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The Cell A Molecular Approach EIGHTH EDITION The Cell A Molecular Approach EIGHTH EDITION Geoffrey M. Cooper BOSTON UNIVERSITY SINAUER ASSOCIATES NEW YORK OXFORD OXFORD UNIVERSITY PRESS The Cell: A Molecular Approach, Eighth Edition Oxford University Press is a department of the Universi...

The Cell A Molecular Approach EIGHTH EDITION The Cell A Molecular Approach EIGHTH EDITION Geoffrey M. Cooper BOSTON UNIVERSITY SINAUER ASSOCIATES NEW YORK OXFORD OXFORD UNIVERSITY PRESS The Cell: A Molecular Approach, Eighth Edition Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and certain other countries. Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America © 2019 Oxford University Press Sinauer Associates is an imprint of Oxford University Press. For titles covered by Section 112 of the US Higher Education Opportunity Act, please visit www.oup.com/us/he for the latest information about pricing and alternate formats. The Cover The cover is a composite of David S. Goodsell paintings from previous editions of The Cell. They illustrate formation of a clathrin-coated pit, the interior of a nucleus, apoptosis, and formation of an autophagosome (clockwise from the upper left). The Artist David S. Goodsell is an Associate Professor of Molecular Biology at the Scripps Research Institute. His illustrated books, The Machinery of Life and Our Molecular Nature, explore biological molecules and their diverse roles within living cells, and his new book, Bionanotechnology: Lessons from Nature, presents the growing connections between biology and nanotechnology. More information may be found at: http://mgl.scripps.edu/ people/goodsell 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, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license, or under terms agreed with the appropriate reproduction rights organization. Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above. You must not circulate this work in any other form and you must impose this same condition on any acquirer. Address editorial correspondence to: Sinauer Associates 23 Plumtree Road Sunderland, MA 01375 U.S.A. [email protected] Address orders, sales, license, permissions, and translation inquiries to: Oxford University Press U.S.A. 2001 Evans Road Cary, NC 27513 U.S.A. Orders: 1-800-445-9714 Library of Congress Cataloging-in-Publication Data Names: Cooper, Geoffrey M., author. Title: The cell : a molecular approach / Geoffrey M. Cooper, Professor Emeritus, Boston University. Description: Eighth edition. | Oxford ; New York : Sinauer Associates, an imprint of Oxford University Press, [2019] Identifiers: LCCN 2018025416 (print) | LCCN 2018026538 (ebook) | ISBN 9781605357713 (ebook) | ISBN 9781605357072 (hardcover) Subjects: LCSH: Cytology. | Molecular biology. | Cells. Classification: LCC QH581.2 (ebook) | LCC QH581.2 .C66 2019 (print) | DDC 571.6--dc23 LC record available at https://lccn.loc.gov/2018025416 987654321 Printed in the United States of America Brief Table of Contents Part I Fundamentals and Foundations Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 1 Introduction to Cells and Cell Research 3 Molecules and Membranes 45 Bioenergetics and Metabolism 81 Fundamentals of Molecular Biology 113 Genomics, Proteomics, and Systems Biology 157 Part II The Flow of Genetic Information 185 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Genes and Genomes 187 Replication, Maintenance, and Rearrangements of Genomic DNA 215 RNA Synthesis and Processing 253 Transcriptional Regulation and Epigenetics 285 Protein Synthesis, Processing, and Regulation 315 Part III Cell Structure and Function 353 Chapter 11 Chapter 12 Chapter 13 Chapter 14 Chapter 15 Chapter 16 The Nucleus 355 Protein Sorting and Transport 383 Mitochondria, Chloroplasts, and Peroxisomes 425 The Cytoskeleton and Cell Movement 453 The Plasma Membrane 501 Cell Walls, the Extracellular Matrix, and Cell Interactions 539 Part IV Cell Regulation 563 Chapter 17 Chapter 18 Chapter 19 Chapter 20 Cell Signaling 565 The Cell Cycle 603 Cell Renewal and Cell Death Cancer 669 637 Contents PART I Fundamentals and Foundations 1 1 Introduction to Cells and Cell Research 3 Key Experiment HeLa Cells: The First Human Cell Line 25 Molecular Medicine Viruses and Cancer 26 1.1 The Origin and Evolution of Cells 4 How did the first cell arise? 4 The evolution of metabolism 7 Prokaryotes 8 Eukaryotic cells 9 The origin of eukaryotes 11 The development of multicellular organisms 1.3 Tools of Cell Biology: Microscopy and Subcellular Fractionation 28 13 1.2 Experimental Models in Cell Biology 18 E. coli 18 Yeasts 19 Caenorhabditis elegans and Drosophila melanogaster 20 Arabidopsis thaliana 21 Vertebrates 21 Animal cell culture 23 Viruses 24 2 Light microscopy 28 Fluorescence microscopy and GFP 31 Following protein movements and interactions Sharpening the focus and seeing cells in three dimensions 33 Super-resolution microscopy: breaking the diffraction barrier 34 Electron microscopy 36 Subcellular fractionation 37 DATA ANALYSIS PROBLEMS 42 SUGGESTED READING 43 ANIMATIONS AND VIDEOS 43 Molecules and Membranes 45 2.1 The Molecules of Cells 45 Chemical bonds 46 Carbohydrates 49 Lipids 51 Nucleic acids 53 Proteins 55 Key Experiment The Folding of Polypeptide Chains 58 2.2 Enzymes as Biological Catalysts 63 The catalytic activity of enzymes 63 Mechanisms of enzymatic catalysis 64 Coenzymes 66 Regulation of enzyme activity 67 2.3 Cell Membranes 71 Membrane lipids 71 Membrane proteins 73 32 viii Contents Key Experiment The Structure of Cell Membranes 74 Transport across cell membranes 75 3 DATA ANALYSIS PROBLEMS 78 SUGGESTED READING 80 ANIMATIONS AND VIDEOS 80 Bioenergetics and Metabolism 81 3.1 Metabolic Energy and ATP 81 The laws of thermodynamics The role of ATP 83 ATP synthesis 100 Synthesis of glucose 101 81 3.4 The Biosynthesis of Cell Constituents 102 3.2 Glycolysis and Oxidative Phosphorylation 85 Glycolysis 86 The citric acid cycle 88 The derivation of energy from lipids 90 Electron transport and oxidative phosphorylation 90 Chemiosmotic coupling 93 Key Experiment The Chemiosmotic Theory 94 3.3 Photosynthesis 97 Electron transport 4 97 Carbohydrates 103 Lipids 104 Proteins 104 Key Experiment Antimetabolites, Cancer, and AIDS 107 Nucleic acids 108 DATA ANALYSIS PROBLEMS 109 SUGGESTED READING 111 ANIMATIONS AND VIDEOS 111 Fundamentals of Molecular Biology 4.1 Heredity, Genes, and DNA 113 Genes and chromosomes 114 Identification of DNA as the genetic material The structure of DNA 117 Replication of DNA 119 4.4 Detection of Nucleic Acids and Proteins 137 Amplification of DNA by the polymerase chain reaction 137 Nucleic acid hybridization 139 Antibodies as probes for proteins 141 117 4.5 Gene Function in Eukaryotes 143 4.2 Expression of Genetic Information 122 The role of messenger RNA 122 The genetic code 123 RNA viruses and reverse transcription 125 Key Experiment The DNA Provirus Hypothesis 4.3 Recombinant DNA 128 Restriction endonucleases 129 Generation of recombinant DNA molecules DNA sequencing 133 Expression of cloned genes 134 113 131 127 Gene transfer in plants and animals 144 Mutagenesis of cloned DNAs 146 Introducing mutations into cellular genes 148 Genome engineering by the CRISPR/Cas system Targeting mRNA 150 Key Experiment RNA Interference 152 DATA ANALYSIS PROBLEMS 154 SUGGESTED READING 155 ANIMATIONS AND VIDEOS 156 149 Contents 5 ix Genomics, Proteomics, and Systems Biology 157 5.1 Genomes and Transcriptomes 157 5.3 Systems Biology 174 The genomes of bacteria and yeast 158 The genomes of Caenorhabditis elegans, Drosophila melanogaster, and Arabidopsis thaliana 159 The human genome 160 The genomes of other vertebrates 161 Key Experiment The Human Genome 163 Next-generation sequencing and personal genomes 164 Global analysis of gene expression 166 5.2 Proteomics 168 Identification of cell proteins 169 Global analysis of protein localization Protein interactions 171 Systematic screens of gene function 175 Regulation of gene expression 176 Networks 177 Synthetic biology 179 Molecular Medicine Malaria and Synthetic Biology 181 DATA ANALYSIS PROBLEM 183 SUGGESTED READING 184 ANIMATIONS AND VIDEOS 184 170 Part II The Flow of Genetic Information 185 6 Genes and Genomes 187 6.1 The Structure of Eukaryotic Genes 187 Introns and exons 189 Key Experiment The Discovery of Introns Roles of introns 193 191 6.2 Noncoding Sequences 195 Noncoding RNAs 196 Key Experiment The ENCODE Project 197 Repetitive sequences 198 Gene duplication and pseudogenes 201 7 6.3 Chromosomes and Chromatin 205 Chromatin 206 Centromeres 209 Telomeres 212 DATA ANALYSIS PROBLEMS 213 SUGGESTED READING 214 ANIMATIONS AND VIDEOS 214 Replication, Maintenance, and Rearrangements of Genomic DNA 215 7.1 DNA Replication 215 DNA polymerases 216 The replication fork 216 The fidelity of replication 224 Origins and the initiation of replication 225 Telomeres and telomerase: Maintaining the ends of chromosomes 228 Key Experiment Telomerase Is a Reverse Transcriptase 229 7.2 DNA Repair 232 Direct reversal of DNA damage 232 Excision repair 234 Molecular Medicine Colon Cancer and DNA Repair 238 x Contents DATA ANALYSIS PROBLEMS 250 SUGGESTED READING 251 ANIMATIONS AND VIDEOS 252 Translesion DNA synthesis 239 Repair of double-strand breaks 240 7.3 DNA Rearrangements and Gene Amplification 242 Antibody genes 243 Gene amplification 248 8 RNA Synthesis and Processing 253 8.1 Transcription in Bacteria 253 RNA polymerase 254 Bacterial promoters 254 Elongation and termination 255 8.2 Eukaryotic RNA Polymerases and General Transcription Factors 258 Eukaryotic RNA polymerases 259 General transcription factors and initiation of transcription by RNA polymerase II 259 Transcription by RNA polymerases I and III 263 8.3 RNA Processing and Turnover 265 Processing of ribosomal and transfer RNAs 9 Processing of mRNA in eukaryotes 267 Splicing mechanisms 270 Key Experiment The Discovery of snRNPs 274 Alternative splicing 276 Molecular Medicine Splicing Therapy for Duchenne Muscular Dystrophy 278 RNA editing 279 RNA degradation 280 DATA ANALYSIS PROBLEMS 282 SUGGESTED READING 284 ANIMATIONS AND VIDEOS 284 266 Transcriptional Regulation and Epigenetics 285 9.1 Gene Regulation in E. coli 285 The lac repressor 285 Positive control of transcription 287 9.2 Transcription Factors in Eukaryotes 288 cis-acting regulatory sequences: promoters and enhancers 288 Transcription factor binding sites 292 Transcriptional regulatory proteins 295 Key Experiment Isolation of a Eukaryotic Transcription Factor 296 Regulation of elongation 298 9.3 Chromatin and Epigenetics 301 Histone modifications 301 Key Experiment The Role of Histone Modification 303 Chromatin remodeling factors 306 Histones and epigenetic inheritance 307 DNA methylation 308 Noncoding RNAs 310 DATA ANALYSIS PROBLEM 312 SUGGESTED READING 313 ANIMATIONS AND VIDEOS 313 Contents 10 Protein Synthesis, Processing, and Regulation 315 10.1 Translation of mRNA 315 Transfer RNAs 316 The ribosome 318 The organization of mRNAs and the initiation of translation 320 The process of translation 322 Regulation of translation 326 10.2 Protein Folding and Processing 331 Chaperones and protein folding 331 Protein misfolding diseases 334 Molecular Medicine Alzheimer’s Disease 336 Enzymes that catalyze protein folding 337 Protein cleavage 337 Attachment of carbohydrates and lipids 338 10.3 Regulation of Protein Function and Stability 341 Regulation by small molecules 341 Protein phosphorylation and other modifications 342 Key Experiment The Discovery of Tyrosine Kinases 345 Protein–protein interactions 346 Protein degradation 347 DATA ANALYSIS PROBLEMS 349 SUGGESTED READING 350 ANIMATIONS AND VIDEOS 351 Part III Cell Structure and Function 353 11 The Nucleus 355 11.1 The Nuclear Envelope and Traffic between the Nucleus and the Cytoplasm 355 Structure of the nuclear envelope 356 The nuclear pore complex 358 Molecular Medicine Nuclear Lamina Diseases 359 Selective transport of proteins to and from the nucleus 362 Key Experiment Identification of Nuclear Localization Signals 363 Transport of RNAs 366 Regulation of nuclear protein import 367 11.2 The Organization of Chromatin 369 Chromosome territories 370 Chromatin localization and transcriptional activity 371 Replication and transcription factories 373 11.3 Nuclear Bodies 375 The nucleolus and rRNA 376 Polycomb bodies: Centers of transcriptional repression 378 Cajal bodies and speckles: Processing and storage of snRNPs 379 DATA ANALYSIS PROBLEMS 380 SUGGESTED READING 382 ANIMATIONS AND VIDEOS 382 xi xii 12 Contents Protein Sorting and Transport The Endoplasmic Reticulum, Golgi Apparatus, and Lysosomes 12.1 The Endoplasmic Reticulum 383 Protein sorting and export from the Golgi apparatus The endoplasmic reticulum and protein secretion 384 Targeting proteins to the endoplasmic reticulum 385 Key Experiment The Signal Hypothesis 387 Insertion of proteins into the ER membrane 390 Protein folding and processing in the ER 395 Quality control in the ER 398 The smooth ER and lipid synthesis 400 Export of proteins and lipids from the ER 402 12.2 The Golgi Apparatus 404 Organization of the Golgi 405 Protein glycosylation within the Golgi 406 Lipid and polysaccharide metabolism in the Golgi 13 407 Organization and function of mitochondria 426 The genetic system of mitochondria 428 Protein import and mitochondrial assembly 430 Molecular Medicine Mitochondrial Replacement Therapy 430 Mitochondrial lipids 434 Transport of metabolites across the inner membrane 435 13.2 Chloroplasts and Other Plastids 437 The structure and function of chloroplasts 438 Cargo selection, coat proteins, and vesicle budding Vesicle fusion 415 12.4 Lysosomes 417 Lysosomal acid hydrolases 417 Molecular Medicine Gaucher Disease 418 Endocytosis and lysosome formation 419 Autophagy 419 DATA ANALYSIS PROBLEMS 422 SUGGESTED READING 423 ANIMATIONS AND VIDEOS 424 The chloroplast genome 440 Import and sorting of chloroplast proteins Other plastids 442 Assembly and organization of actin filaments 454 Association of actin filaments with the plasma membrane 458 Microvilli 461 440 13.3 Peroxisomes 445 Functions of peroxisomes 445 Peroxisome assembly 446 Molecular Medicine Peroxisome Biogenesis Disorders 447 DATA ANALYSIS PROBLEMS 450 SUGGESTED READING 451 ANIMATIONS AND VIDEOS 451 The Cytoskeleton and Cell Movement 14.1 Structure and Organization of Actin Filaments 453 409 12.3 The Mechanism of Vesicular Transport 412 Mitochondria, Chloroplasts, and Peroxisomes 425 13.1 Mitochondria 425 14 383 453 Cell surface protrusions and cell movement 14.2 Myosin Motors 465 Muscle contraction 466 Contractile assemblies of actin and myosin in nonmuscle cells 470 Unconventional myosins 471 462 412 xiii Contents 14.3 Microtubules 472 14.5 Intermediate Filaments 490 Structure and dynamic organization of microtubules Assembly of microtubules 476 MAPs and the organization of microtubules 477 473 14.4 Microtubule Motors and Movement 479 Key Experiment The Isolation of Kinesin 480 Microtubule motor proteins 481 Cargo transport and intracellular organization 483 Cilia and flagella 484 Microtubules during mitosis 487 15 The Plasma Membrane 15.2 Transport of Small Molecules 514 Facilitated diffusion and carrier proteins 514 Ion channels 516 Active transport driven by ATP hydrolysis 521 Active transport driven by ion gradients 525 Molecular Medicine Cystic Fibrosis 525 16 492 501 15.1 Structure of the Plasma Membrane 501 The lipid bilayer 501 Plasma membrane proteins 505 Plasma membrane domains 510 Intermediate filament proteins 490 Assembly of intermediate filaments 491 Intracellular organization of intermediate filaments Key Experiment Function of Intermediate Filaments 495 DATA ANALYSIS PROBLEMS 497 SUGGESTED READING 498 ANIMATIONS AND VIDEOS 499 15.3 Endocytosis 528 Phagocytosis 528 Clathrin-mediated endocytosis 529 Key Experiment The LDL Receptor 531 Transport to lysosomes and receptor recycling DATA ANALYSIS PROBLEMS 535 SUGGESTED READING 537 ANIMATIONS AND VIDEOS 537 533 Cell Walls, the Extracellular Matrix, and Cell Interactions 539 16.1 Cell Walls 539 Bacterial cell walls 539 Eukaryotic cell walls 541 16.2 The Extracellular Matrix and Cell–Matrix Interactions 544 Matrix structural proteins 545 Matrix polysaccharides 547 Adhesion proteins 548 Cell–matrix interactions 549 Key Experiment The Characterization of Integrin 550 16.3 Cell–Cell Interactions 553 Adhesion junctions 553 Tight junctions 555 Gap junctions 557 Plasmodesmata 557 Molecular Medicine Gap Junction Diseases DATA ANALYSIS PROBLEMS 560 SUGGESTED READING 561 ANIMATIONS AND VIDEOS 562 558 xiv Contents Part IV Cell Regulation 17 563 Cell Signaling 565 17.1 Signaling Molecules and Their Receptors 565 Modes of cell–cell signaling 566 Steroid hormones and the nuclear receptor superfamily 567 Signaling by other small molecules 569 Peptide hormones and growth factors 570 17.2 G Proteins and Cyclic AMP 572 G proteins and G protein-coupled receptors 573 Key Experiment G Protein-Coupled Receptors and Odor Detection 574 The cAMP pathway: Second messengers and protein phosphorylation 576 17.3 Tyrosine Kinases and Signaling by the MAP Kinase and PI 3-Kinase Pathways 580 Receptor tyrosine kinases 580 Nonreceptor tyrosine kinases 582 MAP kinase pathways 584 18 Molecular Medicine Cancer: Signal Transduction and the ras Oncogenes 586 The PI 3-kinase/Akt and mTOR pathways 589 17.4 Receptors Coupled to Transcription Factors 594 The TGF-β/Smad pathway 594 NF-κB signaling 595 The Wnt and Notch pathways 595 17.5 Signaling Dynamics and Networks 597 Feedback loops and signaling dynamics Networks and crosstalk 598 DATA ANALYSIS PROBLEMS 600 SUGGESTED READING 601 ANIMATIONS AND VIDEOS 601 598 The Cell Cycle 603 18.1 The Eukaryotic Cell Cycle 603 Phases of the cell cycle 604 Regulation of the cell cycle by cell growth and extracellular signals 606 Cell cycle checkpoints 608 18.2 Regulators of Cell Cycle Progression 610 Protein kinases and cell cycle regulation 610 Key Experiment The Discovery of MPF 611 Key Experiment The Identification of Cyclin 613 Families of cyclins and cyclin-dependent kinases 616 Growth factors and the regulation of G1 Cdk’s 617 S phase and regulation of DNA replication 619 DNA damage checkpoints 621 18.3 The Events of M Phase 623 Stages of mitosis 623 Entry into mitosis 626 The spindle assembly checkpoint and progression to anaphase 629 Cytokinesis 631 DATA ANALYSIS PROBLEMS 633 SUGGESTED READING 634 ANIMATIONS AND VIDEOS 635 Contents 19 Cell Renewal and Cell Death 637 19.1 Stem Cells and the Maintenance of Adult Tissues 637 Proliferation of differentiated cells 638 Stem cells 640 Medical applications of adult stem cells 645 19.2 Pluripotent Stem Cells, Cellular Reprogramming, and Regenerative Medicine 647 Embryonic stem cells 647 Key Experiment Culture of Embryonic Stem Cells 649 Somatic cell nuclear transfer 650 Induced pluripotent stem cells 652 20 xv Transdifferentiation of somatic cells 654 19.3 Programmed Cell Death 655 The events of apoptosis 656 Key Experiment Identification of Genes Required for Programmed Cell Death 658 Caspases: The executioners of apoptosis 659 Central regulators of apoptosis: The Bcl-2 family 660 Signaling pathways that regulate apoptosis 662 Alternative pathways of programmed cell death 664 DATA ANALYSIS PROBLEM 667 SUGGESTED READING 668 ANIMATIONS AND VIDEOS 668 Cancer 669 20.1 The Development and Causes of Cancer 669 Types of cancer 670 The development of cancer 671 Properties of cancer cells 672 Causes of cancer 675 Prevention and early detection 699 Oncogene-targeted drugs 700 Molecular Medicine Imatinib: Cancer Treatment Targeted against the bcr/abl Oncogene 703 Immunotherapy 705 DATA ANALYSIS PROBLEM 706 SUGGESTED READING 707 ANIMATIONS AND VIDEOS 708 Retroviral oncogenes 678 Proto-oncogenes 679 Key Experiment The Discovery of Proto-Oncogenes 681 Oncogenes in human cancer 682 Functions of oncogene products 685 20.3 Tumor Suppressor Genes 690 Answers to Questions 709 Glossary 737 Illustration Credits 755 Index 757 694 20.4 Molecular Approaches to Cancer Treatment 699 20.2 Oncogenes 677 Identification of tumor suppressor genes Functions of tumor suppressor gene products Cancer genomics 697 691 About the Author Geoffrey M. Cooper is a Professor of Biology at Boston University. Receiving a Ph.D. in Biochemistry from the University of Miami in 1973, he pursued postdoctoral work with Howard Temin at the University of Wisconsin, where he developed gene transfer assays to characterize the proviral DNAs of Rous sarcoma virus and related retroviruses. He then joined the faculty of Dana-Farber Cancer Institute and Harvard Medical School in 1975, where he pioneered the discovery of oncogenes in human cancers. He moved to Boston University as Chair of Biology in 1998 and subsequently served as Associate Dean of the Faculty for Natural Sciences, as well as teaching undergraduate cell biology and continuing his research on the roles of oncogenes in the signaling pathways that regulate cell proliferation and programmed cell death. He has authored over 100 research papers, two textbooks on cancer, and an award-winning novel, The Prize, dealing with fraud in medical research. Preface Learning cell biology can be a daunting task because the field is so vast and rapidly moving, characterized by a continual explosion of new information. The challenge is how to master the fundamental concepts without becoming bogged down in details. Students need to understand the principles of cell biology and be able to appreciate new advances, rather than just memorizing “the facts” as we see them today. At the same time, the material must be presented in sufficient depth to thoughtfully engage students and provide a sound basis for further studies. The Eighth Edition of The Cell emphasizes the fundamental concepts of cell biology and includes new features designed to meet the needs of today’s students and their teachers. This edition of The Cell continues the goal of helping students understand the principles and concepts of cell biology while gaining an appreciation of the excitement and importance of ongoing research in this rapidly moving field. Our understanding of cell and molecular biology has progressed in many ways over the last three years, and these important advances have been incorporated into the current edition. Some of the most striking advances have continued to come from progress in genomics and understanding the complex mechanisms of gene regulation in higher eukaryotes. A new chapter in the current edition-—Transcriptional Regulation and Epigenetics—highlights these rapidly advancing areas. Other notable advances covered in the current edition include progress in proteomics, synthetic biology, mitochondrial replacement therapy, splicing therapy for Duchenne’s muscular dystrophy, and immunotherapy of cancer. Beyond incorporating new material, the Eighth Edition of The Cell has been extensively revised to improve its utility as a teachable text for today’s students. It has become abundantly clear that teaching in the sciences is most effective when it is done with a focus on active student engagement. To facilitate this and to avoid overwhelming students with too much information, I have minimized unnecessary detail to focus on concepts and shorten the text. In addition, recognizing that students with many different backgrounds take cell biology, additional introductory material on the nature of chemical bonds and thermodynamics has been added. Even with these additions, The Cell has been substantially shortened, ensuring that it remains an accessible and readable text for undergraduates who are taking their first course in cell and molecular biology. The reorganization of this edition includes the division of each chapter into self-contained sections, enabling instructors to readily change the order in which material is covered. To optimize student engagement, each section begins with Learning Objectives, includes marginal notes that highlight key concepts, and concludes with a summary and expanded series of questions. xx Preface The questions in this edition span several levels of Bloom’s taxonomy, ranging from knowledge and comprehension to analysis and synthesis. Distinguishing features of The Cell include the Molecular Medicine and Key Experiment essays, which highlight clinical applications and describe seminal research papers, respectively. Additional questions have been added to these essays, designed to focus attention on key aspects of the material and give students a sense of how progress in our field is made. A new feature of this edition is the addition of Data Analysis Problems to the end of each chapter. These problems, which present data and figures from original research papers, engage students in the analysis of experimental methods and results. They were included in the Instructor’s Resource Library of the Seventh Edition and a number of instructors found them to be a valuable resource, so a selection has been incorporated directly into the text of the current edition (with answers in the back of the book). Like the Key Experiment and Molecular Medicine essays, they provide excellent material for discussions and opportunities for student participation in active learning. An Active Learning Guide is included in the Instructor’s Resource Library of this edition of The Cell to facilitate this important approach to student engagement. My hope is that these changes to The Cell will stimulate students and help to convey the excitement and challenges of contemporary cell and molecular biology. The opportunities in our field are greater than ever, and today’s students will be responsible for the advances of tomorrow. Acknowledgments I am particularly grateful to Marianna Pap and Jozsef Szeberenyi for providing the Data Analysis Problems. The book has also benefited from the comments and suggestions of reviewers, colleagues, and instructors who used the previous edition. I am pleased to thank the following reviewers for their thoughtful comments and advice: Nancy Bae Esther Biswas-Fiss Paula Bubulya Jason Bush Lucinda Carnell Amanda Charlesworth Gary S. Coombs David P. Gardner Karl R. Fath Laura Francis Jennifer L. Freytag Neil C. Haave Jennifer Hackney Price Philip L. Hertzler Nathan Jebbett Cheryl Jorcyk Ondra M. Kielbasa Faith L. W. Liebl Jeroen Roelofs Germán Rosas-Acosta Midwestern University University of Delaware Wright State University California State University, Fresno Central Washington University University of Colorado Denver Waldorf University Marian University Queens College, City University of New York University of Massachusetts Amherst The Sage Colleges University of Alberta Arizona State University Central Michigan University University of Vermont Boise State University Alvernia University Southern Illinois University Edwardsville Kansas State University The University of Texas at El Paso Preface Ryan A. Shanks John W. Steele Shannon Stevenson Geoffrey Toner Tricia A. Van Laar Leticia Vega Liu Zhiming University of North Georgia Humboldt State University University of Minnesota Duluth Thomas Jefferson University California State University Fresno Barry University Eastern New Mexico University It is also a pleasure to thank Andy Sinauer for his continuing support of this project over the last twenty-plus years. Andy and his colleagues Dean Scudder and Chris Small were once again full of enthusiasm and ideas that made them a pleasure to work with. Ann Chiara did a beautiful job on the page layout of Donna DiCarlo’s design. Tracy Marton was a fantastically helpful and supportive production editor, assisted in her efforts by Kathaleen Emerson. I am grateful for their patient and careful work, as well as that of their colleagues at Sinauer Associates. Geoffrey M. Cooper July, 2018 xxi Organization and Features of The Cell, Eighth Edition The Cell has been designed to be an approachable and teachable text that can be covered in a single semester while allowing students to master the material in the entire book. It is assumed that most students will have had introductory biology and general chemistry courses, but will not have had previous courses in organic chemistry, biochemistry, or molecular biology. Several aspects of the organization and features of the book will help students to approach and understand its subject matter. Organization The Cell is divided into four parts, each of which is self-contained, so that the order and emphasis of topics can be easily varied according to the needs of individual courses. Part I provides background chapters on the evolution of cells, methods for studying cells, the chemistry of cells (including reviews of chemical bonds and thermodynamics), the fundamentals of molecular biology, and the fields of genomics and systems biology. For those students who have a strong background from either a comprehensive introductory biology course or a previous course in cell biology, various parts of these chapters can be skipped or used for review. Part II focuses on the molecular biology of cells and contains chapters dealing with genome organization and sequences; DNA replication and repair; transcription and RNA processing; and the synthesis, processing, and regulation of proteins. Part III contains chapters on cell structure and function, including chapters on the nucleus, cytoplasmic organelles, the cytoskeleton, the plasma membrane, and the extracellular matrix. This part of the book starts with coverage of the nucleus, which puts the molecular biology of Part II within the context of the eukaryotic cell, and then works outward through cytoplasmic organelles and the cytoskeleton to the plasma membrane and the exterior of the cell. These chapters are relatively self-contained, however, and could be used in a different order should that be more appropriate for a particular course. Finally, Part IV focuses on the exciting and fast-moving area of cell regulation, including coverage of topics such as cell signaling, the cell cycle, programmed cell death, and stem cells. This part of the book concludes with a chapter on cancer, which synthesizes the consequences of defects in basic cell regulatory mechanisms. xxiv Organization and Features Features Several pedagogical features have been incorporated into The Cell in order to help students master and integrate its contents. These features are reviewed below as a guide to students studying from this book. CHAPTER ORGANIZATION Each chapter is divided into three to five major sections, which are further divided into a similar number of subsections. An outline listing the major sections at the beginning of each chapter provides a brief overview of its contents. The major sections are numbered and selfcontained to facilitate assignability. LEARNING OBJECTIVES Each of the major sections begins with Learning Objectives, which help to organize and focus students’ attention on the material. SUMMARY AND QUESTIONS The major sections conclude with a review, including a section summary and questions (with answers in the back of the book). The questions span several levels of Bloom’s taxonomy, ranging from knowledge and comprehension to analysis and synthesis. MARGINAL NOTES Major points are summarized as marginal notes throughout the text, providing a running outline of the material. KEY TERMS AND GLOSSARY Key terms are identified as boldfaced words when they are introduced in each chapter and defined in the glossary at the end of the book. ILLUSTRATIONS AND MICROGRAPHS An illustration program of full-color art and micrographs has been carefully developed to complement and visually reinforce the text. KEY EXPERIMENT AND MOLECULAR MEDICINE ESSAYS Each chapter contains either two Key Experiment essays or one Key Experiment and one Molecular Medicine essay. These features are designed to provide the student with a sense of both the experimental basis of cell and molecular biology and its applications to modern medicine. Additional questions have been added to these essays, designed to focus attention on key aspects of the material. These essays are also a useful basis for student discussions, which can be accompanied with a review of the original paper upon which the Key Experiments are based. DATA ANALYSIS PROBLEMS Each chapter concludes with Data Analysis Problems that present data from original research papers, together with questions that engage students in the analysis of experimental methods and results (with answers in the back of the book). Like the Key Experiment and Molecular Medicine essays, the Data Analysis Problems provide excellent material for discussions and opportunities for student participation in active learning. FYIs Each chapter contains sidebars that provide brief descriptive highlights of points of interest. The sidebars supplement the text and provide starting points for class discussion. REFERENCES Two key references for each major section are included at the end of each chapter. Comprehensive lists of references are provided as an online supplement. Review articles and primary papers are distinguished by [R] and [P] designations, respectively. ANIMATION AND VIDEO REFERENCES Boxes in the margin and end-of-chapter descriptions and a Web link (URL) direct students to the website’s animations and videos. Media and Supplements to Accompany The Cell, Eighth Edition eBook (ISBN 9-781-60535-771-3) The Cell, Eighth Edition, is available as an eBook in several formats, including RedShelf and VitalSource. All major mobile devices are supported. For Students Companion Website (www.oup.com/us/cooper8e) The Companion Website for The Cell, Eighth Edition, provides students with a wide range of study and review materials and rich multimedia resources. The site, which is available free of charge (no access code required), includes the following resources: • Chapter Overviews: Brief introductions to each chapter’s content • Videos: Online videos (referenced throughout the book) to help students understand complex cellular and molecular structures and processes • Animations: Narrated animations (referenced throughout the book) of key concepts and processes • Micrographs: Interactive micrographs illustrating cellular structure • Flashcards: Study aids to help students learn the key terminology introduced in each chapter • In-book Reviews: End-of-section questions to reinforce understanding of chapter material • References: A comprehensive list of additional reference material for every chapter • Online Quizzes: Two sets of questions for each chapter, assignable by the instructor (Adopting instructors must register online for their students to access the quizzes.) • Multiple-choice quizzes test comprehension of the chapter’s key material. • Free-response questions ask students to apply what they have learned from the chapter. xxvi Media and Supplements • Web Links: Links that provide additional information about selected textbook topics • Complete Glossary: Easily searchable guide to textbook terminology Dashboard (www.oup.com/us/dashboard) Dashboard delivers a wealth of automatically graded quizzes and study resources for The Cell, along with an interactive eBook, all in an intuitive, web-based learning environment. For Instructors (available to qualified adopters) Ancillary Resource Center (www.oup.com/us/cooper8e) The Ancillary Resource Center includes a wide range of digital resources to aid in planning your course, presenting your lectures, and assessing your students. Contents include the following: • Instructor’s Manual: • Active Learning Guide with in-class exercises, references to relevant media resources, clicker questions, and more, all structured around the in-text Learning Objectives and designed to help you create a dynamic learning environment in the classroom • Data Analysis Problems to challenge students by working with experimental data • Chapter overviews, reviews, and key terms • Textbook Figures and Tables: All available in PowerPoint slides and as both high- and low-resolution JPEGs • Animations: The collection of animations from the Companion Website, for use in lectures • Online Quiz Questions: The Cell’s Companion Website features prebuilt chapter quizzes that report into an online gradebook. Adopting instructors have access to these quizzes and can choose to either assign them or let students use them for review. (Instructors must register in order for their students to be able to take the quizzes.) Instructors also have the ability to add their own questions and create their own quizzes. • Test Bank: Revised and updated for the Eighth Edition, the Test Bank includes more than 1,300 multiple-choice, fill-in-the-blank, true/false, and short-answer questions covering the full range of content in every chapter. All questions are referenced to Bloom’s Taxonomy, making it easier to select the right balance of questions when building assessments. • Computerized Test Bank: The entire test bank plus all of the online quiz questions are provided in Blackboard’s Diploma software. Diploma makes it easy to assemble quizzes and exams from any combination of publisher-provided questions and instructorcreated questions. In addition, quizzes and exams can be exported to many different course management systems, such as Blackboard and Moodle. Media and Supplements Dashboard (www.oup.com/us/dashboard) Dashboard delivers an abundance of study resources and automatically graded quizzes for The Cell in an intuitive, web-based learning environment. A built-in, color-coded gradebook allows instructors to track student progress. Dashboard includes: • Interactive eBook • All Student Companion Website Resources: Videos, Animations, Micrographs, Flashcards, Overviews, Reviews, Quizzes, Web Links, and Glossary To learn more about any of these resources, or to get access, please contact your local OUP representative. xxvii PART Fundamentals and Foundations Chapter 1 Introduction to Cells and Cell Research Chapter 2 Molecules and Membranes Chapter 3 Bioenergetics and Metabolism Chapter 4 Fundamentals of Molecular Biology Chapter 5 Genomics, Proteomics, and Systems Biology I CHAPTER 1 Introduction to Cells and Cell Research U nderstanding the molecular biology of cells is one of the most active and fundamental areas of research in the biological sciences. This is true not only from the standpoint of basic science, but also with respect to the numerous applications of cell and molecular biology to medicine, biotechnology, and agriculture. Especially with the ability to obtain rapid sequences of complete genomes, progress in cell and molecular biology is opening new horizons in the practice of medicine. Striking examples include genome editing; the identification of genes that contribute to susceptibility to a variety of common diseases, such as heart disease, rheumatoid arthritis, and diabetes; the development of new drugs specifically targeted to interfere with the growth of cancer cells; and the potential use of stem cells to replace damaged tissues and treat patients suffering from conditions like diabetes, Parkinson’s disease, Alzheimer’s disease, and spinal cord injuries. Because cell and molecular biology is such a rapidly growing field of research, it is important to understand its experimental basis as well as the current state of our knowledge. This chapter will therefore focus on how cells are studied, as well as review some of their basic properties. Appreciating the similarities and differences between cells is particularly important to understanding cell biology. The first section of this chapter discusses both the unity and the diversity of present-day cells in terms of their evolution from a common ancestor. On the one hand, all cells share common fundamental properties that have been conserved throughout evolution. For example, all cells employ DNA as their genetic material, are surrounded by plasma membranes, and use the same basic mechanisms for energy metabolism. On the other hand, present-day cells have evolved a variety of different lifestyles. Many organisms, such as bacteria, amoebas, and yeasts, consist of single cells that are capable of independent self-replication. More complex organisms are composed of collections of cells that function in a coordinated manner, with different cells specialized to perform particular tasks. The human body, for example, is composed of more than 200 different kinds of cells, each specialized for such distinctive functions as memory, sight, movement, and digestion. The diversity exhibited by the many different kinds of cells is striking; for example, consider the differences between bacteria and the cells of the human brain. The fundamental similarities between different types of cells provide a unifying theme to cell biology, allowing the basic principles learned from experiments with one kind of cell to be extrapolated and generalized to other cell types. Several kinds of cells and organisms are widely used to study different aspects of cell and molecular biology; the second section of this chapter discusses some of the properties of these cells that make them particularly 1.1 The Origin and Evolution of Cells 4 1.2 Experimental Models in Cell Biology 18 1.3 Tools of Cell Biology: Microscopy and Subcellular Fractionation 28 Key Experiment HeLa Cells: The First Immortal Cell Line 25 Molecular Medicine Viruses and Cancer 26 4 Chapter 1 valuable as experimental models. Finally, it is important to recognize that progress in cell biology depends heavily on the availability of experimental tools that allow scientists to make new observations or conduct novel kinds of experiments. This introductory chapter therefore concludes with a discussion of some of the experimental approaches used to study cells, as well as a review of some of the major historical developments that have led to our current understanding of cell structure and function. 1.1 The Origin and Evolution of Cells Learning Objectives You should be able to: • Explain how the first cell originated. • Describe the major steps in evolution of metabolism. • Illustrate the structures of eukaryotic and prokaryotic cells. • Outline the evolution of eukaryotic cells and multicellular organisms. Cells are divided into two main classes, initially defined by whether they contain a nucleus. Prokaryotic cells, such as bacteria, lack a nuclear envelope and are generally smaller and simpler than eukaryotic cells, which include the highly specialized cells of multicellular organisms. In spite of these differences, the same basic molecular mechanisms govern the lives of both prokaryotes and eukaryotes, indicating that all present-day cells are descended from a single primordial ancestor. How did this first cell develop? And how did the complexity and diversity exhibited by present-day cells evolve? How did the first cell arise? Organic molecules formed spontaneously in primitive Earth’s atmosphere. It appears that life first emerged at least 3.8 billion years ago, approximately 750 million years after Earth was formed. How life originated and how the first cell came into being are matters of speculation, since these events cannot be reproduced in the laboratory. Nonetheless, several types of experiments provide important evidence bearing on some steps of the process. It was first suggested in the 1920s that simple organic molecules could form and spontaneously polymerize into macromolecules under the conditions thought to exist in primitive Earth’s atmosphere. At the time life arose, the atmosphere of Earth is thought to have contained little or no free oxygen, instead consisting principally of CO2 and N2 in addition to smaller amounts of gases such as H2, H2S, and CO. Such an atmosphere provides reducing conditions in which organic molecules, given a source of energy such as sunlight or electrical discharge, can form spontaneously. The spontaneous formation of organic molecules was first demonstrated experimentally in the 1950s when Stanley Miller (then a graduate student) showed that the discharge of electric sparks into a mixture of H2, CH4, and NH3, in the presence of water, leads to the formation of a variety of organic molecules, including several amino acids (Figure 1.1). Although Miller’s experiments did not precisely reproduce the conditions of primitive Earth, they clearly demonstrated the plausibility of the spontaneous synthesis of organic molecules, providing the basic materials from which the first living organisms arose. Introduction to Cells and Cell Research The next step in evolution was the formation of macromolecules. The monomeric building blocks of macromolecules have been demonstrated to polymerize spontaneously under plausible prebiotic conditions. Heating dry mixtures of amino acids, for example, results in their polymerization to form polypeptides. But the critical characteristic of the macromolecule from which life evolved must have been the ability to replicate itself. Only a macromolecule capable of directing the synthesis of new copies of itself would have been capable of reproduction and further evolution. Of the two major classes of informational macromolecules in present-day cells (nucleic acids and proteins), only the nucleic acids are capable of directing their own self-replication. Nucleic acids can serve as templates for their own synthesis as a result of specific base pairing between complementary nucleotides (Figure 1.2). A critical step in understanding molecular evolution was thus reached in the early 1980s, when it was discovered in the laboratories of Sid Altman and Tom Cech that RNA is capable of catalyzing a number of chemical reactions, including the polymerization of nucleotides. Further studies have extended the known catalytic activities of RNA, including the description of RNA molecules that direct the synthesis of a new RNA strand from an RNA template. RNA is thus uniquely able to both serve as a template and to catalyze its own replication. Consequently, RNA is generally believed to have been the initial genetic system, and an early stage of chemical evolution is thought to have been based on self-replicating Electrode CH4 NH3 H2O H2 Electric discharge H2O H2 Water vapor was re uxed through an atmosphere consisting of H2, CH4, and NH3, into which electric sparks were discharged. CH4 NH3 Cooling Water Heat Analysis of the reaction products revealed the formation of a variety of organic molecules, including the amino acids alanine, aspartic acid, glutamic acid, and glycine. Organic molecules Alanine Aspartic acid Glutamic acid Glycine Urea Lactic acid Acetic acid Formic acid Figure 1.1 Spontaneous formation of organic molecules The formation of macromolecules was the next step in evolution, achieved by the polymerization of monomeric building blocks. The critical characteristic of the macromolecule from which life evolved was the ability to replicate itself. Only nucleic acids are capable of directing their own self-replication. RNA is capable of catalyzing a number of chemical reactions, including the polymerization of nucleotides, and can serve as a template and catalyze its own replication. RNA is believed to have been the initial genetic system. C C G A G A U U G A C G A C G C U C A U A C U G C G A G A U U G C U C U A A C G A G A U U G C U C U A A C G A G A U U G A C C U G G A C C U G G A C Figure 1.2 Self-replication of RNA Complementary pairing between nucleotides (adenine [A] with uracil [U] and guanine [G] with cytosine [C]) allows one strand of RNA to serve as a template for the synthesis of a new strand with the complementary sequence. G C U C U G C U C U A A G A C C U G G A U A C U G U C G A G A U U 5 6 Chapter 1 RNA molecules—a period of evolution known as the RNA world. Ordered interactions between RNA and amino acids then evolved into the present-day genetic code, and DNA eventually replaced RNA as the genetic material. As discussed further in Chapter 4, all present-day cells use DNA as the All present-day cells use the same genetic material and employ the same basic mechanisms for DNA replication genetic mechanisms. and expression of the genetic information. Genes are the functional units of inheritance, corresponding to segments of DNA that encode proteins or RNA molecules. The nucleotide sequence of a gene is copied into RNA by a process called transcription. For RNAs that encode proteins, their nucleotide sequence is then used to specify the order of amino acids in a protein by a process called translation. The first cell is presumed to have arisen by the enclosure of self-replicating Phospholipids are the basic RNA in a membrane composed of phospholipids (Figure 1.3). As discussed components of biological in detail in the next chapter, phospholipids are the basic components of all membranes. present-day biological membranes, including the plasma membranes of both prokaryotic and eukaryotic cells. The key characteristic of the phospholipids that form membranes is that they are amphipathic molecules, meaning that one portion of the molecule is soluble in water and another portion is not. 1. **RNA's Early Role:** RNA played a big part in the Phospholipids have long, water-insoluble (hydrophobic) hydrocarbon chains joined to water-soluble (hydrophilic) head groups that contain phosphate. When start of life [RNA World]. It mixed with amino acids, which later turned into the genetic code. placed in water, phospholipids spontaneously aggregate into a bilayer with their phosphate-containing head groups on the outside in contact with water and their 2. **DNA Takes Over:** Later on, DNA replaced hydrocarbon tails in the interior in contact with each other. Such a phospholipid RNA as our main genetic material. bilayer forms a stable barrier between two aqueous compartments—for example, 3. **Genes and Proteins:** Genes are like our body's separating the interior of the cell from its external environment. instruction manuals, written in DNA. They make The enclosure of self-replicating RNA and associated molecules in a proteins through transcription [copying DNA into phospholipid membrane would thus have maintained them as a unit, capable RNA] and translation [turning RNA into proteins]. of self-reproduction and further evolution. RNA-directed protein synthesis RNA can catalyze its own replication. 4. **First Cell Formation:** The very first cell likely formed when self-replicating RNA was enclosed in a protective [phospholipid] membrane. 5. **Role of Phospholipid Membrane:** This special membrane kept everything inside the cell safe, allowing self-reproduction and further evolution. This membrane consists of water-attracting (hydrophilic) and water-repelling (hydrophobic) components, creating a stable barrier between two watery compartments. RNA Phospholipid membrane Water 6. **Protein Making:** RNA helps in making proteins, which is vital for life. Phospholipid molecule: Hydrophilic head group Hydrophobic tail RNA-directed protein synthesis may already have evolved by this time, in which case the first cell wouldhave consisted of self-replicating RNA and its encoded proteins. Water Figure 1.3 Enclosure of self-replicating RNA in a phospholipid membrane The first cell is thought to have arisen by the enclosure of self-replicating RNA and associated molecules in a membrane composed of phospholipids. Each phospholipid molecule has two long hydrophobic tails attached to a hydrophilic head group. The hydrophobic tails are buried in the lipid bilayer; the hydrophilic heads are exposed to water on both sides of the membrane. Introduction to Cells and Cell Research 7 may already have evolved by this time, in which case the first cell would have consisted of self-replicating RNA and its encoded proteins. The evolution of metabolism Because cells originated in a sea of organic molecules, they were able to obtain food and energy directly from their environment. But such a situation is self-limiting, so cells needed to evolve their own mechanisms for generating energy and synthesizing the molecules necessary for their replication. The generation and controlled utilization of metabolic energy is central to all cell activities, and the principal pathways of energy metabolism (discussed in detail in Chapter 3) are highly conserved in present-day cells. All cells use adenosine 5′-triphosphate (ATP) as their source of metabolic energy to drive the synthesis of cell constituents and carry out other energy-requiring activities, such as movement (e.g., muscle contraction). The mechanisms used by cells for the generation of ATP are thought to have evolved in three stages, corresponding to the evolution of glycolysis, photosynthesis, and oxidative metabolism (Figure 1.4). The development of these metabolic pathways changed Earth’s atmosphere, thereby altering the course of further evolution. In the initially anaerobic atmosphere of Earth, the first energy-generating reactions presumably involved the breakdown of organic molecules in the absence of oxygen. These reactions are likely to have been a form of presentday glycolysis—the anaerobic breakdown of glucose to lactic acid, with the net energy gain of two molecules of ATP. In addition to using ATP as their source of intracellular chemical energy, all present-day cells carry out glycolysis, consistent with the notion that these reactions arose very early in evolution. Glycolysis provided a mechanism by which the energy in preformed organic molecules (e.g., glucose) could be converted to ATP, which could then be used as a source of energy to drive other metabolic reactions. The development of photosynthesis is generally thought to have been the next major evolutionary step, which allowed the cell to harness energy from sunlight and provided independence from the utilization of preformed organic molecules. The first photosynthetic bacteria probably utilized H2S to convert CO2 to organic The first cells obtained energy by glycolysis. Photosynthesis made cells independent of organic molecules in the environment. Glycolysis C6H12O6 2 C3H6O3 Glucose Lactic acid Generates 2 ATP Existence of organisms in extreme conditions has led to the hypothesis that life could exist in similar environments elsewhere in the solar system. The field of astrobiology (or exobiology) seeks to find signs of this extraterrestrial life. Photosynthesis 6 CO2 + 6 H2O C6H12O6 + 6 O2 Glucose Oxidative metabolism C6H12O6 + 6 O2 6 CO2 + 6 H2O FYI Generates 36–38 ATP Glucose Figure 1.4 Generation of metabolic energy Glycolysis is the anaerobic breakdown of glucose to lactic acid. Photosynthesis utilizes energy from sunlight to drive the synthesis of glucose from CO2 and H2O, with the release of O2 as a by-product. The O2 released by photosynthesis is used in oxidative metabolism, in which glucose is broken down to CO2 and H2O, releasing much more energy than can be obtained from glycolysis. 8 Chapter 1 The oxidation of glucose to carbon dioxide and water yields much more energy than glycolysis. molecules—a pathway of photosynthesis still used by some bacteria. The use of H2O as a donor of electrons and hydrogen for the conversion of CO2 to organic compounds evolved later and had the important consequence of changing Earth’s atmosphere. The use of H2O in photosynthetic reactions produces the by-product free O2; this mechanism is thought to have been responsible for making O2 abundant in Earth’s atmosphere, which occurred about 2.4 billion years ago. The release of O2 as a consequence of photosynthesis changed the environment in which cells evolved and is commonly thought to have led to the development of oxidative metabolism. Alternatively, oxidative metabolism may have evolved before photosynthesis, with the increase in atmospheric O2 then providing a strong selective advantage for organisms capable of using O2 in energy-producing reactions. In either case, O2 is a highly reactive molecule, and oxidative metabolism, utilizing this reactivity, has provided a mechanism for generating energy from organic molecules that is much more efficient than anaerobic glycolysis. For example, the complete oxidative breakdown of glucose to CO2 and H2O yields energy equivalent to that of 36 to 38 molecules of ATP, in contrast to the 2 ATP molecules formed by anaerobic glycolysis (see Figure 1.4). With few exceptions, present-day cells use oxidative reactions as their principal source of energy. Prokaryotes Plasma membrane Cell wall Prokaryotes are smaller and simpler than eukaryotes. Nucleoid Prokaryotes include cells of two domains, the Archaea and the Bacteria, which diverged early in evolution. The Archaea include cells that live in extreme environments that are unusual today but may have been prevalent in primitive Earth. For example, thermoacidophiles live in hot sulfur springs with temperatures as high as 80°C and pH values as low as 2. The Bacteria include the common forms of present-day prokaryotes—a large group of organisms that live in a wide range of environments, including soil, water, and other organisms (e.g., human pathogens). Prokaryotic cells are smaller and simpler than most eukaryotic cells, their genomes are less complex, and they do not contain nuclei or cytoplasmic organelles (Table 1.1). Most prokaryotic cells are spherical, rod-shaped, or spiral, with diameters of 1 to 10 m. Their DNA contents range from about 0.6 million to 5 million base pairs, an amount sufficient to encode about 5000 different proteins. The largest and most complex prokaryotes are the cyanobacteria—bacteria in which photosynthesis evolved. The structure of a typical bacterial cell is illustrated by Escherichia coli (E. coli), a common inhabitant of the human intestinal tract (Figure 1.5). The cell is rod-shaped, about 1 m in diameter and about 2 m long. Like most other prokaryotes, E. coli is surrounded by a rigid cell wall composed of polysaccharides and peptides. Beneath the cell wall is the plasma membrane, which is a bilayer of phospholipids and associated proteins. Whereas the cell wall is porous and readily penetrated by a variety of molecules, the plasma membrane provides the functional separation between the inside of the cell and its external environment. The DNA of E. coli is a single circular molecule in the nucleoid, which, in contrast to the nucleus of eukaryotes, Figure 1.5 Electron micrograph of E. coli The cell is surrounded by a cell 0.5 m wall, beneath which is the plasma membrane. DNA is located in the nucleoid. Artificial color has been added. (© Biophoto Associates/Science Source.) Introduction to Cells and Cell Research Table 1.1 Prokaryotic and Eukaryotic Cells Characteristic Prokaryote Eukaryote Nucleus Absent Present Diameter of a typical cell ≈1 m 10–100 m Cytoplasmic organelles Absent 6 9 Prokaryotes are smaller and simpler than eukaryotes. Present 6 DNA content (base pairs) 1 × 10 to 5 × 10 Chromosomes Single circular DNA molecule 1.5 × 107 to 5 × 109 Multiple linear DNA molecules is not surrounded by a membrane separating it from the cytoplasm. The cytoplasm contains approximately 30,000 ribosomes (the sites o