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Metabolism
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
The combustion of fatty acids, the major energy component of fats, commences with their activation to CoA derivatives such as palmitoyl CoA. Palmitoyl CoA must be first converted to palmitoylcarnitine by carnitine-palmitoyltransferase in the outer mitochondrial membrane before it can enter the mitochondrion. At the inner mitochondrial membrane, palmitoyl carnitine is reconverted to palmitoyl CoA and then oxidized by β-oxidation, which releases two carbon compounds as acetyl CoA until the entire fatty acid molecule is broken down. β-Oxidation of free fatty acids provides a major source of acetyl CoA, an important substrate for the citric acid cycle. Free fatty acids in blood, derived from the diet or by the action of lipoprotein lipase on lipoproteins at the endothelial cell layer of tissue, are oxidized in the mitochondria. Growth hormone and glucocorticoid increase the mobilization of fat stores by increasing the amount of triglyceride lipase. Initially, free fatty acid is converted to acyl CoA utilizing one ATP. Acyl CoA is oxidized to acetyl CoA, and the residual carbon atoms re-enter the cycle to produce more acetyl CoA (Figure 65.6). This partial oxidation of free fatty acids produces hydrogen ions that are removed as NADH and reduced flavoproteins.
Multiple acyl CoA dehydrogenase deficiency/glutaric aciduria type II ethylmalonic-adipic aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The fundamental molecular defect is in the mitochondrial transport of electrons from the acylCoAs to ubiquinone (CoQ10) of the main electron transport chain [5–7]. The transfer of electrons from the 2,3 positions of a number of important energy-providing substrates requires the concerted activities of the electron transfer flavoprotein (ETF), a mitochondrial matrix protein, and the electron transfer flavoprotein: Ubiquinone oxidoreductase (ETF-QO), which is an inner mitochondrial membrane protein that transfers electron to coenzyme Q in the respiratory chain. The defect may be in any of three proteins, the alpha or beta subunits of ETF or its dehydrogenase, ETF-QO (EC 1.5.5.1). Both are flavoproteins. Another designation has been IIA and IIB for defects in the α and β proteins and IIC for ETF-QO defects.
The vitamins
Published in Geoffrey P. Webb, Nutrition, 2019
Riboflavin gives rise to flavin mononucleotide and flavin adenine dinucleotide. These flavin nucleotides are essential components (prosthetic groups) of several key flavoprotein enzymes involved in oxidation-reduction reactions. These flavin nucleotides are involved in both the Krebs cycle and oxidative phosphorylation, and so riboflavin deficiency leads to a general depression of oxidative metabolism. Glutathione reductase, an enzyme involved in the disposal of free radicals, also has a flavin prosthetic group.
Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Zofia Chrienova, Eugenie Nepovimova, Rudolf Andrys, Rafael Dolezal, Jana Janockova, Lubica Muckova, Lenka Fabova, Ondrej Soukup, Patrik Oleksak, Martin Valis, Jan Korabecny, José Marco-Contelles, Kamil Kuca
Monoamine oxidases (EC 1.4.3.4) catalyse the oxidation of monoamines. These flavoproteins are bound to the outer mitochondrial membrane. In humans, there are two types of MAO: MAO-A and MAO-B. Both isoforms are abundantly present in neurons and glial cells. MAO-A is omnipresent in liver, gastrointestinal tract, or placenta, whereas MAO-B, apart from the central nervous system (CNS), is also produced by blood platelets9. The main biological role of MAO-A is the catabolism of neurotransmitters such as serotonin, epinephrine, norepinephrine, and dopamine. The activity of this enzyme increases only slightly with age10. On the other hand, MAO-B is responsible for the decomposition of phenylethylamine, benzylamine, and dopamine11. The most significant increase in MAO-B concentration is caused by the proliferation of glial cells10. Such phenomenon may thus contribute to an excessive reduction of MAO levels in the brain in the elderly. Moreover, it has been confirmed that the activity of MAO increases with the progression of AD. Within the process of amines oxidation, MAO produces aldehydes, ammonia, and hydrogen peroxide. It is particularly hydrogen peroxide that evokes the development of neuronal oxidative stress by disrupting mitochondria. Excessive MAO activation is also responsible for an increase in β- and γ-secretase expression10. Thus, not surprisingly, MAO inhibitors have been considered promising and attractive targets for the therapy of neurodegenerative diseases12,13.
Functional imaging of mitochondria in genetically confirmed retinal dystrophies using flavoprotein fluorescence
Published in Ophthalmic Genetics, 2022
Matthew W. Russell, Justin C. Muste, Kanika Seth, Madhukar Kumar, Collin A. Rich, Rishi P. Singh, Elias I. Traboulsi
Mitochondrial flavoproteins are proteins containing riboflavin derivatives that serve essential roles in mitochondrial electron transport (3,4). In a pro-oxidant environment, flavoproteins display properties of autofluorescence (FPF), emitting green light (520–540 nm) when excited by a blue spectrum light (455–470 nm) (6,7). The green emission signal can then be quantified and used as a direct marker of oxidative stress and mitochondrial dysfunction (8). FPF may be reported as intensity, a cumulative value reflecting global signal strength, and/or heterogeneity, which quantifies the variation of the relative intensity of points in the image. Together, these signals are meant to facilitate early disease detection for a given patient. Twelve peer reviewed clinical studies have demonstrated that FPF intensity and heterogeneity increase in various ocular pathologies including diabetic retinopathy, glaucoma, central serous chorioretinopathy, and AMD (8–14). Elner et al. examined FPF intensity in one patient with retinitis pigmentosa (RP) and found increased FPF intensity compared to a similarly aged control patient (12). However, this was a single case report, leaving the utility of FPF in patients with retinal dystrophies largely unknown.
Diagnostic challenges in metabolic myopathies
Published in Expert Review of Neurotherapeutics, 2020
Corrado Angelini, Roberta Marozzo, Valentina Pegoraro, Sabrina Sacconi
About 700 MADD patients have been reported all over the world [40–54,55,56,57,58,59,60,61] and over 600 were affected by RR-MADD. The mutational spectrum of RR-MADD shows various types of variants identified in the ETFDH gene. The majority are missense [55,56,57,58,59,60,61,62,63,64] mutations (73%), the other variants are frameshift (13%), splice site variations (8%), and nonsense mutations (6%) [49]. Patients presenting RR-MADD carry at least one missense variation that impair FAD binding, which plays a central role in the conformational stabilization of flavoenzymes and might change the catalytic activity and the folding of flavoprotein [62,63,64,6666,67,68,69,70]. The riboflavin supplementation likely increases the intra-mitochondrial FAD concentration, promoting FAD binding. To investigate the stability and activity of ETFDH, several studies have been performed with fibroblasts obtained from MADD patients. These studies have demonstrated an increase of protein stability, mild impairment of native folding of ETFDH, and the rescue of its enzymatic activity with riboflavin treatment.