Superoxide Dismutase, Mitochondrial Dysfunction, and Neurodegenerative Diseases
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
Like all SODs, a systematic proton relay is thought to exist at the active site for IC-CuZnSOD. Of note, IC-CuZnSOD and MnSOD are believed to have evolved independently, representing examples of convergent evolution where both enzymes adopted different but highly efficient proton shuttles [70]. The principal use of the proton transfers is to drive electron transfers (i.e., redox reactions) by changing the charge at the active site in addition to protonating O2•– to H2O2 [69,70,72]. The efficiency of the proton transfers and electron transfers for IC-CuZnSOD is represented by the rate of 2 × 109 M-1 s-1. This rate exceeds “diffusion controlled” rates at physiological pH, in part due to electrostatic guidance of the substrate to the active site [69,70]. An orderly series of proton transfers contribute to the extreme catalytic efficiency of IC-CuZnSOD, though the series of transfers is unclear due to difficulty in probing protons.
Experimental Strategies
Clive R. Bagshaw in Biomolecular Kinetics, 2017
Protonation reactions are ubiquitous. In considering a ligand binding to a protein, not only is the ionization state of the ligand important, but also the ionization state of the residues at the active site and more distant residues that control protein structure. As a result, working backward from the observed pK for ligand binding to the ionization state of a specific functional group on the ligand or protein is often difficult. NMR methods provide the least ambiguous approach to assignments because, in favorable cases, individual residues are resolved in the spectrum, and their pH dependence is observed directly. The assignment of pK values from kinetic and equilibrium data alone has received considerable discussion and cautionary warnings [11,43,388].
Structural Aspects of Luteinizing Hormone Actions
Mario Ascoli in Luteinizing Hormone Action and Receptors, 2019
The imidazole group on histidine has a pK. in proteins in the range 6.5 to 7.1; thus it is one of the few functional groups that may actually change its degree of protonation under physiological conditions. For this reason it may be subject to useful physiological modulation as, for example, in enzyme active sites. Among the lutropin molecules, only two histidine residues are invariant, and these are at positions 83 and 94 on the α-subunit (Figure 1). The histidine at residue 87 on this subunit is present in all but the equine α-subunit, where there is a tyrosine-histidine transposition between positions 87 and 93.79
New cyclopentaquinoline and 3,5-dichlorobenzoic acid hybrids with neuroprotection against oxidative stress for the treatment of Alzheimer’s disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Kamila Czarnecka, Małgorzata Girek, Paweł Kręcisz, Robert Skibiński, Kamil Łątka, Jakub Jończyk, Marek Bajda, Piotr Szymczyk, Grzegorz Galita, Jacek Kabziński, Ireneusz Majsterek, Alba Espargaró, Raimon Sabate, Paweł Szymański
Corina online (Molecular Networks and Altamira) was used to create three-dimensional structures of compounds, that were then prepared using Sybyl 8.0 (Tripos). Protonation states were inspected, hydrogen atoms were added, atom types were checked and Gesteiger-Marsili charges were assigned. All ligands were docked to acetylcholinesterase from 2CKM and to butyrylcholinesterase based on a 1P0I crystal structure using GoldSuite 5.1 (CCDC). Before docking, the proteins were prepared in the following way: all histidine residues were protonated at Nε, the hydrogen atoms were added, ligand and water molecules were removed; the binding site was defined as all amino acid residues within 10 Å from bis-(7)-tacrine for AChE, and 20 Å from the glycerol molecule for BuChE. A standard set of genetic algorithms with a population size of 100, number of operations 100 000, and clustering with a tolerance of 1 Å was applied. After docking process, 10 ligand poses, sorted by GoldScore (for AChE) and ChemScore (for BuChE) were obtained. The results were visualised by PyMOL 0.99rc6 (DeLano Scientific LLC).
Constructing new acid-activated anticancer peptide by attaching a desirable anionic binding partner peptide
Published in Journal of Drug Targeting, 2022
Yun Zhang, Linlin Chang, Hexin Bao, Xiaoyan Wu, Hui Liu, Sanhu Gou, Jingying Zhang, Jingman Ni
LK (LKKLLKLLKKLLKL-NH2) is a cationic α-helical peptide of 14 amino acids. It is effective against tumour cells by disrupting their cell membrane [37]. However, this peptide causes remarkable damage to normal cells at concentrations close to the effective one, which greatly narrows its therapeutic index. In a previous study, a new pH-responsive ACP was designed with a histidine modification strategy by using the acidic tumour microenvironment as a trigger to increase the selectivity of LK [37]. Consequently, protonation could occur to obtain a net positive charge in the acidic tumour microenvironment, in contrast to the predominance of no charge under normal physiological conditions. The newly designed histidine-rich peptide L9H5-1 showed an excellent pH-responsive antitumor activity with a reduced cytotoxic effect compared with that of LK [37]. Thus, pH-triggered charge conversion enabled by introducing histidine may be an effective method to improve LK selectivity.
Chitosan-biotin topical film: preparation and evaluation of burn wound healing activity
Published in Pharmaceutical Development and Technology, 2022
Faisal Al-Akayleh, Nisrein Jaber, Mayyas Al-Remawi, Ghazi Al Odwan, Nidal Qinna
In the current work, CS was dissolved in 0.1 N HCl. In such an acidic environment, CS molecules will acquire positive charges due to the protonation of the amino groups, NH3+, along the chitosan backbone. On the other hand, BIO acquires a negative charge by dissolving it in an aqueous sodium bicarbonate solution (HBIO-). Therefore, when the two solutions were added to each other, there is likely to be an electrostatic interaction between the protonated amino groups of chitosan NH3+ with the negatively charged biotin anion (HBIO-). Such proposed interaction was confirmed by FTIR and DCS studies. Figure 1 shows the FTIR spectra of CS, CS/BIO composite film, and BIO. The spectra of CS showed the bending bands of amine, asymmetric (N–H) at 1655 cm−1 and symmetric (N–H) at 1540 cm−1. However, BIO has a stretch band of (C = O) vibration of carboxylic acid at 1735 cm−1 that was shifted in CS/BIO composite film is at 1712 cm−1. This shift is consistent with the partial delocalization that occurred in the carboxylate ion of BIO. The new peaks at 1712 and 1625 cm−1 of CS/BIO are assigned to stretching (C = O) of the carboxylate group and bending (N–H) of ammonium ion, respectively. This suggested that BIO and CS may develop ionic interaction (Mauricio-Sánchez et al. 2018; Ji et al. 2018; Barbosa and Cavalheiro 2019, Jaber et al 2021).
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