Daniel M. Quinn

Bio: Daniel M. Quinn is an academic researcher from University of Iowa. The author has contributed to research in topics: Active site & Acylation. The author has an hindex of 25, co-authored 84 publications receiving 3343 citations. Previous affiliations of Daniel M. Quinn include University of Cincinnati Academic Health Center & University of California, San Diego.

The X-ray structure of a transition state analog complex reveals the molecular origins of the catalytic power and substrate specificity of acetylcholinesterase.

Abstract: The structure of a complex of Torpedo californica acetylcholinesterase with the transition state analog inhibitor m-(N,N,N-trimethylammonio)-2,2,2-trifluoroacetophenone has been solved by X-ray crystallographic methods to 2.8 A resolution. Since the inhibitor binds to the enzyme about 1010-fold more tightly than the substrate acetylcholine, this complex provides a visual accounting of the enzyme−ligand interactions that provide the molecular basis for the catalytic power of acetylcholinesterase. The enzyme owes about 8 kcal mol-1 of the 18 kcal mol-1 of free energy of stabilization of the acylation transition state to interactions of the quaternary ammonium moiety with three water molecules, with the carboxylate side chain of E199, and with the aromatic side chains of W84 and F330. The carbonyl carbon of the trifluoroketone function interacts covalently with S200 of the S200−H440−E327 catalytic triad. The operation of this triad as a general acid−base catalytic network probably provides 3−5 kcal mol-1 of ...

Enzymes of the cholinesterase family

Abstract: GENE STRUCTURE AND EXPRESSION OF CHOLINESTERASES: Presentations: Antisense Oligonucleotides Suppressing Expression of Cholinesterase Genes Modulate Hematopoiesis in vivo and ex vivo (H. Soreq et al.). Posters: Alternative Exon 6 Directs Synaptic Localization of Recombinant Human Acetylcholinesterase in Neuromuscular Junctions of Xenopus laevis Embryos (M. Sternfeld et al.). POLYMORPHISM AND STRUCTURE OF CHOLINESTERASES: Presentations: Structures of Complexes of Acetylcholinesterase with Covalently and Noncovalently Bound Inhibitors (J.L. Sussman et al.). Posters: Hydrophobicity on Esterase Activity of Human Serum Cholinesterase (L. Jaganathan et al.). MECHANISM OF CATALYSIS OF CHOLINESTERASES: Presentations: Amino Acid Residues that Control Mono and Bisquaternary Oximeinduced Reactivation of OEthyl Methylphosphorylated Cholinesterases (Y. Ashani et al.). Posters. CELLULAR BIOLOGY OF CHOLINESTERASES: Presentations. Posters. STRUCTURE-FUNCTION RELATIONSHIPS OF ANTICHOLINESTERASE AGENTS: Presentations. Posters. NONCHOLINERGIC FUNCTIONS OF CHOLINESTERASES: Presentations. Posters. PHARMACOLOGICAL UTILIZATION OF ANTICHOLINESTERASES: Presentations. Posters. 99 additional articles. Appendixes. Index.

Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein

Abstract: The three-dimensional structure of acetylcholinesterase from Torpedo californica electric organ has been determined by x-ray analysis to 2.8 angstrom resolution. The form crystallized is the glycolipid-anchored homodimer that was purified subsequent to solubilization with a bacterial phosphatidylinositol-specific phospholipase C. The enzyme monomer is an alpha/beta protein that contains 537 amino acids. It consists of a 12-stranded mixed beta sheet surrounded by 14 alpha helices and bears a striking resemblance to several hydrolase structures including dienelactone hydrolase, serine carboxypeptidase-II, three neutral lipases, and haloalkane dehalogenase. The active site is unusual because it contains Glu, not Asp, in the Ser-His-acid catalytic triad and because the relation of the triad to the rest of the protein approximates a mirror image of that seen in the serine proteases. Furthermore, the active site lies near the bottom of a deep and narrow gorge that reaches halfway into the protein. Modeling of acetylcholine binding to the enzyme suggests that the quaternary ammonium ion is bound not to a negatively charged "anionic" site, but rather to some of the 14 aromatic residues that line the gorge.

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

Abstract: Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer's disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases.

Fluorine in medicinal chemistry and chemical biology

Abstract: Introduction Chapter 1 "Unique Properties of Fluorine and Their Relevance to Medicinal Chemistry and Chemical Biology" by Takashi Yamazaki, Takeo Taguchi and Iwao Ojima Medicinal Chemistry Chapter 2 "Fluorinated Prostanoids: Development of Tafluprost, a New Anti-glaucoma Agent" by Yasushi Matsumura Chapter 3 "Fluorinated conformationally restricted glutamate analogs for CNS drug discovery and development" by Atsuro Nakazato Chapter 4 "Fluorinated Inhibitors of Matrix Metalloproteinases" by Roberta Sinisi, Monika Jagodzinska, Gabriele Candiani, Florent Huguenot, Monica Sani, Alessandro Volonterio, Raffaella Maffezzoni and Matteo Zanda Chapter 5 "Fluoro-Taxoid Anticancer Agents" by Antonella Pepe, Larisa Kuznetsova, Liang Sun and Iwao Ojima Chapter 6 "Antimalarial Fluoroartemisinins: Increased Metabolic and Chemical Stability"by Jean-Pierre Begue, Daniele Bonnet-Delpon Chapter 7 "Synthesis and Biological Activity of Fluorinated Nucleosides" by Tokumi Maruyama, Masahiro Ikejiri, Kunisuke Izawa and Tomoyuki Onishi Synthetic methods for medicinal chemistry and chemical biology Chapter 8 "Synthesis of gem -Difluoromethylenated Nucleosides via gem -Difluoromethylene-Containing Building Blocks" by Wei-Dong Meng and Feng-Ling Qing Chapter 9 "Recent Advances in the Syntheses of Fluorinated Amino Acids" by Kenji Uneyama Chapter 10 "Fluorinated Moieties for Replacement of Amide and Peptide Bonds" by Takeo Taguchi and Hikaru Yanai Chapter 11 "Perfluorinated Heteroaromatic Systems as Scaffolds for Drug Discovery" by David Armstrong, Matthew W. Cartwright, Emma L. Parks, Graham Pattison, Graham Sandford, Rachel Slater, John A. Christopher, David D. Miller, Paul W. Smith and Antonio Vong Chapter 12 " gem -Difluorocyclopropanes as key building blocks for novel biologically active molecules" by Toshiyuki Itoh Chapter 13 "Fluorous Mixture Synthesis (FMS) of Drug-Like Molecules and Enantiomers, Stereoisomers, and Analogs of Natural Products" by Wei Zhang Chapter 14 "Fluorine-18 Radiopharmaceuticals" by Michael R. Kilbourn and Xia Shao Applications of fluorinated amino acids and peptides to chemical biology and pharmacology Chapter 15 "Application of Artificial Model Systems to Study the Interactions of Fluorinated Amino Acids within the Native Environment of Coiled Coil Proteins" by Mario Salwiczek, Toni Vagt and Beate Koksch Chapter 16 "Fluorinated Amino Acids and Biomolecules in Protein Design and Chemical Biology" by He Meng, Ginevra A. Clark , and Krishna Kumar Chapter 17 "Effects of Fluorination on the Bioorganic Properties of Methionine" by John F. Honek Chapter 18 "Structure analysis of membrane-active peptides using 19 F-labeled amino acids and solid state NMR" by Parvesh Wadhwani and Erik Strandberg Chapter 19 "Metabolism of Fluorine-containing Drugs using in vivo Magnetic Resonance Spectroscopy" by Erika Schneider Appendix "FDA-Approved Active Pharmaceutical Ingredients Containing Fluorine" by Elizabeth Pollina-Cormier, Manisha Das, and Iwao Ojima

Acetylcholinesterase New roles for an old actor

Abstract: The discovery of the first neurotransmitter — acetylcholine — was soon followed by the discovery of its hydrolysing enzyme, acetylcholinesterase. The role of acetylcholinesterase in terminating acetylcholine-mediated neurotransmission made it the focus of intense research for much of the past century. But the complexity of acetylcholinesterase gene regulation and recent evidence for some of the long-suspected 'non-classical' actions of this enzyme have more recently driven a profound revolution in acetylcholinesterase research. Although our understanding of the additional roles of acetylcholinesterase is incomplete, the time is ripe to summarize the evidence on a remarkable diversity of acetylcholinesterase functions.