For The Want of a Nail … Trace Elements in Health and Disease
Owen M. Rennert, Wai-Yee Chan in Metabolism of Trace Metals in Man, 2017
With a few exceptions, enzymes have iron as part of the active center if they are involved in redox reactions. The participation of iron in the enzyme aconitase, a key step in respiration via the Krebs cycle, is significant. Histidine decarboxylase converts this amino acid to histamine in an iron mediated reaction. In all redox reactions, iron shuttles back and forth between its oxidized and reduced forms, Fe3+ and Fe2+, respectively. Iron in biological systems is primarily responsible for the generation of metabolic energy through the oxidative respiration of mitochondria. Both cytochromes and nonheme iron proteins participate directly in the linkage of electron transport to ATP synthesis within the cells. Some biochemical pathways require iron to shuttle electrons, activate oxygen, and substitute hydroxyl groups in the synthesis of essential intermediates.
Effector Mechanisms for Macrophage-Induced Cytostasis and Cytolysis of Tumor Cells
Gloria H. Heppner, Amy M. Fulton in Macrophages and Cancer, 2019
As shown in Figure 10, aconitase was inhibited prior to inhibition of complex I and complex II of the mitochondrial electron-transport system. However, inhibition of aconitase activity may not have a significant effect on mitochondrial respiration and ATP synthesis. As shown in Table 1, aconitase activity was completely inhibited in target cells that had been co-cultivated with activated macrophages for 6 hr, but endogenous coupled and uncoupled respiration was unchanged from that measured in control target cells.44 These results suggest that a citric acid cycle block at the level of aconitase, which occurs early in the cocultivation period, does not inhibit mitochondrial respiration and that as long as complex I and complex II are still functional, endogenous substrates are able to circumvent the aconitase block. However, after 24 hr of co-cultivation of target cells, both endogenous coupled and uncoupled respiration was markedly inhibited. In addition, when complex I and complex II becomes inhibited, the cell loses 95% of its energy production potential. This would lead to cell death unless compensated for by increased glycolysis and the presence of high glucose in the medium. We propose that the observed variation in time to the expression of death is a function of how long the cell can survive on this severely limited energy production and its ability to restore respiratory function (or initiate glycolysis) when macrophages can no longer produce the appropriate effector molecules resulting in iron release.
Antioxidant Supplements and Exercise Adaptations
James N. Cobley, Gareth W. Davison in Oxidative Eustress in Exercise Physiology, 2022
Elevated cellular concentrations of ROS/RNS may impair selective redox-sensitive pathways of energy metabolism. For instance, hydrogen peroxide (H2O2) and peroxynitrite (ONOO–) can inhibit glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity by reacting directly with the active site thiol, thus potentially impairing glycolysis (Quijano et al., 2016). Further, ROS can impair activity of the enzyme aconitase by releasing an Fe atom from an Fe-S cluster that functions as a Lewis acid during catalysis in the tricarboxylic acid cycle, potentially diminishing the supply of reducing agents to the electron transport chain and thus diminishing the rate of ROS production (Quijano et al., 2016). Elevated ROS and RNS may also reduce beta-oxidation efficiency through the generation of nitro-fatty acids that can undergo beta-oxidation in the mitochondria (Quijano et al., 2016). Despite the known interplay between oxidants and energy metabolism, effects of elevated ROS/RNS on these pathways of energy metabolism during exercise are unclear. Moreover, effects of antioxidants on energy metabolism pathways have been scarcely explored in the context of acute exercise or exercise training adaptations. Effects of exogenous antioxidants on substrate metabolism are likely complex and will depend on the specific antioxidant compound, its bioavailability, and dosing regimen administered.
A metabolomic study on the anti-depressive effects of two active components from Chrysanthemum morifolium
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Tong Liu, Ning Zhou, Ruihao Xu, Yangang Cao, Yanli Zhang, Zhen Liu, Xiaoke Zheng, Weisheng Feng
A systematic review and meta-analysis found that oxidative stress is elevated in major depressive disorders [34]. Meanwhile, evidence that successful anti-depressant treatment may improve oxidative stress status [35]. As shown in Figure 6, citric acid is catalyzed by aconitase to form cis-aconitic acid [36]. cis-Aconitic acid is related to oxidative stress. During stages of electrophilic stress, cis-aconitic acid can react with superoxide to form ˙OH, rendering them inactive [37]. After the administration of Chr/Nar, the level of citric acid did not increase, while the level of cis-aconitic acid increased significantly and indicated that Chr and Nar may convert more citric acid into cis-aconitic acid by promoting the expression of aconitase to ameliorates the deficiency of cis-aconitic acid secretion in depressed mice. Therefore, Chr/Nar could promote the expression of aconitase to improve oxidative stress of depressed mice.
Multi-organ system failure secondary to difluoroethane toxicity in a patient “huffing” air duster: a case report
Published in Journal of Addictive Diseases, 2022
Benjamin Fogelson, David Qu, Milind Bhagat, Paul R Branca
Biochemically, 1,1-difluoroethane has the potential to affect any organ system and cause multi-organ system failure. The mechanism of organ injury is primarily due to fluorocitrate accumulation.18 Difluoroethane is metabolized into fluoroacetate and then converted to fluorocitrate by the citric acid cycle in place of acetate.18 Through competitive inhibition of aconitase, fluorocitrate prevents the conversion of citrate to isocitrate, ultimately disrupting cellular energy production.18 Kumar et al. presented a case of 1,1-difluoroethane induced acute myocardial injury with concomitant acute liver failure and renal injury in a patient with a two-day history of “huffing” household aerosol products.14 Our patient, with at least a three-month history of daily “huffing” air duster, presented with multi-organ system failure with evidence of myocardial injury, hepatic failure, and acute kidney injury with severe metabolic acidosis. Additionally, our patient was found to have severe hypocalcemia associated with her acute renal failure and 1,1-difluoroethane toxicity. The mechanism of profound hypocalcemia in patients with 1,1-difluoroethane toxicity is secondary to chelation of calcium by isocitrate.18 Fortunately, our patient recovered from her metabolic derangements and end organ damage with aggressive fluid resuscitation, bicarbonate infusion, and electrolyte replacement.
Cardioprotective effect of rosmarinic acid against myocardial ischaemia/reperfusion injury via suppression of the NF-κB inflammatory signalling pathway and ROS production in mice
Published in Pharmaceutical Biology, 2021
Wei Quan, Hui-xian Liu, Wei Zhang, Wei-juan Lou, Yang-ze Gong, Chong Yuan, Qing Shao, Na Wang, Chao Guo, Fei Liu
The body’s oxidative function can be reflected by changes in ROS. ROS determination can be used to measure oxidative tissue and cell damage (Qiu et al. 2019), and previous studies have reported that RosA has a powerful antioxidation effect. Thus, DHE-ROS was adopted to detect the oxidation state of myocardial tissue and cells. Simply stated, the DHE-ROS detection kit detects active oxygen utilizing the fluorescent probe dihydroethidium. DHE is freely accessible to the cell through the living cell membrane and is oxidized by ROS in the cell to form ethidium oxide, which can mix with chromosomal DNA to produce red fluorescence. It is possible to estimate the amount of ROS and change in its content in cells according to the red fluorescence produced in living cells (Hardy et al. 2015). Accordingly, the obtained results demonstrated that RosA could reduce ROS generation in the myocardial I/R injury area and after cell OGD/R injury. Aconitase (ACO) is an important iron-sulfur (Fe-S) protease in cells that is attacked by ROS when its Fe-S active centre undergoes I/R injury, leading to ACO oxidative inactivation (Lou et al. 2014). According to aconitase detection, RosA was found to alleviate oxidative inactivation of ACO in the myocardial I/R injury area in mice and after cell OGD/R injury. The above experiments verified that the myocardial protective effect of RosA is closely correlated with a reduction in ROS generation.
Related Knowledge Centers
- Aconitic Acid
- Active Site
- Citric Acid
- Isocitric Acid
- Isomerization
- Stereochemistry
- Citric Acid Cycle
- Redox
- N-Terminus
- C-Terminus