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Ageing, Neurodegeneration and Alzheimer's Disease
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Richard J. Elsworthy, Sarah Aldred
Mitochondria are critical in the production of ATP as they are the site for oxidative phosphorylation. The oxidation of NADH and FADH2, formed in glycolysis, fatty acid oxidation and the tricarboxylic acid cycle (TCA), is used to reduce ground state molecular dioxygen to water in the electron transport chain (ETC) which traverses the inner mitochondrial membrane (Zhao et al., 2019). During this process, protons are pumped into the intramembrane space to create a pH gradient and mitochondrial membrane potential (Belenguer et al., 2019), termed the proton-motive force (Mitchell, 1966). The entry of protons back into the matrix via the ATPase enzyme enables the phosphorylation of ADP to synthesis ATP (Belenguer et al., 2019). Mitochondrial oxidative phosphorylation accounts for a large portion of ATP synthesis in the brain, and therefore, a sufficient supply of metabolites is critical for effective cellular respiration. Although predominantly associated with their role in generating ATP, mitochondria are also involved in a number of other critical cellular processes, which include programmed cell death, calcium signalling, fatty acid oxidation and the innate immune response (Scott and Youle, 2010). Therefore, the development of mitochondrial dysfunction in an ageing brain would pose a significant challenge to cell function.
Targeted Therapy for Cancer Stem Cells
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Rama Krishna Nimmakayala, Saswati Karmakar, Garima Kaushik, Sanchita Rauth, Srikanth Barkeer, Saravanakumar Marimuthu, Moorthy P. Ponnusamy
In normal or non-transformed cells, the main store of energy production is the mitochondria, where ATP is produced through the tricarboxylic acid (TCA) cycle coupled to oxidative phosphorylation. As carbon fuels such as pyruvate, glutamine, and fatty acids pass through the TCA cycle, reducing equivalents including nicotinamide adenine dinucleotide phosphate (NADH) and flavin adenine dinucleotide (FADH2) are generated that are subsequently used as electron donors for the electron transport chain (ETC). Proton motive force is generated via coupling of movement of electrons across the different complexes of the electron transport chain and is used by ATP synthase to generate ATPs.
Introduction to lactic acidemias
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
Energy conversion takes place in mitochondria in which the exergonic oxidation/reduction reactions of the electron transport chain, as in chloroplasts and bacteria, are coupled to the endergonic synthesis of adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate [14]. The electron flow generates a proton motive force. The ATP synthase is a large asymmetric enzyme complex of an F0F1 structure, in which the F0 is a hydrophobic, membrane-embedded unit that serves as a proton channel, while the F1 contains the nucleotide binding sites and catalytic sites for ATP synthesis. When solubilized and uncoupled from its F0 energy source, the F1 is capable of ATP hydrolysis, and this is why it is referred to as an ATPase.
Iron homeostasis in host and gut bacteria – a complex interrelationship
Published in Gut Microbes, 2021
Yohannes Seyoum, Kaleab Baye, Christèle Humblot
In Gram-negative bacteria, ferric-siderophore complexes are internalized via specific outer membrane (OM) receptors, a periplasmic binding protein (PBP), and an inner membrane ATP-binding cassette (ABC) transporter (Figure 4a). OM siderophore receptors are induced by iron deficiency and are consequently not present in iron-sufficient conditions. The ligand-binding sites of the receptors are specific to each siderophore. However, bacteria have multiple OM receptors, thus enabling the use of siderophores, which they are unable to synthesize themselves. Gram-negative outer membrane lacks an established ion gradient or ATP to provide the energy for transport. This energy requirement is satisfied by coupling the proton motive force of the cytoplasmic membrane to the outer membrane via three proteins, TonB, ExbB, and ExbD.58 Periplasmic binding proteins shuttle ferric-siderophores from the OM receptors to CM ATP-binding cassette (ABC) transporters, which in turn, deliver the ferric-siderophores to the cytosol where the complexes are probably dissociated by reduction.54
Emerging opportunities of exploiting mycobacterial electron transport chain pathway for drug-resistant tuberculosis drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Kuldeep K. Roy, Mushtaq Ahmad Wani
Bacteria maintain energy homeostasis by producing ATP by either substrate-level phosphorylation of fermentable carbon sources by using oxidative phosphorylation or ETC pathway [6]. Studies have revealed that Mycobacterium tuberculosis and related species are highly dependent on oxidative phosphorylation for growth because they cannot produce enough energy by substrate-level phosphorylation [6,34–36]. However, various reports have redefined the metabolic flexibility of the mycobacterium genus, and the progress in understanding the role of mycobacterial energetic targets is extensively reviewed by Cook et al [37]. Figure 1 depicts the different components of oxidative phosphorylation or the ETC pathway of Mycobacterium tuberculosis. The reducing equivalents resulted from the TCA cycle enter and pass through NDH-2 or other dehydrogenases to the menaquinone pool (MK/MKH2) in the ETC pathway. The mycobacteria employ NDH-2 or succinate dehydrogenase (SDH) [38,39] or fumarate reductase [40] to reduce the menaquinone pool. The electrons from menaquinone pool can be passed through cytochrome bcc and cytochrome aa3 or through cytochrome bd oxidase to oxygen to generate water. During the electron transfer through the ETC, protons are pumped across the membrane leading to a proton motive force (PMF), powering ATP synthase to synthesize ATP [21,36,41].
Design of α-helical antimicrobial peptides with a high selectivity index
Published in Expert Opinion on Drug Discovery, 2019
In this review, we shall mostly consider cationic linear AMPs with high selectivity and activity having at least one known or predicted amphipathic helical segment. Some natural lytic proteins, longer peptides, and bacteriocins are known to be top achievers with respect to their antibacterial activity and selectivity, but our favorites in this review will be peptides with less than 50 amino acid residues and proteinogenic amino acid residues. The focus will be on simple methods with which nature’s design can be improved by using expert knowledge, computer-guided design, and user-friendly web servers. Magainin-2 and its pexiganan (MSI-78) analogue [2] have been abundantly examined during the past 30 years [3]. They are convenient yardsticks for judging design success for other helical AMPs, either by natural evolution or by rational design. Most short AMPs, like magainins, have a random structure in an aqueous solution but are induced by bacterial-like anionic membranes to assume partially helical amphipathic conformation suitable for dynamic membrane pore formation. Subsequent short-circuits of proton transport cannot be tolerated by bacteria, which is highly dependent on creating and maintaining proton-motive force through a proton gradient and a very strong electric field. Intracellular targets for some cationic AMPs with antibiotic activity also require membrane-active peptides with the ability to interact with and pass through the cytoplasmic membrane.