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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 Friday 10th April, 2015. 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 (full color, hardcover binding) is now available at amazon and other retailers. For bulk orders at reduced rates, contact me directly. Copyright© Michael Palmer, 2014. All rights reserved (see section 20.3 for details). Cover design by Jana Rade (impactstudiosonline.com). The cover illustration is a model of a glycogen molecule. 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 20. 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 histologi- cal 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 restric- tions apply concerning the copying and redistribution of these materials; refer to the copyright notice in chapter 20 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. These notes were put together with a collection of excellent free software tools. Apart from the well-known tools LATEX, Pymol, and Gnuplot, I would like to highlight the outstanding chemfig LATEX package written by Christian Tellechea that was used to draw all of the chemical structures and reaction mechanisms. iii Contents Preface ............................................. iii Chapter1 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 The digestive system ................................ 6 1.7 Answers to practice questions.......................... 15 Chapter2 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.......................... 29 Chapter3 Glycolysis ................................... 31 3.1 Overview of glucose metabolism ........................ 31 3.2 Reactions in glycolysis............................... 33 3.3 Mechanisms of enzyme catalysis in glycolysis . 34 3.4 Glycolysis under aerobic and anaerobic conditions . 40 3.5 Transport and utilization of glucose in the liver and in other organs. 42 3.6 Answers to practice questions.......................... 44 Chapter4 Catabolism of sugars other than glucose . 47 4.1 Dietary sugars other than glucose ....................... 47 4.2 Degradation of fructose and sucrose ..................... 48 4.3 Lactose and galactose ............................... 50 4.4 Sorbitol is an intermediate of the polyol pathway . 53 4.5 Answers to practice questions.......................... 54 v Contents Chapter5 Pyruvate dehydrogenase and the citric acid cycle . 57 5.1 Overview........................................ 57 5.2 Structure and function of pyruvate dehydrogenase . 58 5.3 Regulation of pyruvate dehydrogenase .................... 62 5.4 The citric acid cycle................................. 63 5.5 Regulation of the citric acid cycle........................ 67 5.6 Reactions that divert and replenish TCA cycle intermediates . 68 5.7 Answers to practice questions.......................... 68 Chapter6 The respiratory chain ........................... 71 6.1 Introduction ..................................... 71 6.2 Overview........................................ 72 6.3 ATP synthesis can be separated from electron transport . 73 6.4 Molecules in the electron transport chain . 75 6.5 The energetics of electron transport ...................... 79 6.6 Interfacing different types of electron carriers . 82 6.7 How is electron transport linked to proton pumping? . 85 6.8 ATP synthesis .................................... 87 6.9 Auxiliary shuttles for the mitochondrial reoxidation of cytosolic NADH.......................................... 92 6.10 Regulation of the respiratory chain ...................... 94 6.11 ATP yield of complete glucose oxidation ................... 97 6.12 Answers to practice questions.......................... 99 Chapter7 Gluconeogenesis............................... 101 7.1 Introduction ..................................... 101 7.2 Reactions in gluconeogenesis . 102 7.3 Energy balance of gluconeogenesis. 105 7.4 Interactions of gluconeogenesis with other pathways. 106 7.5 Regulation of gluconeogenesis . 108 7.6 Answers to practice questions. 111 Chapter8 Glycogen metabolism . 113 8.1 Overview........................................ 113 8.2 Glycogen structure ................................. 113 8.3 Glycogen synthesis and degradation. 116 8.4 Regulation of glycogen metabolism . 121 8.5 Interorgan relationships in glycogen metabolism . 123 8.6 Glycogen storage diseases ............................ 126 8.7 Answers to practice questions. 128 Chapter9 The hexose monophosphate shunt . 131 9.1 Outline of the pathway .............................. 131 9.2 Reactions in the hexose monophosphate shunt. 132 9.3 The physiological role of NADPH . 136 9.4 Glucose-6-phosphate dehydrogenase deficiency . 142 vi Contents 9.5 Answers to practice questions. 144 Chapter10 Triacylglycerol metabolism . 147 10.1 Overview........................................ 147 10.2 Digestion and uptake of dietary triacylglycerol . 149 10.3 Utilization of fatty acids: β-oxidation . 153 10.4 Ketone body metabolism ............................. 160 10.5 Fatty acid synthesis................................. 164 10.6 The glyoxylate cycle ................................ 170 10.7 Answers to practice questions. 171 Chapter11 Cholesterol metabolism . 173 11.1 Biological significance of cholesterol. 173 11.2 Cholesterol synthesis ............................... 174 11.3 Regulation of cholesterol synthesis . 179 11.4 Cholesterol transport ............................... 182 11.5 Bile acid metabolism and transport . 188 11.6 Cholesterol and atherosclerosis . 190 11.7 Cholesterol metabolism and the treatment of atherosclerosis . 198 11.8 Gene defects in cholesterol transport and metabolism . 202 11.9 Answers to practice questions. 204 Chapter12 Amino acid metabolism . 207 12.1 Metabolic uses of amino acids . 207 12.2 Transamination of amino acids . 209 12.3 Nitrogen disposal and excretion . 211 12.4 Degradative pathways of individual amino acids . 219 12.5 Hereditary enzyme defects in amino acid metabolism . 223 12.6 Answers to practice questions. 227 Chapter13 Hormonal regulation of metabolism. 229 13.1 Hormones that affect energy metabolism . 229 13.2 Insulin ......................................... 230 13.3 Other hormones ................................... 240 13.4 Answers to practice questions. 246 Chapter14 Diabetes mellitus .............................. 247 14.1 Introduction ..................................... 247 14.2 Mechanism of renal glucose loss . 248 14.3 Metabolic dysregulation in diabetes mellitus . 252 14.4 The role of coxsackieviruses in the pathogenesis of type 1 diabetes . 256 14.5 Therapy of diabetes ................................ 259 14.6 Answers to practice questions. 267 Chapter15 Biosynthetic pathways using tetrahydrofolate and vitamin B12 ........................................ 269 15.1 Overview.......................................
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