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Free Radicals and Antioxidants
Published in Chuong Pham-Huy, Bruno Pham Huy, Food and Lifestyle in Health and Disease, 2022
Chuong Pham-Huy, Bruno Pham Huy
Copper (Cu) is an essential trace element for the human body, which contains approximately 100 mg Cu (209–212). Copper is a redox active metal in aqueous solution. In biological systems copper can exist in two ionic forms: Cu2+ and Cu1+, which are dominant in the extracellular oxidative and intracellular reductive environment, respectively (210). Copper is a cofactor of many copper redox enzymes such as ceruloplasmin, superoxide dismutase, and cytochrome C oxidase. Ceruloplasmin is a Cu-dependent ferroxidase enzyme, while superoxide dismutase is a strong antioxidant enzyme which is responsible for eliminating the superoxide anion, and cytochrome C oxidase is the terminal oxidase of cellular respiration (15, 111, 209). The ionic conversion between Cu2+ and Cu1+ provides a rich and potent redox reaction, acting as a reactive center for many critical enzymatic catalytic reactions which are important for numerous vital biological processes (211). Cu ions are delivered to the sites of utilization by special proteins called copper chaperones which are important components of the Cu metabolism (210).
A Brief Background
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Reactions of organic molecules are, for the most part, governed by the presence of heteroatoms. They have the ability to disturb the electron density within the local area of the hydrocarbon skeleton and therefore create a reactive centre. The positioning and nature of the bonding of heteroatoms in organic molecules are identified as functional groups, which will undergo characteristic reactions.
Physiology, Biochemistry, and Pathology of Neuromuscular Transmission
Published in Marc H. De Baets, Hans J.G.H. Oosterhuis, Myasthenia Gravis, 2019
There are three classes of substances that block AChE. The first class blocks in a competitive manner at the anionic site of the enzyme. Edrophonium, which is used as a diagnostic test in myasthenia gravis, belongs to this class. The second class are the carbamates, for instance neostigmine and pyridostigmine, which react chemically with the active center of the enzyme. The carbamyl group of these drugs gets covalently attached to the active site; the active site is regenerated by hydrolysis only very slowly (cf. Figure 10). The third class is formed by the organophosphates which comprises compounds that are produced as insecticides (e.g., parathion) and nerve gases (e.g., tabun). These substances also react with the reactive center of the AChE in the same way as carbamates (a phosphate derivative is attached to the active center), the main difference being that the enzyme-phosphate bond cannot be hydrolyzed spontaneously, so that the enzyme activity does not recover (see Figure 10).
Granzyme B as a therapeutic target: an update in 2022
Published in Expert Opinion on Therapeutic Targets, 2022
Alexandre Aubert, Michael Lane, Karen Jung, David J. Granville
Murine Serpina3N (Serine peptidase inhibitor, Clade A, Member 3 N hereafter referred to as SA3N) is a 44–55 kDa member of the Serpin superfamily of serine protease inhibitors that has been identified as an inhibitor of extracellular human GzmB [88]. It shares 61% amino-acid homology with its human ortholog SERPINA3, also known as α-1-antichymotrypsin (ACT), that is not a GzmB inhibitor because they do not physically interact [89]. Interestingly, the incorporation of a SA3N reactive center loop into ACT by site-directed mutagenesis (P1Leu>Met, P3Tyr>Val and P4ʹVal>Leu) creates a human chimeric protein that can bind human GzmB, leading to the inhibition of its pro-apoptotic activity in vitro [90]. However, SA3N is not specific to GzmB, as it also inhibits the proteolytic activity of neutrophil elastase, neutrophil cathepsin G, mast cell chymase, pancreatic chymotrypsin, and MMP-9 [91]. While SA3N overexpression attenuates murine GzmB cleavage of decorin in a model of abdominal aortic aneurysms [92] and accelerates wound healing in a diabetic skin ulcer model [33], immunogenicity due to its murine origin as well as lack of specificity renders the use of SA3N as a GzmB-targeting drug very challenging. As SA3N has roles and implications in a variety of models that have already been discussed by others [3,91], the following section will only focus on the most recent findings.
Genetic Study of Hereditary Angioedema Type I and Type II (First Report from Iranian Patients: Describing Three New Mutations)
Published in Immunological Investigations, 2022
Susan Nabilou, Fatemeh Pak, Zahra Alizadeh, Mohammad Reza Fazlollahi, Masoud Houshmand, Maryam Ayazi, Iraj Mohammadzadeh, Mohammad Hasan Bemanian, Abbas Fayezi, Mohammad Nabavi, Shiva Saghafi, Sajedeh Mohammadian, Parviz Kokhaei, Mostafa Moin, Zahra Pourpak
C1-INH is regarded as the serine protease inhibitor which controls the complement, contact, coagulation, and fibrinolytic systems. C1-INH deficiency removes the inhibitory effect of kallikrein activation, which results in increasing levels of bradykinin in the contact system proteases and vascular permeability leading to edema (Kaplan and Joseph 2016). C1-INH is a secretary protein comprising nine α-helices and three β-sheets with a reactive center loop (RCL) which protrude outside of the molecule. RCL is located in the conserved C-terminal domain which can bind to the target protease with essential residues P1-P1´ (Arg466-Thr467) (Davis 1989). C1-INH can non-covalently bind to other proteins, cell surfaces, and lipids by its glycosylated N-terminal. The N-terminal domain of C1-INH is essential for being stable in plasma (Johnsrud et al. 2015). C1-INH gene (C1NH, SERPING1; OMIM #606860, NM_000062.2) is located on chromosome 11q12q 13.1, and comprises eight exons (one non-coding exon and seven coding exons).(Carter et al. 1991; Johnsrud et al. 2015). To date, more than 570 mutations (Human Genome Mutation Database, http://www.hgmd.cf.ac.uk/ac) including nucleotide substitution, small insertion, small deletions to large deletions, and duplications (HAEdb, http://www.hae.enzim.hu) have been identified leading to reduced levels or activity of C1-INH.
Granzyme B as a therapeutic target for wound healing
Published in Expert Opinion on Therapeutic Targets, 2019
Christopher T. Turner, Sho Hiroyasu, David J. Granville
Serpins are serine protease inhibitors belonging to the largest protease inhibitor superfamily [95]. Inhibitory serpins form enzymatically inactive and irreversible stoichiometric complexes, where substrate binding to the reactive center loop triggers irreversible protease inhibition and a cleaved C-terminal fragment [96]. Of the 35 human serpins, three can inhibit granzymes, including serpinb9 which specifically inhibits granzyme B [41]. However, serpinb9 only inhibits granzyme B internally within cells and is therefore unlikely to be function outside the cell due to oxidation sensitivity [41]. Additional granzyme inhibitors, however, have been identified in mice (serpinb9b and serpina3n). Of these, only serpina3n, a mouse orthologue of human anti-chymotrypsin that is not found in humans, has been identified in vitro as an inhibitor of both mouse and human granzyme B [97]. Unlike in humans where a single-gene encodes anti-chymotrypsin, in mice, there is a cluster of 13 closely related genes at the same locus resulting from repeated duplications [98]. The role of serpina3n in disease pathogenesis has been evaluated in a variety of mouse models of disease, with these discussed below.