations are unproductive. It is shown that the oscillatory metabolism can be eradicated and reinstated and that the period of oscillations can be altered by modification of the operating parameters. Synchronized oscillatory metabolism impacted the product profile such that it lowered the selectivity for butanol and increased the selectivity for ethanol. This elucidates a possible cause for the variability in the product profile of C. pasteurianum that has been reported in many previous studies.


2008 ◽  
Vol 294 (6) ◽  
pp. H2516-H2523 ◽  
Author(s):  
Jeffrey G. Williams ◽  
Caroline Ojaimi ◽  
Khaled Qanud ◽  
Suhua Zhang ◽  
Xiaobin Xu ◽  
...  

The aim of this study was to examine the role of nitric oxide (NO) in the control of cardiac metabolism at 60 days of pregnancy (P60) in the dog. There was a basal increase in diastolic coronary blood flow during pregnancy and a statistically significant increase in cardiac output (55 ± 4%) and in cardiac NOx production (44 ± 4 to 59 ± 3 nmol/min, P < 0.05). Immunohistochemistry of the left ventricle showed an increase in endothelial nitric oxide synthase staining in the endothelial cells at P60. NO-dependent coronary vasodilation (Bezold-Jarisch reflex) was increased by 20% and blocked by NG-nitro-l-arginine methyl ester (l-NAME). Isotopically labeled substrates were infused to measure oleate, glucose uptake, and oxidation. Glucose oxidation was not significantly different in P60 hearts (5.4 ± 0.5 vs. 6.2 ± 0.4 μmol/min) but greatly increased in response to l-NAME injection (to 19.9 ± 0.9 μmol/min, P < 0.05). Free fatty acid (FFA) oxidation was increased in P60 (from 5.3 ± 0.6 to 10.4 ± 0.5 μmol/min, P < 0.05) and decreased in response to l-NAME (to 4.5 ± 0.5 μmol/min, P < 0.05). There was an increased oxidation of FFA for ATP production but no change in the respiratory quotient during pregnancy. Genes associated with glucose and glycogen metabolism were downregulated, whereas genes involved in FFA oxidation were elevated. The acute inhibition of NO shifts the heart away from FFA and toward glucose metabolism despite the downregulation of the carbohydrate oxidative pathway. The increase in endothelium-derived NO during pregnancy results in a tonic inhibition of glucose oxidation and reliance on FFA uptake and oxidation to support ATP synthesis in conjunction with upregulation of FFA metabolic enzymes.


2018 ◽  
Vol 48 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Qunzi Zhang ◽  
Qiongxia Deng ◽  
Jun Zhang ◽  
JianTing Ke ◽  
Ye Zhu ◽  
...  

Background/Aims: Previously we have shown that activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element (ARE) attenuated hyperglycemia-induced damage in podocytes, but the molecular mechanism remains unknown. Methods: Tert-butylhydroquinone (t-BHQ) and small interfering RNAs (siRNAs) were used to regulate Nrf2 expression, while nicotinamide and siRNAs were used to regulate sirtuin 1 (Sirt1) activity and expression, respectively. Mitochondrial superoxide, membrane potential and ATP levels were measured to assess changes in mitochondrial function. Nephrin and synaptopodin expression were measured by western blot analysis. Human podocytes and db/db diabetic mice were used in this study. Results: t-BHQ pretreatment of human podocytes exposed to high glucose (HG) alleviated mitochondrial dysfunction, enhanced the expression of Sirt1, nephrin and synaptopodin and lowered BSA permeability compared with podocytes exposed to HG without t-BHQ pretreatment (p< 0.05). Human podocytes exposed to HG had more severe mitochondrial dysfunction, lower expression of Sirt1, synaptopodin and nephrin and higher BSA permeability than podocytes exposed to HG when Nrf2 expression was downregulated by siRNAs (p< 0.05). The protection provided by activation of the Nrf-ARE pathway in podocytes exposed to HG was partially diminished when Sirt1 expression or activity was decreased by siRNAs or inhibitor compared with podocytes exposed to HG and pretreated with t-BHQ (p< 0.05). When nicotinamide and t-BHQ were both administered to db/db mice, we observed higher levels of urinary albumin/creatinine, lower nephrin and synaptopodin expression, more severe mesangial matrix deposition, collagen deposition on pathological slides and mitochondrial structural damage in podocytes compared to db/db mice treated only with t-BHQ. Conclusions: Our findings suggest that crosstalk between Sirt1 and the Nrf2-ARE anti-oxidative pathway forms a positive feedback loop and that protection provided by t-BHQ activation of the Nrf2-ARE pathway in db/db mice is partly dependent on Sirt1.


1999 ◽  
Vol 65 (12) ◽  
pp. 5636-5638 ◽  
Author(s):  
Kenzo Koike ◽  
Katsutoshi Ara ◽  
Shigehito Adachi ◽  
Hirofumi Takigawa ◽  
Hajime Mori ◽  
...  

ABSTRACT A mutant Rhodococcus strain lacking the ability to utilize 1-chlorohexadecane was found to cis-desaturate aliphatic compounds, such as 1-chlorohexadecane,n-hexadecane, and heptadecanonitrile, yielding corresponding products with a double bond mainly at the ninth carbon from the terminal methyl groups. A new oxidative pathway involving thecis-desaturation step was suggested for alkane utilization by Rhodococcus spp.


2019 ◽  
Vol 85 (13) ◽  
Author(s):  
Oscar A. Sosa ◽  
John R. Casey ◽  
David M. Karl

ABSTRACTThe marine unicellular cyanobacteriumProchlorococcusis an abundant primary producer and widespread inhabitant of the photic layer in tropical and subtropical marine ecosystems, where the inorganic nutrients required for growth are limiting. In this study, we demonstrate thatProchlorococcushigh-light strain MIT9301, an isolate from the phosphate-depleted subtropical North Atlantic Ocean, can oxidize methylphosphonate (MPn) and hydroxymethylphosphonate (HMPn), two phosphonate compounds present in marine dissolved organic matter, to obtain phosphorus. The oxidation of these phosphonates releases the methyl group as formate, which is both excreted and assimilated into purines in RNA and DNA. Genes encoding the predicted phosphonate oxidative pathway of MIT9301 were predominantly present inProchlorococcusgenomes from parts of the North Atlantic Ocean where phosphate availability is typically low, suggesting that phosphonate oxidation is an ecosystem-specific adaptation of someProchlorococcuspopulations to cope with phosphate scarcity.IMPORTANCEUntil recently, MPn was only known to be degraded in the environment by the bacterial carbon-phosphorus (CP) lyase pathway, a reaction that releases the greenhouse gas methane. The identification of a formate-yielding MPn oxidative pathway in the marine planctomyceteGimesia maris(S. R. Gama, M. Vogt, T. Kalina, K. Hupp, et al., ACS Chem Biol 14:735–741, 2019,https://doi.org/10.1021/acschembio.9b00024) and the presence of this pathway inProchlorococcusindicate that this compound can follow an alternative fate in the environment while providing a valuable source of P to organisms. In the ocean, where MPn is a major component of dissolved organic matter, the oxidation of MPn to formate byProchlorococcusmay direct the flow of this one-carbon compound to carbon dioxide or assimilation into biomass, thus limiting the production of methane.


Sign in / Sign up

Export Citation Format

Share Document