ENZYME-CATALYZED REACTIONS
David M. Gibson, Robert A. Harris in Metabolic Regulation in Mammals, 2001
Each enzyme possesses an external region designated the "active site" where the specific reactants (substrates) bind tightly but reversibly. Depending on the concentrations of the substrates and of the enzyme the amount of an "enzyme-substrate complex" formed in this very rapici equilibration ordinarily will determine the rate at which the réaction will proceed. The active sites are physical templates constructed w ith certain of the projecting amino acid side chains of the enzyme. These create the three-dimensional contours of the surface and present patches of variously charged or hydrophobic groups. (See amino acid structures in Chapter I.) The geometric arrangement ol the side chains not onlv restricts what particular substrates can bind, but also defines the orientations of the bound substrates to each other. The precision in spatial
Chemistry of Essential Oils
K. Hüsnü Can Başer, Gerhard Buchbauer in Handbook of Essential Oils, 2020
The general scheme of biosynthetic reactions (Bu'Lock, 1965; Mann et al., 1994) is shown in Figure 6.1. Through photosynthesis, green plants convert carbon dioxide and water into glucose. Cleavage of glucose produces phosphoenolpyruvate (1), which is a key building block for the shikimate family of natural products. Decarboxylation of phosphoenolpyruvate gives the two-carbon unit of acetate and this is esterified with coenzyme-A to give acetyl CoA (2). Self-condensation of this species leads to the polyketides and lipids. Acetyl CoA is also a starting point for synthesis of mevalonic acid (3), which is the key starting material for the terpenoids. In all of these reactions and indeed all the natural chemistry described in this chapter, nature uses the same reactions that chemists do (Sell, 2003). However, nature's reactions tend to be faster and more selective because of the catalysts it uses. These catalysts are called enzymes, and they are globular proteins in which an active site holds the reacting species together. This molecular organization in the active site lowers the activation energy of the reaction and directs its stereochemical course (Matthews and van Holde, 1990; Lehninger, 1993).
Simple Enzyme Substrate Interactions
John C. Matthews in Fundamentals of Receptor, Enzyme, and Transport Kinetics, 2017
The enzyme and substrate combine to form the ES complex. Then, the substrate is converted to product in the enzyme active site. Finally, the enzyme-product complex dissociates. Each of the steps in this mechanism is reversible. We did not include a reverse arrow for the last step since all the measurements we will make with an enzyme-catalyzed reaction will be the initial rate where [P] = zero. We also can ignore the middle step, conversion of ES to EP. This step is kinetically indistinguishable in the mechanism. This is the rapid equilibrium assumption. There may be many steps involved in the conversion of ES to E + P, however, they all can be lumped together under a single rate constant. The slowest step in the sequence will determine the magnitude of this constant. We can then assign rate constants to the various steps to yield Mechanism 19:
Mixed and non-competitive enzyme inhibition: underlying mechanisms and mechanistic irrelevance of the formal two-site model
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
With most enzymes, it is not possible to make a clear distinction between the portion of the active site involved in the binding of the substrate and the actual catalytic site because the catalytic site also contributes to substrate stabilisation, at least to some extent. In this respect, enzymes that catalyse the covalent modification of large macromolecular substrates as endonucleases56, protein kinases/phosphatases57, proteases58 and in general, all post-translational modification enzymes, represent a notable exception. Often, this type of enzyme derives most of the affinity for their substrates from a region of the protein surface that is distinct and remote from the catalytic site. The substrate recognition site, in this case, is called an exo-site58.
Novel 3-chloro-6-nitro-1H-indazole derivatives as promising antileishmanial candidates: synthesis, biological activity, and molecular modelling studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mohamed Mokhtar Mohamed Abdelahi, Youness El Bakri, Chin-Hung Lai, Karthikeyan Subramani, El Hassane Anouar, Sajjad Ahmad, Mohammed Benchidmi, Joel T. Mague, Jelena Popović-Djordjević, Souraya Goumri-Said
The binding modes of the active 3-chloro-6-nitro-1H-indazole derivatives (4, 5, 11, and 13) as potent antileishmanial agents against Leishmania infantum trypanothione reductase (TryR) were predicted using the Autodock 4.0 packages40. TryR was selected as a receptor in docking studies based on the literature reported works where this enzyme was targeted by indazole derivatives31–33. X-ray coordinates of TryR (PDB codes 2JK6) and its corresponding co-crystallized docked ligand flavin adenine dinucleotide were retrieved from RCSB Protein Data Bank (PDB). As a starting step, water molecules were removed, polar hydrogen atoms and Kollman charges were added to the extracted receptor structure using AutoDock Tools. The active site information was extracted from the enzyme crystal structure. Re-docking of the original ligand flavin adenine dinucleotide into the active site of trypanothione reductase was conducted to validate docking protocol and is well reproduced with RMSD values of 1.16 Å. 3D molecular structures geometries of 3-chloro-6-nitro-1H-indazole derivatives (4, 5, 11, and 13) were minimised via the Merck molecular force field 94 (MMFF94). The optimised geometries were saved as pdb files. Non-polar hydrogens were merged and rotatable bonds were defined for each docked ligand. The docking study was performed following the same steps used in our previous methodology41.
New benzothiazole hybrids as potential VEGFR-2 inhibitors: design, synthesis, anticancer evaluation, and in silico study
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Mohammad M. Al-Sanea, Abdelrahman Hamdi, Ahmed A. B. Mohamed, Hamed W. El-Shafey, Mahmoud Moustafa, Abdullah A. Elgazar, Wagdy M. Eldehna, Hidayat Ur Rahman, Della G. T. Parambi, Rehab M. Elbargisy, Samy Selim, Syed Nasir Abbas Bukhari, Omnia Magdy Hendawy, Samar S. Tawfik
Concerning compound 4a, interaction with important residues in the active site was achieved through hydrogen bonding such as Asp1046 through its carbonyl group and Glu885 through the NH in the amide group which is a known requirement to achieve good inhibitory activity against this enzyme. In addition, certain hydrophobic interactions have been achieved with IL888, ILE892, Leu1019, ILE1025, and His1026 residues. Furthermore, the nitro group of benzothiazole was able to form hydrogen bond with Ile1025, and ionic bond with ASP814 and Arg1027 which could explain the superior activity of our compound 4a over the previously reported non-nitrated derivative X45. The thiazolidine-2,4-dione moiety was found to occupy the linker area in the active site interacting with Lys868, Val 899, Val916, and Phe1047 allowing the fluoro-phenyl ring to interact with several residues in the hydrophobic groove such as Leu840, Ala866, and Leu1035 through hydrophobic interactions and with Cys919 through halogen hydrogen bond as demonstrated in Figure S1. These extensive interactions with the active site may explain its ability to inhibit the enzyme experimentally at low nanomolar concentration.