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Introduction to Bioorganic Chemistry and Introduction Chemical Biology to Bioorganic David Van Vranken Chemistry and and Gregory Weiss Chemical Biology ISBN 0-8153-4076-1 David Van Vranken 9 780815 340768 www.garlandscience.com and Gregory Weiss Introduction to Bioorganic Chemistry David Van Vranken and Gregory Weiss and Chemical Biology Introduction to Bioorganic Chemistry and Chemical Biology David Van Vranken and Gregory Weiss Introduction to Bioorganic Chemistry and Chemical Biology David Van Vranken and Gregory Weiss Garland Science David Van Vranken earned his PhD in chemistry from Stanford Vice President: Denise Schanck University. He is a professor of chemistry at UC Irvine, where he Editor: Summers Scholl carries out research on chemical structure and reactivity in peptides, Senior Editorial Assistant: Kelly O’Connor bioactive natural products, and transition metal catalyzed reactions. Illustrator, Cover, and Text Design: Matthew McClements, Blink Studio, Ltd. Gregory Weiss earned his PhD in chemical biology from Harvard Production Editor and Layout: EJ Publishing Services University. He is a professor of chemistry, molecular biology, and Development Editor: John Murdzek biochemistry at UC Irvine, where his laboratory focuses on the Copyeditor: Bruce Goatly interface between chemistry and biology, including combinatorial Proofreader: Jo Clayton chemistry applied to antiviral drug discovery, membrane proteins, Indexer: Bill Johncocks and bioelectronics. © 2013 by Garland Science, Taylor & Francis Group, LLC Tis book contains information obtained from authentic and highly regarded sources. Every efort has been made to trace copyright holders and to obtain their permission for the use of copyright material. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable eforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means—graphic, electronic, or mechanical, including photocopying, recording, taping, or information storage and retrieval systems—without permission of the copyright holder. ISBN 978-0-8153-4214-4 Library of Congress Cataloging-in-Publication Data Van Vranken, David L. Introduction to bioorganic chemistry and chemical biology / David L. Van Vranken, Gregory A. Weiss. p. cm. Includes bibliographical references and index. ISBN 978-0-8153-4214-4 (pbk.) 1. Biochemistry. I. Weiss, Gregory A. II. Title. QD415.V36 2013 572--dc23 2012019693 Published by Garland Science, Taylor & Francis Group, LLC, an informa business, 711 Tird Avenue, New York, NY 10017, USA, and 3 Park Square, Milton Park, Abingdon, OX14 4RN, UK. Printed in the United States of America 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Visit our website at http://www.garlandscience.com v Preface his textbook provides a chemical blueprint with which to understand the synthesis Tand function of molecules that comprise living cells. In order to tackle chemical biology—a feld of vast breadth and depth—as it continues to expand and evolve, we focus on the organic chemistry of biooligomers. Biooligomers are responsible for every main function of the cell, including control, communications, and manufacturing. Te central dogma of molecular biology serves as an organizing principle for students embarking on a tour of these molecules. Starting at the level of genes and advancing through each class of biooligomer—DNA, RNA, proteins, glycans, polyketides, and terpenes—we study their chemistry, structure, and interactions with other molecules. Ultimately, we return to the topic of chemical control over gene expression. Although the majority of studies during the past millennium were based on model organisms, we concentrate on human cells as much as possible. Introduction to Bioorganic Chemistry and Chemical Biology is written for upper- division undergraduate students and graduate-level students who have completed a year of organic chemistry. No initial knowledge of biology is assumed, but some famil- iarity is benefcial. Te book is also appropriate for advanced students in the health sciences. A series of chemical biology courses we teach at the University of California, Irvine, inspired the development of this book. Every student in our courses speaks a common language—organic chemistry—but there was no single textbook to provide an adequate description of the cell at the level of atoms, bonds, and arrow-pushing reaction mechanisms. Starting with foundational and simple concepts, the book gradually builds in complexity, across sections and chapters. For the undergraduate course, we simply skip the more advanced topics in both the reading assignments and lectures. Tis format ofers fexibility in coverage, depending on the length of the course and the level of student. Tis book is organized according to the central dogma of molecular biology. Chapters 1 and 2 cover the fundamentals of chemical biology and the chemical origins of biology, respectively. Each subsequent chapter (3–8) focuses largely on one type of biooligomer in a human cell: DNA, RNA, proteins, glycans, polyketides, and terpenes. We steer clear of the metabolic and biosynthetic pathways, which have become synonymous with introductory biochemistry courses. Chapter 9 catapults the student beyond the central dogma to explain mechanisms of cellular control over the production of biooligomers. Tis fnal chapter will bring students closest to an understanding of modern biology, physiology, and medicine. We recognize the relentless pace of new technology to emerge and quickly become antiquated; therefore, we limit our discussion of instrumentation and laboratory techniques. Since Introduction to Bioor- ganic Chemistry and Chemical Biology is not intended to be comprehensive, many well-known examples and techniques from the feld of chemical biology are omitted. Furthermore, we fully expect that instructors will select from and supplement the material in the book with additional information that best meets the needs of their students. vi PReFAce From experience, we know that composing moving, informative lectures consti- tutes the fun part of teaching. In this vein, each chapter begins with a snapshot of a signifcant discovery by luminaries such as Dorothy Crowfoot Hodgkins, Phoebus Levene, and Hermann Emil Fischer. We tell the stories of early examples of chemical biology illustrated in the Iliad and ancient Egyptian pharmacopeias. Our book com- bines rich, full color imagery with relevant biological examples to engage the reader as the combinatorial molecular architecture of life is revealed. Our choice of colors is deliberate: in general, we use red for DNA, green for RNA, blue for proteins, purple for glycans, and brown for polyketides and terpenes. Terefore, when biooligomers are represented by abstract shapes, the color of the shape ofers an additional level of biochemical information. We employ modern depictions of organic structures and mechanistic arrow-pushing in a way that will be familiar to all students who have taken an introductory course in organic chemistry. Biological macromolecules are rendered to reveal their secondary structures and PDB codes are included to allow students to interact directly using the Protein Data Bank website. In-text problems are situated throughout the chapters, contextualized for greater understanding; additional problems are found at the end of each chapter. We have starred (*) those problems best suited to self-study, and solutions are available online at the Student Resource Site. Chapters also begin with a list of general Learning Objectives and end with a list of specifc Learning Outcomes to focus students on important topics of comprehension. David L. Van Vranken and Gregory A. Weiss Online ResOuRces Accessible from www.garlandscience.com/bioorganic-chembio, the Student and Instructor Resource Websites provide learning and teaching tools created for Intro- duction to Bioorganic Chemistry and Chemical Biology. Te Student Resource Site is open to everyone, and users have the option to register in order to use book-marking and note-taking tools. Te Instructor Resource Site requires registration and access is available to instructors who have assigned the book to their course. To access the Instructor Resource Site, please contact your local sales representative or email vii Acknowledgments irst and foremost, without the unwavering love and support of our families, this Fbook wouldn’t have become a reality. Our love and deep appreciation are given to Maureen, Julia, and Kim. Tis book also owes a debt of gratitude to a cast of thousands—the researchers in the feld who did the work we have had the privilege of describing. It’s impossible to single out every one of these deserving scientists for acknowledgement. Limitations of space in this introductory text imposed agonizing brevity. We omitted important contributions made by key players, and we mentioned seminal discoveries without attribution. We greatly appreciate the eforts of those who drove the feld forward. We thank the following authors for writing textbooks we found particularly inspi- rational: Bruce Alberts, Ian Fleming, Clayton Heathcock, Alexander Johnson, Jack Kyte, Julian Lewis, Martin Raf, Keith Roberts, Richard Silverman, Wolfram Saenger, Andrew Streitwieser, Christopher Walsh, and Peter Walter. We also appreciate the countless students at UC Irvine who patiently endured our test drives of the material during our teaching. We are also grateful for the friendship and support of our col- leagues at UC Irvine. Te Garland Science team made this challenging project manageable. We would like to thank our editor, Summers Scholl, who managed this project with panache; tal- ented developmental editor John Murdzek; the unfappable senior editorial assistant Kelly O’Connor who kept the project on track and watched over a million details; and production editor Emma Jefcock for expert layout and other crucial matters. Addi- tionally, the illustrations benefted from the wonderful artistry of Matt McClements; and Becky Hainz-Baxter sifted through thousands of possibilities to fnd perfect pho- tos and permissions. Te following people provided valuable commentary as readers, reviewers, and advisors during the development of the project: Peter A. Beal (University of California, Davis); Annette Beck-Sickinger (University of Leipzig); Danielle Dube (Bowdoin College); Marina Gobbo (University of Padova); David Grayson (Trinity College, Dublin); Paul Harrison (McMaster University); Jessica Hollenbeck (Trinity University, Texas); Gerwald Jogl (Brown University); Andrej Lup- ták (University of California, Irvine); José Luis Mascareñas (University of Santiago); Christian Melander (North Carolina State University); Nicola Pohl (Indiana State Uni- versity); James Redman (Cardif University); Carmelo J. Rizzo (Vanderbilt University); Erland P. Stevens (Davidson College); Terry Smith (University of St. Andrews); Ali Tavassoli (University of Southampton); Doug Tobias (University of California, Irvine). viii Dedication Tis book is dedicated to our graduate mentors, Pete and Stuart. ix Contents chapter 1 The Fundamentals of chemical Biology 1 chapter 2 The chemical Origins of Biology 27 chapter 3 DnA 57 chapter 4 RnA 131 chapter 5 Peptide and Protein structure 179 chapter 6 Protein Function 229 chapter 7 Glycobiology 281 chapter 8 Polyketides and Terpenes 339 chapter 9 chemical control of signal Transduction 397 Glossary 461 index 469