scholarly journals A chemical screen for suppressors of dioxygenase inhibition in a yeast model of familial paraganglioma

2021 ◽  
Author(s):  
William Beimers ◽  
Megan Braun ◽  
Kaleb Schwinefus ◽  
Keenan Pearson ◽  
Brandon Wilbanks ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Metabolic Pathways ◽  
Hydrolysis Product ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Oxygen Species ◽  
Pharmaceutically Active Compounds ◽  
Cycle Enzyme ◽  
Chemical Screen ◽  
Yeast Model

A fascinating class of familial paraganglioma (PGL) neuroendocrine tumors is driven by loss of the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) resulting in succinate accumulation as an oncometabolite, and other metabolic derangements. Here we exploit a S. cerevisiae yeast model of SDH loss where accumulating succinate, and possibly reactive oxygen species, poison a dioxygenase enzyme required for sulfur scavenging. Using this model we performed a chemical suppression screen for compounds that relieve dioxygenase inhibition. After testing 1280 pharmaceutically-active compounds we identified meclofenoxate HCL, and its hydrolysis product, dimethylaminoethanol (DMAE), as suppressors of dioxygenase intoxication in SDH-loss cells. We show that DMAE acts to alter metabolism so as to normalize the succinate:2-ketoglutarate ratio, improving dioxygenase function. This work raises the possibility that oncometabolite effects might be therapeutically suppressed by drugs that rewire metabolism to reduce the flux of carbon into pathological metabolic pathways.

scholarly journals Inactivation of Pyruvate Dehydrogenase Kinase 2 by Mitochondrial Reactive Oxygen Species

2012 ◽  
Vol 287 (42) ◽  
pp. 35153-35160 ◽  
Author(s):  
Thomas R. Hurd ◽  
Yvonne Collins ◽  
Irina Abakumova ◽  
Edward T. Chouchani ◽  
Bartlomiej Baranowski ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Reactive Oxygen ◽  
Tca Cycle ◽  
Pyruvate Dehydrogenase Kinase ◽  
Oxygen Species ◽  
Complex Activity ◽  
Cycle Enzyme ◽  
Dehydrogenase Complex

Reactive oxygen species are byproducts of mitochondrial respiration and thus potential regulators of mitochondrial function. Pyruvate dehydrogenase kinase 2 (PDHK2) inhibits the pyruvate dehydrogenase complex, thereby regulating entry of carbohydrates into the tricarboxylic acid (TCA) cycle. Here we show that PDHK2 activity is inhibited by low levels of hydrogen peroxide (H2O2) generated by the respiratory chain. This occurs via reversible oxidation of cysteine residues 45 and 392 on PDHK2 and results in increased pyruvate dehydrogenase complex activity. H2O2 derives from superoxide (O2̇̄), and we show that conditions that inhibit PDHK2 also inactivate the TCA cycle enzyme, aconitase. These findings suggest that under conditions of high mitochondrial O2̇̄ production, such as may occur under nutrient excess and low ATP demand, the increase in O2̇̄ and H2O2 may provide feedback signals to modulate mitochondrial metabolism.

scholarly journals Reactive Oxygen Species as the Brainbox in Malaria Treatment

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1872
Author(s):  
Chinedu Ogbonnia Egwu ◽  
Jean-Michel Augereau ◽  
Karine Reybier ◽  
Françoise Benoit-Vical
Keyword(s):  
Reactive Oxygen Species ◽  
Metabolic Pathways ◽  
Reactive Oxygen ◽  
Mechanisms Of Action ◽  
Ros Generation ◽  
Oxygen Species ◽  
Pharmacological Activities ◽  
Antiparasitic Activity ◽  
Development Of Resistance ◽  
Antioxidant Machinery

Several measures are in place to combat the worldwide spread of malaria, especially in regions of high endemicity. In part, most common antimalarials, such as quinolines and artemisinin and its derivatives, deploy an ROS-mediated approach to kill malaria parasites. Although some antimalarials may share similar targets and mechanisms of action, varying levels of reactive oxygen species (ROS) generation may account for their varying pharmacological activities. Regardless of the numerous approaches employed currently and in development to treat malaria, concerningly, there has been increasing development of resistance by Plasmodium falciparum, which can be connected to the ability of the parasites to manage the oxidative stress from ROS produced under steady or treatment states. ROS generation has remained the mainstay in enforcing the antiparasitic activity of most conventional antimalarials. However, a combination of conventional drugs with ROS-generating ability and newer drugs that exploit vital metabolic pathways, such antioxidant machinery, could be the way forward in effective malaria control.

scholarly journals Host nutrient milieu drives an essential role for aspartate biosynthesis during invasiveStaphylococcus aureusinfection

2020 ◽  
Vol 117 (22) ◽  
pp. 12394-12401 ◽  
Author(s):  
Aimee D. Potter ◽  
Casey E. Butrico ◽  
Caleb A. Ford ◽  
Jacob M. Curry ◽  
Irina A. Trenary ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Aerobic Glycolysis ◽  
Bacterial Pathogen ◽  
Tca Cycle ◽  
Acid Synthesis ◽  
Tricarboxylic Acid ◽  
Staphylococcal Infection ◽  
Amino Acid Synthesis ◽  
The Tca Cycle ◽  
Host Tissues

The bacterial pathogenStaphylococcus aureusis capable of infecting a broad spectrum of host tissues, in part due to flexibility of metabolic programs.S. aureus, like all organisms, requires essential biosynthetic intermediates to synthesize macromolecules. We therefore sought to determine the metabolic pathways contributing to synthesis of essential precursors during invasiveS. aureusinfection. We focused specifically on staphylococcal infection of bone, one of the most common sites of invasiveS. aureusinfection and a unique environment characterized by dynamic substrate accessibility, infection-induced hypoxia, and a metabolic profile skewed toward aerobic glycolysis. Using a murine model of osteomyelitis, we examined survival ofS. aureusmutants deficient in central metabolic pathways, including glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, and amino acid synthesis/catabolism. Despite the high glycolytic demand of skeletal cells, we discovered thatS. aureusrequires glycolysis for survival in bone. Furthermore, the TCA cycle is dispensable for survival during osteomyelitis, andS. aureusinstead has a critical need for anaplerosis. Bacterial synthesis of aspartate in particular is absolutely essential for staphylococcal survival in bone, despite the presence of an aspartate transporter, which we identified as GltT and confirmed biochemically. This dependence on endogenous aspartate synthesis derives from the presence of excess glutamate in infected tissue, which inhibits aspartate acquisition byS. aureus. Together, these data elucidate the metabolic pathways required for staphylococcal infection within bone and demonstrate that the host nutrient milieu can determine essentiality of bacterial nutrient biosynthesis pathways despite the presence of dedicated transporters.

scholarly journals Reactive Oxygen Species, Metabolic Plasticity, and Drug Resistance in Cancer

2020 ◽  
Vol 21 (10) ◽  
pp. 3412 ◽  
Author(s):  
Vikas Bhardwaj ◽  
Jun He
Keyword(s):  
Reactive Oxygen Species ◽  
Cancer Cells ◽  
Reactive Oxygen ◽  
Tca Cycle ◽  
Metabolic Adaptation ◽  
Oxygen Species ◽  
Metabolic Plasticity ◽  
The Tca Cycle ◽  
Clinical Benefits ◽  
High Level

The metabolic abnormality observed in tumors is characterized by the dependence of cancer cells on glycolysis for their energy requirements. Cancer cells also exhibit a high level of reactive oxygen species (ROS), largely due to the alteration of cellular bioenergetics. A highly coordinated interplay between tumor energetics and ROS generates a powerful phenotype that provides the tumor cells with proliferative, antiapoptotic, and overall aggressive characteristics. In this review article, we summarize the literature on how ROS impacts energy metabolism by regulating key metabolic enzymes and how metabolic pathways e.g., glycolysis, PPP, and the TCA cycle reciprocally affect the generation and maintenance of ROS homeostasis. Lastly, we discuss how metabolic adaptation in cancer influences the tumor’s response to chemotherapeutic drugs. Though attempts of targeting tumor energetics have shown promising preclinical outcomes, the clinical benefits are yet to be fully achieved. A better understanding of the interaction between metabolic abnormalities and involvement of ROS under the chemo-induced stress will help develop new strategies and personalized approaches to improve the therapeutic efficiency in cancer patients.

scholarly journals Modulation of Obesity and Insulin Resistance by the Redox Enzyme and Adaptor Protein p66Shc

2019 ◽  
Vol 20 (4) ◽  
pp. 985 ◽  
Author(s):  
Stefano Ciciliot ◽  
Gian Fadini
Keyword(s):  
Insulin Resistance ◽  
Reactive Oxygen Species ◽  
Metabolic Pathways ◽  
Adaptor Protein ◽  
Oxygen Species ◽  
Related Protein ◽  
Redox Enzyme ◽  
Obesity And Diabetes ◽  
Promising Therapeutic Target

Initially reported as a longevity-related protein, the 66 kDa isoform of the mammalian Shc1 locus has been implicated in several metabolic pathways, being able to act both as an adaptor protein and as a redox enzyme capable of generating reactive oxygen species (ROS) when it localizes to the mitochondrion. Ablation of p66Shc has been shown to be protective against obesity and the insurgence of insulin resistance, but not all the studies available in the literature agree on these points. This review will focus in particular on the role of p66Shc in the modulation of glucose homeostasis, obesity, body temperature, and respiration/energy expenditure. In view of the obesity and diabetes epidemic, p66Shc may represent a promising therapeutic target with enormous implications for human health.

scholarly journals Systems-Level Metabolic Flux Profiling Elucidates a Complete, Bifurcated Tricarboxylic Acid Cycle in Clostridium acetobutylicum

2010 ◽  
Vol 192 (17) ◽  
pp. 4452-4461 ◽  
Author(s):  
Daniel Amador-Noguez ◽  
Xiao-Jiang Feng ◽  
Jing Fan ◽  
Nathaniel Roquet ◽  
Herschel Rabitz ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Genome Annotation ◽  
Clostridium Acetobutylicum ◽  
Metabolic Flux ◽  
Tricarboxylic Acid Cycle ◽  
Anaerobic Bacteria ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Fermentation Products

ABSTRACT Obligatory anaerobic bacteria are major contributors to the overall metabolism of soil and the human gut. The metabolic pathways of these bacteria remain, however, poorly understood. Using isotope tracers, mass spectrometry, and quantitative flux modeling, here we directly map the metabolic pathways of Clostridium acetobutylicum, a soil bacterium whose major fermentation products include the biofuels butanol and hydrogen. While genome annotation suggests the absence of most tricarboxylic acid (TCA) cycle enzymes, our results demonstrate that this bacterium has a complete, albeit bifurcated, TCA cycle; oxaloacetate flows to succinate both through citrate/α-ketoglutarate and via malate/fumarate. Our investigations also yielded insights into the pathways utilized for glucose catabolism and amino acid biosynthesis and revealed that the organism's one-carbon metabolism is distinct from that of model microbes, involving reversible pyruvate decarboxylation and the use of pyruvate as the one-carbon donor for biosynthetic reactions. This study represents the first in vivo characterization of the TCA cycle and central metabolism of C. acetobutylicum. Our results establish a role for the full TCA cycle in an obligatory anaerobic organism and demonstrate the importance of complementing genome annotation with isotope tracer studies for determining the metabolic pathways of diverse microbes.

scholarly journals Emerging Role of TCA Cycle-Related Enzymes in Human Diseases

2021 ◽  
Vol 22 (23) ◽  
pp. 13057
Author(s):  
Woojin Kang ◽  
Miki Suzuki ◽  
Takako Saito ◽  
Kenji Miyado
Keyword(s):  
Metabolic Pathways ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Human Diseases ◽  
Comprehensive Overview ◽  
Cellular Energy ◽  
Neurometabolic Disorders ◽  
Related Enzyme ◽  
The Relationship

The tricarboxylic acid (TCA) cycle is the main source of cellular energy and participates in many metabolic pathways in cells. Recent reports indicate that dysfunction of TCA cycle-related enzymes causes human diseases, such as neurometabolic disorders and tumors, have attracted increasing interest in their unexplained roles. The diseases which develop as a consequence of loss or dysfunction of TCA cycle-related enzymes are distinct, suggesting that each enzyme has a unique function. This review aims to provide a comprehensive overview of the relationship between each TCA cycle-related enzyme and human diseases. We also discuss their functions in the context of both mitochondrial and extra-mitochondrial (or cytoplasmic) enzymes.

scholarly journals Reactive Oxygen Species: Its Effects on various Diseases

2013 ◽  
Vol 3 (1) ◽  
pp. 132-134
Author(s):  
Avinash Marwal ◽  
Sandeep S Verma ◽  
Swati Trivedi ◽  
Rajneesh Prajapat
Keyword(s):  
Reactive Oxygen Species ◽  
Metabolic Pathways ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Free Electrons ◽  
Cell Organelles ◽  
Pathologic Processes ◽  
Independent Existence

A free radical is any molecule capable of independent existence that contains one or more free electrons. These free radicals fall under the broader category of reactive oxygen species (ROS). ROS such as O2- , H2O2, NO-, OH-, HOCl, ONOO- are toxic to cells. ROS act largely by driving several important molecular pathways that play important roles in pathologic processes including neurodegeneration. injury, atherosclerosis, and inflammatory responses and ischemia-reperfusion. ROS, as in various radicals ions leads to mitochondrial dysfunction and consequently other cell organelles damage either through environmental effect or through genetic or metabolic disorders. Reactive molecular species also disturbs other metabolic pathways in a manner that cell’s normal functionality gets disrupted. Though diseases caused by reactive oxygen species are many, this review has covered its effect on major diseases. The present review paper will provide the detail of mechanism of ROS and its effect on different pathological states.  

scholarly journals The Role of CYP2E1 in the Drug Metabolism or Bioactivation in the Brain

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
W. A. García-Suástegui ◽  
L. A. Ramos-Chávez ◽  
M. Rubio-Osornio ◽  
M. Calvillo-Velasco ◽  
J. A. Atzin-Méndez ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Free Radical ◽  
Metabolic Pathways ◽  
The Body ◽  
Oxygen Species ◽  
Brain Disorders ◽  
Toxic Agents ◽  
Major Organ ◽  
The Brain

Organisms have metabolic pathways that are responsible for removing toxic agents. We always associate the liver as the major organ responsible for detoxification of the body; however this process occurs in many tissues. In the same way, as in the liver, the brain expresses metabolic pathways associated with the elimination of xenobiotics. Besides the detoxifying role of CYP2E1 for compounds such as electrophilic agents, reactive oxygen species, free radical products, and the bioactivation of xenobiotics, CYP2E1 is also related in several diseases and pathophysiological conditions. In this review, we describe the presence of phase I monooxygenase CYP2E1 in regions of the brain. We also explore the conditions where protein, mRNA, and the activity of CYP2E1 are induced. Finally, we describe the relation of CYP2E1 in brain disorders, including the behavioral relations for alcohol consumption via CYP2E1 metabolism.

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