Cholinergic Ligand Interactions
By J.F. Moran
()
About this ebook
Related to Cholinergic Ligand Interactions
Related ebooks
Molecular Architecture of Proteins and Enzymes Rating: 0 out of 5 stars0 ratingsMolecular Approaches to Ecology Rating: 0 out of 5 stars0 ratingsFormation and Fate of Cell Organelles Rating: 0 out of 5 stars0 ratingsMultiple Equilibria in Proteins Rating: 0 out of 5 stars0 ratingsAdvances in Developmental Biochemistry Rating: 0 out of 5 stars0 ratingsChemical Induction of Cancer: Structural Bases and Biological Mechanisms Rating: 0 out of 5 stars0 ratingsTranslating Epigenetics to the Clinic Rating: 0 out of 5 stars0 ratingsProteins in Biology and Medicine Rating: 0 out of 5 stars0 ratingsDrug Metabolism in Diseases Rating: 0 out of 5 stars0 ratingsGap Junction Structure and Chemical Regulation: Direct Calmodulin Role in Cell-to-Cell Channel Gating Rating: 3 out of 5 stars3/5Molecular Action of Toxins and Viruses Rating: 0 out of 5 stars0 ratingsMammalian Protein Metabolism: Volume III Rating: 0 out of 5 stars0 ratingsCellular Endocrinology in Health and Disease Rating: 0 out of 5 stars0 ratingsPhysiological Genetics Rating: 0 out of 5 stars0 ratingsThe Interpretation of Ultrastructure Rating: 0 out of 5 stars0 ratingsHormone Action in Plant Development — A Critical Appraisal Rating: 0 out of 5 stars0 ratingsMolecular Approaches to Neurobiology Rating: 0 out of 5 stars0 ratingsIntracellular Transport Rating: 0 out of 5 stars0 ratingsNeuroendocrine Perspectives: Volume 3 Rating: 0 out of 5 stars0 ratingsHormones Rating: 5 out of 5 stars5/5Molecular Pharmacology V3: The Model of Action of Biology Active Compounds Rating: 0 out of 5 stars0 ratingsFetal-Placental Disorders Rating: 5 out of 5 stars5/5Advances in Enzymology and Related Areas of Molecular Biology, Part A: Amino Acid Metabolism Rating: 5 out of 5 stars5/5New Horizons in Evolution Rating: 0 out of 5 stars0 ratingsLymphocyte Differentiation, Recognition, and Regulation Rating: 0 out of 5 stars0 ratingsNeurosciences Research: Volume 4 Rating: 0 out of 5 stars0 ratingsCell Polarity in Development and Disease Rating: 0 out of 5 stars0 ratingsMolecular Basis of Biological Activity Rating: 0 out of 5 stars0 ratingsMammalian Protein Metabolism Rating: 0 out of 5 stars0 ratings
Biology For You
Dopamine Detox: Biohacking Your Way To Better Focus, Greater Happiness, and Peak Performance Rating: 3 out of 5 stars3/5Your Brain: A User's Guide: 100 Things You Never Knew Rating: 4 out of 5 stars4/5Sapiens: A Brief History of Humankind Rating: 4 out of 5 stars4/5Anatomy and Physiology For Dummies Rating: 4 out of 5 stars4/5Fantastic Fungi: How Mushrooms Can Heal, Shift Consciousness, and Save the Planet Rating: 5 out of 5 stars5/5Nursing Anatomy & Physiology Rating: 4 out of 5 stars4/5Ultralearning: Master Hard Skills, Outsmart the Competition, and Accelerate Your Career Rating: 4 out of 5 stars4/5This Will Make You Smarter: 150 New Scientific Concepts to Improve Your Thinking Rating: 4 out of 5 stars4/5Anatomy 101: From Muscles and Bones to Organs and Systems, Your Guide to How the Human Body Works Rating: 4 out of 5 stars4/5Peptide Protocols: Volume One Rating: 4 out of 5 stars4/5Why We Sleep: Unlocking the Power of Sleep and Dreams Rating: 4 out of 5 stars4/5How Emotions Are Made: The Secret Life of the Brain Rating: 4 out of 5 stars4/5All That Remains: A Renowned Forensic Scientist on Death, Mortality, and Solving Crimes Rating: 4 out of 5 stars4/5The Obesity Code: the bestselling guide to unlocking the secrets of weight loss Rating: 4 out of 5 stars4/5The Grieving Brain: The Surprising Science of How We Learn from Love and Loss Rating: 4 out of 5 stars4/5Genius Kitchen: Over 100 Easy and Delicious Recipes to Make Your Brain Sharp, Body Strong, and Taste Buds Happy Rating: 0 out of 5 stars0 ratingsThe Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race Rating: 4 out of 5 stars4/5The Soul of an Octopus: A Surprising Exploration into the Wonder of Consciousness Rating: 4 out of 5 stars4/5Homo Deus: A Brief History of Tomorrow Rating: 4 out of 5 stars4/5Mother of God: An Extraordinary Journey into the Uncharted Tributaries of the Western Amazon Rating: 4 out of 5 stars4/5Gut: The Inside Story of Our Body's Most Underrated Organ (Revised Edition) Rating: 4 out of 5 stars4/5A Crack In Creation: Gene Editing and the Unthinkable Power to Control Evolution Rating: 4 out of 5 stars4/5Written in Bone: Hidden Stories in What We Leave Behind Rating: 4 out of 5 stars4/5Other Minds: The Octopus, the Sea, and the Deep Origins of Consciousness Rating: 4 out of 5 stars4/5The Blood of Emmett Till Rating: 4 out of 5 stars4/5Lifespan: Why We Age—and Why We Don't Have To Rating: 4 out of 5 stars4/5The Winner Effect: The Neuroscience of Success and Failure Rating: 5 out of 5 stars5/5Woman: An Intimate Geography Rating: 4 out of 5 stars4/5The Coming Plague: Newly Emerging Diseases in a World Out of Balance Rating: 4 out of 5 stars4/5
Reviews for Cholinergic Ligand Interactions
0 ratings0 reviews
Book preview
Cholinergic Ligand Interactions - D. J. Triggle
Colorado
PREFACE
A continuing theme in neurotransmitter literature concerns the possibility of equating the neurotransmitter receptors with enzymes. Among the various possibilities that have been discussed is that the receptors are identical with those enzymes responsible for the metabolic destruction of the neurotransmitter, i.e., monoamine oxidase and the receptors for phenyl and indoly-lethylamines, catechol-O-methyl transferase and the receptors for catecholamines, and acetylcholinesterase and the receptors for acetylcholine. It is clear, however, that this possibility is not correct in the sense that the initiation of the physiological response is dependent upon the neurotransmitters serving as substrates of these enzymes since inhibition of the latter does not produce corresponding inhibition of the neurotransmitter-induced processes. Nevertheless, the possibility does remain that interaction of the neurotransmitter with the enzyme independent of the catalytic processes could be involved in the initiation of responses to neurotransmitters. This may be particularly true for acetylcholinesterase. Whether or not the general hypothesis expressed above is proved correct, the use of the more readily characterizable enzyme systems, such as acetylcholinesterase, can serve, at the very least, as valuable model systems for the understanding of neurotransmitter-receptor interactions.
In 1937 Roepke, describing certain analogies in the interaction of cholinergic ligands with acetylcholinesterase and the cholinergic receptor, advanced the suggestion that the possibility of the identity of the two systems warranted further investigation. Despite continued interest in the potential interrelationship of these systems the question of their identity, partial identity, or nonidentity has simply not been solved.
The recent purification and crystallization of acetylcholinesterase together with real progress in the purification of receptor components indicated the desirability of organizing a symposium to discuss not only these aspects but also the structural bases for cholinergic ligand interaction with these macromolecules, the conformational changes involved with ligand binding, the quantitation of cholinergic ligand binding sites, and the roles of acetylcholinesterase and its isozymes in muscle disease. This volume presents the papers read at this symposium which was held at the State University of New York at Buffalo on May 25 and 26, 1970.
We wish to thank the Continuing Education Programs of the Schools of Medicine and Pharmacy for their support of this Symposium. Our grateful acknowledgments are also extended to Burroughs Wellcome, Ciba, Mead Johnson, and Smith, Kline and French, whose generous donations contributed very significantly to this meeting.
Much of the detailed planning of the meeting was carried out by Miss J. Falconer. Mrs. E. Olczak prepared the manuscripts for publication. We extend to them our sincere appreciation of their efforts.
D.J. Triggle, J.F. Moran and E.A. Barnard
THE POSSIBILITY OF CONFORMATIONAL CHANGES IN ACETYLCHOLINESTERASE
Irwin B. Wilson, Department of Chemistry, University of Colorado, Boulder, Colorado
Publisher Summary
This chapter reviews the possibility of conformational changes in acetylcholinesterase. Conformational changes in proteins and the related phenomenon of allosterism has received great impetus from the studies in rationalizing the kinetics of enzyme-catalyzed reactions. There has been considerable interest in conformational changes in cholinesterase as a possible indication of corresponding changes in the acetylcholine receptor. The enzyme and receptor might be structurally and genetically related, having evolved from a common gene in the distant past perhaps by gene duplication and mutation. Cholinesterase itself may be the acetylcholine receptor. All proteins are allosteric proteins; all proteins can undergo conformational changes by interaction with some small molecule. The surface of a protein presents a certain constellation of chemical structural groups, some charged, some uncharged, some polar, some non-polar, some aromatic, some alkyl, and some capable of forming hydrogen bonds, all arranged in a defined order. There are hundreds of small molecules that are complementary to some small portion of this protein surface and can interact strongly with it.
Conformational changes in proteins and the related phenomenon of allosterism has received great impetus from the work of Koshland (1963), Koshland, Nemethy and Filmer (1966) and Monod, Wyman and Changeux (1965), as well as from the studies of many others in explaining or at least rationalizing the kinetics of enzyme catalyzed reactions. For some time now, several workers have been interested in possible conformational changes in cholinesterase. Aside from interest in the role of conformational changes in the catalytic process, there has been considerable interest in conformational changes in cholinesterase as a possible indication of corresponding changes in the acetylcholine receptor. There has been some thought that the enzyme and receptor might be structurally and genetically related having evolved from a common gene in the distant past perhaps by gene duplication and mutation. There is also some thought that cholinesterase itself may be the acetylcholine receptor (Changeux, Podleski and Meunier, 1969).
It is well to recognize that in a certain sense, perhaps a legalistic sense, all proteins are allosteric proteins, all proteins can undergo conformational changes by interaction with some small molecule. This can be seen in the following way. The surface of a protein presents a certain constellation of chemical structural groups, some charged, some uncharged, some polar, some non-polar, some aromatic, some alkyl, some capable of forming hydrogen bonds, all arranged in a defined order. It is apparent that there must be hundreds of small molecules that are complementary to some small portion of this protein surface and can interact strongly with it. These substances become bound and must affect the kinetics, if only to a very slight degree, but an effect which would be revealed if we could make sufficiently precise measurements.
Evidently allosterism and conformational changes are important only when they produce sizable effects and are of physiological or pharmacological significance.
I will describe some observations in which an effector molecule produces a large kinetic effect which suggests a conformational change in acetylcholinesterase. I will start by reviewing some of the reactions of acetylcholinesterase.
THE HYDROLYTIC MECHANISM
During the enzymic hydrolysis of acetylcholine
the acetyl group is transferred to a hydroxyl group of a serine residue in the enzyme to form an acetyl enzyme derivative and release choline. The acetyl enzyme then hydrolyzes in about 0.1 msec to form acetic acid and free enzyme (Wilson, Bergman and Nachmanson, 1950a):
The reversible enzyme-substrate complex involves binding at two subsites of the active site. One, the esteratic site, contains the enzymic nucleophile and possibly an electrophilic group represented by H of Figure 1 (Wilson, Bergman and Nachmanson, 1950b). The second is called the anionic site and interacts with the substrate via coulombic and hydrophobic forces (Wilson and Bergmann, 1950, Wilson, 1952, Adams and Whittaker, 1950). The coulombic interaction corresponds to a single negative charge at a distance of 5 Å from the positively charged nitrogen of the quaternary amine function in acetylcholine, and increases binding by a factor of thirty. The hydrophobic interactions contribute on the average a factor of 7 per CH3 group to binding, except for the fourth group which makes a statistical contribution of a factor of three. It might be noted that the hydrophobic interactions 7³ × 4 = 1400 far outweigh the coulombic interaction.
Figure 1
The enzymic nucleophile is thought to be the hydroxyl group of serine in which nucleophilicity is enhanced by hydrogen bond formation with a neighboring imidazole group (Cunningham, 1957; Brestkin and Rozengart, 1965). The imidazole group thus functions as a general base catalyst (Fig. 1).
ACID TRANSFERRING INHIBITORS
There are numerous compounds, belonging to three well known and broad classes of compounds that inhibit cholinesterase by reaction at the esteratic site in a manner similar to the reaction of acetylcholine with the enzyme (Wilson and Bergmann, 1950; Wilson, 1951; Aldridge, 1953; Myers and Kemp, 1954; Wilson, Hatch and Ginsburg, 1960; Kitz and Wilson, 1962). I have called these classes of compounds (organophosphates, carbamates and sulfonates), acid transferring inhibitors. They react with the enzyme to transfer an acid group, i.e., a phosphoryl group, a carbamyl group or a sulfonyl group to the enzyme. The second order rate constants for these reactions are well below the second order rate constant for acetylation of the enzyme by acetylcholine but in some cases higher than the second order rate constant for acetylation of the enzyme by ethyl