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Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
Ketone bodies acetoacetate and 3-hydroxybutyric acid are metabolites derived from fatty acids and ketogenic amino acids, such as leucine. They are mainly produced in the liver, via reactions catalysed by the ketogenic enzymes HMG CoA synthase and HMG CoA lyase. After prolonged starvation, ketone bodies can provide up to two-thirds of the brain’s energy requirements. The rate-limiting enzyme of ketone body utilisation (ketolysis) is succinylcoenzyme A: 3-oxoacid coenzyme A transferase. The subsequent step of ketolysis is catalysed by 2-methylactoacetyl-coenzyme A thiolase (beta-ketothiolase), which is also involved in isoleucine catabolism.
Lower-intensity aerobic endurance sports
Published in Nick Draper, Helen Marshall, Exercise Physiology, 2014
In the second reaction of β oxidation the addition of water hydrates the transenoyl CoA molecule to form 3-hydroxyacyl CoA; this is catalysed by the enzyme enoyl CoA hydratase. The third reaction is similar to the first in that the enzyme, in this case 3-hydroxyacyl CoA dehydrogenase, catalyses the removal of two hydrogen atoms, but the carrier in this instance is NAD+. In the final reaction, CoA is attached to the final two carbon atoms during their split from the acyl CoA molecule, creating acetyl CoA. This reaction is catalysed by acyl CoA thiolase. The newly formed acetyl CoA molecule is then available to enter Krebs cycle while the new acyl CoA molecule re-enters the β oxidation cycle. For the process of β oxidation to continue, FAD and NAD+ must be regenerated. This occurs through the transfer of electrons from FADH2 and NADH to the electron transport chain. In common with the Krebs cycle and the ETC, therefore, β oxidation is an oxygen-dependent process.
Alternate Pathways of Steroid Biosynthesis and the Origin, Metabolism, and Biological Effects of Ring B Unsaturated Estrogens
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
B. R. Bhavnani, C. A. Woolever
Three molecules of acetic acid in the form of acetyl-CoA (coenzyme A) thioester condense to form mevalonic acid (Figure 2). All of the intermediates involved are bound to coenzyme A, and the required enzymes are present in both the cytoplasmic particles and the soluble fraction of mammalian and avian liver3–6 and in yeast.7,8 The first step, catalyzed by a soluble enzyme β-keto-thiolase, results in the formation of acetoacetyl-CoA. In the presence of 3-hydroxy-3-methyl-glutaryl-CoA synthase (which is located in the mitochondria and the soluble fraction of liver9,10 but not in the microsomal fraction as had been reported previously11,12), the acetoacetyl-CoA condenses with a third molecule of acetyl-CoA to give 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA), the immediate precursor of mevalonic acid. The reduction of this precursor to mevalonic acid is catalyzed by mevalonate: NADP+ oxidoreductase (EC 1.1.1.34), which is present in both yeast mitochondria13 and in the mammalian liver microsomes.14,15 This microsomal system is thought to be the rate-limiting step in the biosynthesis of cholesterol in mammalian liver.12,16,17 Although this scheme is generally believed to be the major pathway of mevalonate biosynthesis, an alternate minor pathway involving malonyl-CoA has been described by Brodie et al.18,19 The mechanisms involved in these transformations have been recently reviewed by Beytia and Porter.20
A comprehensive proteomics analysis of the response of Pseudomonas aeruginosa to nanoceria cytotoxicity
Published in Nanotoxicology, 2023
Lidija Izrael Živković, Nico Hüttmann, Vanessa Susevski, Ana Medić, Vladimir Beškoski, Maxim V. Berezovski, Zoran Minić, Ljiljana Živković, Ivanka Karadžić
The upregulation of several enzymes involved in lipid catabolism through the β-oxidation of fatty acids were found: acetyl-CoA acetyltransferase, acyl-CoA dehydrogenase, acyl-CoA thiolase, and long-chain-fatty-acid-CoA ligase (Table 1), suggesting increased generation of acetyl-CoA, which enters the citric acid cycle, and NADH and FADH2 that are used for further oxidation and energy production. Interestingly, dihydrolipoyl dehydrogenase, which contains lipoamide as a cofactor, was downregulated, indicating reduced synthesis of lipid structures. Impaired structures and reduced biosynthesis of fatty acids and lipids in association with ROS that cause lipid peroxidation in P. aeruginosa produce a strong effect on maintaining bacterial cell integrity, primarily through the effects on membrane phospholipids, lipidated membrane proteins that are tightly connected to transport machinery, and lipopolysaccharides of the outer membrane, responsible for permeability. Notably, even the intact outer membrane of P. aeruginosa has low permeability to various compounds, not only toxic, but also nutritional substrates (Tamber, Ochs, and Hancock 2006).
Antinociceptive effect of ranolazine and trimetazidine
Published in Expert Review of Cardiovascular Therapy, 2021
Trimetazidine can be preferred with its low side effect profile in the treatment of patients with persistent angina who are not suitable for percutaneous and surgical revascularization. Trimetazidine (1-2,3,4-trimethoxybenzyl piperazine dihydrochloride), a member of the 3-ketoacyl coenzyme A class of thiolase inhibitors, is a metabolic modulator. It inhibits the β-oxidation of fatty acids; increases myocardial glucose utilization, prevents a decrease in ATP and phosphocreatine levels in response to hypoxia or ischemia; It minimizes free radical production and protects against intracellular calcium overload and acidosis. The most common side effects of trimetazidine are nausea, vomiting, tiredness, dizziness and muscle pain. The drug may increase extrapyramidal stiffness, bradykinesia, and tremor by inducing Parkinson’s symptoms. Although the mechanism responsible for these reactions is unknown, it is thought that trimetazidine is a piperazine derivative and causes such side effects because it causes blockage of central D2 dopamine receptors [16].
The development and hepatotoxicity of acetaminophen: reviewing over a century of progress
Published in Drug Metabolism Reviews, 2020
Mitchell R. McGill, Jack A. Hinson
Immunoblot analysis using anti-nitrotyrosine antibody indicated nitration affected a number of specific proteins (Hinson et al. 2000) and later subcellular fractionation revealed that nitration occurs primarily on mitochondrial proteins (Cover et al. 2005). Since nitration had been reported to occur specifically on the mitochondrial protein manganese superoxide dismutase (MnSOD) in renal cells (MacMillan-Crow et al. 1996), the possible nitration of this protein in the liver was investigated in mice treated with APAP (Agarwal et al. 2010). MnSOD is a critical mitochondrial antioxidant enzyme that detoxifies superoxide and thus prevents peroxynitrite formation within the mitochondria (Macmillan-Crow and Cruthirds 2001). A dose-responsive decrease in MnSOD activity was observed after treatment with APAP at 100, 200, and 300 mg/kg. Immunoprecipitation of MnSOD from livers of APAP-treated mice followed by Western blot analysis revealed nitrated MnSOD. APAP-MnSOD adducts were not detected (Agarwal et al. 2010). Thus, a vital enzyme preventing peroxynitrite formation in APAP toxicity was inhibited. In addition to MnSOD, other nitrated mitochondrial and cytosolic proteins have been more recently identified: mitochondrial aldehyde dehydrogenase, GSH peroxidase, ATP synthase, and 3-ketoacyl-CoA thiolase (Abdelmegeed et al. 2013).