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Human Metabolism Lecture Notes Human metabolism lecture notes Michael Palmer, MD Department of Chemistry University of Waterloo Waterloo, ON N2L 3G1 Canada [email protected] This version is from Saturday 16th February, 2019. The latest electronic version of these notes and accompanying slides is available for free at watcut.uwaterloo.ca/webnotes/Metabolism/. No other website is authorized to publicly distribute these notes or accompanying slides. A printed version used to be available, but I have discontinued it. Copyright© Michael Palmer, 2019. All rights reserved (see section 21.3 for details). Cover design by Jana Rade (impactstudiosonline.com). The cover illustration is a model of a glycogen molecule; the protein molecule at the center is glycogenin, whereas the green rods represent the branched glucose polymer. Preface These lecture notes, and the accompanying slides, are intended for teaching human metabolism at the undergraduate level. They aim to give a big picture view of the field that takes into account physiological and some clinical aspects. They also strive to be up to date. Some biochemistry texts present all the latest and greatest enzyme crystal structures, but seem stuck in the 1960s when it comes to updating metabolic pathways. It is likely that these notes are not completely free from this disease either, and I therefore welcome any corrections and suggestions for improvement. The notes and the slides are meant to be used in conjunction; the notes mostly present the slides in sequence, augmenting each with explanatory text. Keeping the figures and the corresponding text closely together may not always look as polished as a conventional book layout, but it makes on-screen reading easier. This structure also encourages me to stay on topic and to advance the plot with each successive slide. Finally, it makes it easier to recapitulate or anticipate the content of a lecture; this goes for both the students and the lecturer. Another conscious choice is to make these materials freely available. The text is entirely my own work. So is the majority of the images; all exceptions are listed in chapter 21. Regarding those images, I would like to thank all individuals and institutions who gave me permission to reuse them in these notes. In particular, I thank Katharina Glatz of Basel University for permission to use multiple histological pictures from her excellent website pathorama.ch. You are free and welcome to use these notes and slides for self-study or for classroom teaching. Some restrictions apply concerning the copying and redistribution of these materials; refer to the copyright notice in chapter 21 for details. I hope that, in return, you will bring to my attention any errors or shortcomings that you may notice. I would also like to thank my students, who have helped to improve these notes by challenging and questioning me about the material and its presentation. In particular, Stefanie Malatesta and Julia Plakhotnik have helped substantially in this manner. Finally, I thank Thorsten Dieckmann, Alexey J. Merz, and Karen Borges for pointing out errors in previous editions. These notes were put together with a collection of excellent free software tools. Apart from the well-known tools LATEX, Pymol, and Gnuplot, I must highlight the outstanding chemfig LATEX package written by Christian Tellechea that was used to draw all of the chemical structures and reaction mechanisms. iii Update 2019: New material on reactive species has been added as chapter 18. This is a fairly complex subject, and my attempt to do it justice has produced a text that may strike some fairly long. I feel, however, that this is justified, considering the extensive overlap of this topic with metabolism in health and disease. While some of the slides and text that had been present in other chapters have now been moved to this new one to limit redundancy in this text, the slides still exist (now as duplicates) in their original location in the accompanying Powerpoint and PDF slide sets so as to better maintain flow and context. iv Contents Preface......................................... iii Chapter 1 Introduction ............................. 1 1.1 Motivation: Why would you study metabolism?............. 1 1.2 Significance of metabolism in medicine ................. 1 1.3 Catabolic and anabolic reactions ..................... 2 1.4 Diversity of metabolism: pathways in plants and bacteria. 3 1.5 Types of foodstuffs ............................. 4 1.6 Functional anatomy of the digestive system............... 6 1.7 Answers to practice questions ....................... 15 Chapter 2 Refresher ............................... 17 2.1 Preliminary note ............................... 17 2.2 How enzymes work: active sites and catalytic mechanisms . 17 2.3 Energetics of enzyme-catalyzed reactions . 20 2.4 The role of ATP in enzyme-catalyzed reactions . 22 2.5 Regulation of enzyme activity ....................... 23 2.6 Answers to practice questions ....................... 28 Chapter 3 Glycolysis ............................... 30 3.1 Overview of glucose metabolism ..................... 30 3.2 Reactions in glycolysis ........................... 32 3.3 Mechanisms of enzyme catalysis in glycolysis . 34 3.4 Glycolysis under aerobic and anaerobic conditions. 39 3.5 Transport and utilization of glucose in the liver and in other organs 41 3.6 Answers to practice questions ....................... 43 Chapter 4 Catabolism of sugars other than glucose . 45 4.1 Dietary sugars other than glucose..................... 45 4.2 Degradation of fructose and sucrose ................... 46 4.3 Lactose and galactose ............................ 47 4.4 Sorbitol is an intermediate of the polyol pathway . 51 4.5 Answers to practice questions ....................... 52 v Contents Chapter 5 Pyruvate dehydrogenase and the citric acid cycle. 54 5.1 Overview ................................... 54 5.2 Structure and function of pyruvate dehydrogenase . 55 5.3 Regulation of pyruvate dehydrogenase. 59 5.4 The citric acid cycle ............................. 60 5.5 Regulation of the citric acid cycle ..................... 64 5.6 Reactions that divert and replenish TCA cycle intermediates . 65 5.7 Answers to practice questions ....................... 66 Chapter 6 The respiratory chain ........................ 67 6.1 Introduction ................................. 67 6.2 Overview ................................... 67 6.3 ATP synthesis can be separated from electron transport . 69 6.4 Molecules in the electron transport chain . 71 6.5 The energetics of electron transport ................... 75 6.6 Interfacing different types of electron carriers . 78 6.7 How is electron transport linked to proton pumping? . 81 6.8 ATP synthesis ................................ 83 6.9 Auxiliary shuttles for the mitochondrial reoxidation of cytosolic NADH ..................................... 87 6.10 Regulation of the respiratory chain .................... 90 6.11 ATP yield of complete glucose oxidation. 93 6.12 Answers to practice questions ....................... 95 Chapter 7 Gluconeogenesis ........................... 96 7.1 Introduction ................................. 96 7.2 Reactions in gluconeogenesis ....................... 97 7.3 Energy balance of gluconeogenesis . 100 7.4 Interactions of gluconeogenesis with other pathways . 101 7.5 Regulation of gluconeogenesis. 103 7.6 Answers to practice questions . 106 Chapter 8 Glycogen metabolism . 108 8.1 Overview ................................... 108 8.2 Glycogen structure ............................. 108 8.3 Glycogen synthesis and degradation . 111 8.4 Regulation of glycogen metabolism . 116 8.5 Interorgan relationships in glycogen metabolism . 118 8.6 Glycogen storage diseases . 121 8.7 Answers to practice questions . 124 Chapter 9 The hexose monophosphate shunt . 125 9.1 Outline of the pathway . 125 9.2 Reactions in the hexose monophosphate shunt . 126 9.3 The physiological role of NADPH . 130 vi Contents 9.4 Glucose-6-phosphate dehydrogenase deficiency . 136 9.5 Answers to practice questions . 138 Chapter 10 Triacylglycerol metabolism . 140 10.1 Overview ................................... 140 10.2 Digestion and uptake of dietary triacylglycerol . 142 10.3 Utilization of fatty acids: β-oxidation . 147 10.4 Ketone body metabolism . 153 10.5 Fatty acid synthesis ............................. 157 10.6 The glyoxylate cycle ............................. 164 10.7 Answers to practice questions . 165 Chapter 11 Cholesterol metabolism . 167 11.1 Biological significance of cholesterol . 167 11.2 Cholesterol synthesis ............................ 168 11.3 Regulation of cholesterol synthesis . 173 11.4 Cholesterol transport ............................ 176 11.5 Bile acid metabolism and transport . 182 11.6 Cholesterol and atherosclerosis . 185 11.7 Cholesterol metabolism and the treatment of atherosclerosis . 191 11.8 Gene defects in cholesterol transport and metabolism . 195 11.9 Answers to practice questions . 196 Chapter 12 Amino acid metabolism . 198 12.1 Metabolic uses of amino acids . 198 12.2 Transamination of amino acids . 200 12.3 Nitrogen disposal and excretion. 202 12.4 Degradative pathways of individual amino acids . 211 12.5 Hereditary enzyme defects in amino acid metabolism . 215 12.6 Answers to practice questions . 218 Chapter 13 Hormonal regulation of metabolism . 220 13.1 Hormones that affect energy metabolism . 220 13.2 Insulin..................................... 221 13.3 Other hormones ............................... 231 13.4 Answers to practice questions . 236 Chapter 14 Diabetes
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