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The aim of this monograph is to summarize the essential features which characterize the behavior of regulatory systems. Firstly we discuss the laws which govern ligand binding in thermodynamic terms. The basic cooperative and allosteric phenomena are des cribed in thermodynamic terms without assuming any particular mo del. Then the molecular models developed by Monod, Wyman and Changeux and by Koshland, Nemethy and Filmer are presented in detail. Special emphasis has been given to the analysis of the Hill coefficient and its meaning both in thermodynamic terms and in terms of the two allosteric models: the concerted model of Monod, Wyman and Changeux and the sequential model of Koshland, Nemethy and Filmer. Special types of cooperativities are dis cussed in some detail namely, cooperativity stemming from ligand coupled protein association or dissociation, negative cooperati vity and half-of-the-sites reactivity. A slightly extended space was devoted to the discussion of negative cooperativity and half of-the-sites reactivity, since the existence of these phenomena and their possible biological importance is less of a common knowledge than positive cooperativity. This monograph does not attempt to be a review of specific examples analyzed according to one model or another. Rather, an attempt is made to provide the reader with the quantitative tools to analyze any specific regulatory system. Last but not least, I would like to thank Prof. F. W. Dahlquist from the Institute of Molecular Biology, the University of Oregon (Eugene) and Prof. D. E. Koshland, Jr.
This book covers the most recent developments in the analysis of allosteric enzymes and provides a logical introduction to the limits for enzyme function as dictated by the factors that are limits for life. The book presents a complete description of all the mechanisms used for changing enzyme activity. It is extensively illustrated to clarify kinetic and regulatory properties. Eight enzymes are used as model systems after extensive study of their mechanisms. Wherever possible, the human form of the enzyme is used to illustrate the regulatory features.
The aim of this monograph is to summarize the essential features which characterize the behavior of regulatory systems. Firstly we discuss the laws which govern ligand binding in thermodynamic terms. The basic cooperative and allosteric phenomena are des cribed in thermodynamic terms without assuming any particular mo del. Then the molecular models developed by Monod, Wyman and Changeux and by Koshland, Nemethy and Filmer are presented in detail. Special emphasis has been given to the analysis of the Hill coefficient and its meaning both in thermodynamic terms and in terms of the two allosteric models: the concerted model of Monod, Wyman and Changeux and the sequential model of Koshland, Nemethy and Filmer. Special types of cooperativities are dis cussed in some detail namely, cooperativity stemming from ligand coupled protein association or dissociation, negative cooperati vity and half-of-the-sites reactivity. A slightly extended space was devoted to the discussion of negative cooperativity and half of-the-sites reactivity, since the existence of these phenomena and their possible biological importance is less of a common knowledge than positive cooperativity. This monograph does not attempt to be a review of specific examples analyzed according to one model or another. Rather, an attempt is made to provide the reader with the quantitative tools to analyze any specific regulatory system. Last but not least, I would like to thank Prof. F. W. Dahlquist from the Institute of Molecular Biology, the University of Oregon (Eugene) and Prof. D. E. Koshland, Jr.
This book compiles detailed information concerning a dozen of the best known allosteric enzymes, and so allows the comparison of their regulatory mechanisms and the confrontation of these mechanisms with the theoretical models. Stimulating and unexpected ideas emerge from these comparisons and emphasize the importance of developing various methods of investigation such as crystallography, X-ray solution scattering, and the study of fast movements in proteins and site-directed mutagenesis. This book is addressed to students and researchers interested in structure-function relationship in proteins, enzymology and metabolic regulation. It is also a basis for teaching.
In all living cells, proteins are performing a vast amount of functions. These functions are often controlled by a mechanism called allosteric regulation. In allosteric regulation, binding affinities in one site are affected by events in distant binding sites. The present study focuses on the protein dynamics underlying the allosteric regulation for the cooperative oxygen binding in hemoglobin and the interaction between the two catalytic sites of ABCE1. To elucidate the mechanism of hemoglobin's cooperativity on an atomistic level, a novel computational technique was developed to analyse t...
The book focuses on protein allostery in drug discovery. Allosteric regulation, ʹthe second secret of lifeʹ, fine-tunes virtually most biological processes and controls physiological activities. Allostery can both cause human diseases and contribute to development of new therapeutics. Allosteric drugs exhibit unparalleled advantages compared to conventional orthosteric drugs, rendering the development of allosteric modulators as an appealing strategy to improve selectivity and pharmacodynamic properties in drug leads. The Series delineates the immense significance of protein allostery—as demonstrated by recent advances in the repertoires of the concept, its mechanistic mechanisms, and networks, characteristics of allosteric proteins, modulators, and sites, development of computational and experimental methods to predict allosteric sites, small-molecule allosteric modulators of protein kinases and G-protein coupled receptors, engineering allostery, and the underlying role of allostery in precise medicine. Comprehensive understanding of protein allostery is expected to guide the rational design of allosteric drugs for the treatment of human diseases. The book would be useful for scientists and students in the field of protein science and Pharmacology etc.
This volume commemorates the 50th anniversary of the appearance in Volume 4 in 1948 of Dr. Jeffries Wyman's famous paper in which he "laid down" the foundations of linkage thermodynamics. Experts in this area contribute articles on the state-of-the-art of this important field and on new developments of the original theory. Among the topics covered in this volume are electrostatic contributions to molecular free energies in solution; site-specific analysis of mutational effects in proteins; allosteric transitions of the acetylcholine receptor; and deciphering the molecular code of hemoglobin allostery.
This presentation describes various aspects of the regulation of tissue oxygenation, including the roles of the circulatory system, respiratory system, and blood, the carrier of oxygen within these components of the cardiorespiratory system. The respiratory system takes oxygen from the atmosphere and transports it by diffusion from the air in the alveoli to the blood flowing through the pulmonary capillaries. The cardiovascular system then moves the oxygenated blood from the heart to the microcirculation of the various organs by convection, where oxygen is released from hemoglobin in the red blood cells and moves to the parenchymal cells of each tissue by diffusion. Oxygen that has diffused into cells is then utilized in the mitochondria to produce adenosine triphosphate (ATP), the energy currency of all cells. The mitochondria are able to produce ATP until the oxygen tension or PO2 on the cell surface falls to a critical level of about 4–5 mm Hg. Thus, in order to meet the energetic needs of cells, it is important to maintain a continuous supply of oxygen to the mitochondria at or above the critical PO2 . In order to accomplish this desired outcome, the cardiorespiratory system, including the blood, must be capable of regulation to ensure survival of all tissues under a wide range of circumstances. The purpose of this presentation is to provide basic information about the operation and regulation of the cardiovascular and respiratory systems, as well as the properties of the blood and parenchymal cells, so that a fundamental understanding of the regulation of tissue oxygenation is achieved.