Essential biochemistry

Description

Cover Essential_Biochemistry © About the Authors Brief Contents Contents Preface Acknowledgments Part 1 Foundations 1 The Chemical Basis of Life 1.1 What Is Biochemistry? 1.2 Biological Molecules Cells contain four major types of biomolecules There are three major kinds of biological polymers Box 1.A Units Used in Biochemistry 1.3 Energy and Metabolism Enthalpy and entropy are components of free energy ΔG is less than zero for a spontaneous process Life is thermodynamically possible 1.4 The Origin and Evolution of Life The prebiotic world Origins of modern cells Box 1.B How Does Evolution Work? 2 Aqueous Chemistry 2.1 Water Molecules and Hydrogen Bonds Hydrogen bonds are one type of electrostatic force Box 2.A Why Do Some Drugs Contain Fluorine? Water dissolves many compounds 2.2 The Hydrophobic Effect Amphiphilic molecules experience both hydrophilic interactions and the hydrophobic effect The hydrophobic core of a lipid bilayer is a barrier to diff usion Box 2.B Sweat, Exercise, and Sports Drinks 2.3 Acid–Base Chemistry [H+] and [OH–] are inversely related The pH of a solution can be altered Box 2.C Atmospheric CO2 and Ocean Acidification A pK value describes an acid’s tendency to ionize The pH of a solution of acid is related to the pK 2.4 Tools and Techniques: Buffers 2.5 Clinical Connection: Acid–Base Balance in Humans Part 2 Molecular Structure and Function 3 From Genes to Proteins 3.1 Nucleotides Nucleic acids are polymers of nucleotides Some nucleotides have other functions 3.2 Nucleic Acid Structure DNA is a double helix RNA is single-stranded Nucleic acids can be denatured and renatured 3.3 The Central Dogma DNA must be decoded A mutated gene can cause disease 3.4 Genomics Gene number is roughly correlated with organismal complexity Genes are identified by comparing sequences Genomic data reveal biological functions 3.5 Tools and Techniques: Manipulating DNA Cutting and pasting generates recombinant DNA The polymerase chain reaction amplifies DNA Box 3.A Genetically Modified Organisms Box 3.B DNA Fingerprinting DNA sequencing uses DNA polymerase to make a complementary strand DNA can be altered 4 Protein Structure 4.1 Amino Acids, the Building Blocks of Proteins The 20 amino acids have different chemical properties Box 4.A Does Chirality Matter? Box 4.B Monosodium Glutamate Peptide bonds link amino acids in proteins The amino acid sequence is the first level of protein structure 4.2 Secondary Structure: The Conformation of the Peptide Group The a helix exhibits a twisted backbone conformation The ß sheet contains multiple polypeptide strands Proteins also contain irregular secondary structure 4.3 Tertiary Structure and Protein Stability Proteins have hydrophobic cores Protein structures are stabilized mainly by the hydrophobic effect Other interactions help stabilize proteins Protein folding begins with the formation of secondary structures Some proteins have more than one conformation 4.4 Quaternary Structure 4.5 Clinical Connection: Protein Misfolding and Disease 4.6 Tools and Techniques: Analyzing Protein Structure Chromatography takes advantage of a polypeptide’s unique properties Mass spectrometry reveals amino acid sequences Protein structures are determined by X-ray crystallography, electron crystallography, and NMR spectroscopy Box 4.C Mass Spectrometry Applications 5 Protein Function 5.1 Myoglobin and Hemoglobin: Oxygen-Binding Proteins Oxygen binding to myoglobin depends on the oxygen concentration Myoglobin and hemoglobin are related by evolution Oxygen binds cooperatively to hemoglobin A conformational shift explains hemoglobin’s cooperative behavior Box 5.A Carbon Monoxide Poisoning H+ ions and bisphosphoglycerate regulate oxygen binding to hemoglobin in vivo 5.2 Clinical Connection: Hemoglobin Variants 5.3 Structural Proteins Actin filaments are most abundant Actin filaments continuously extend and retract Tubulin forms hollow microtubules Some drugs aff ect microtubules Keratin is an intermediate filament Collagen is a triple helix Box 5.B Vitamin C Deficiency Causes Scurvy Collagen molecules are covalently cross-linked Box 5.C Bone and Collagen Defects 5.4 Motor Proteins Myosin has two heads and a long tail Myosin operates through a lever mechanism Kinesin is a microtubule-associated motor protein Box 5.D Myosin Mutations and Deafness Kinesin is a processive motor 6 How Enzymes Work 6.1 What Is an Enzyme? Enzymes are usually named after the reaction they catalyze 6.2 Chemical Catalytic Mechanisms A catalyst provides a reaction pathway with a lower activation energy barrier Enzymes use chemical catalytic mechanisms Box 6.A Depicting Reaction Mechanisms The catalytic triad of chymotrypsin promotes peptide bond hydrolysis 6.3 Unique Properties of Enzyme Catalysts Enzymes stabilize the transition state Eff icient catalysis depends on proximity and orientation effects The active-site microenvironment promotes catalysis 6.4 Chymotrypsin in Context Not all serine proteases are related by evolution Enzymes with similar mechanisms exhibit different substrate specificity Chymotrypsin is activated by proteolysis Protease inhibitors limit protease activity 6.5 Clinical Connection: Blood Coagulation 7 Enzyme Kinetics and Inhibition 7.1 Introduction to Enzyme Kinetics 7.2 Derivation and Meaning of the Michaelis–Menten Equation Rate equations describe chemical processes The Michaelis–Menten equation is a rate equation for an enzyme-catalyzed reaction KM is the substrate concentration at which velocity is half-maximal The catalytic constant describes how quickly an enzyme can act kcat/KM indicates catalytic efficiency KM and Vmax are experimentally determined Not all enzymes fit the simple Michaelis–Menten model 7.3 Enzyme Inhibition Some inhibitors act irreversibly Competitive inhibition is the most common form of reversible enzyme inhibition Transition state analogs inhibit enzymes Box 7.A Inhibitors of HIV Protease Other types of inhibitors aff ect Vmax Allosteric enzyme regulation includes inhibition and activation Several factors may influence enzyme activity 7.4 Clinical Connection: Drug Development 8 Lipids and Membranes 8.1 Lipids Fatty acids contain long hydrocarbon chains Box 8.A Omega-3 Fatty Acids Some lipids contain polar head groups Lipids perform a variety of physiological functions Box 8.B The Lipid Vitamins A, D, E, and K 8.2 The Lipid Bilayer The bilayer is a fluid structure Natural bilayers are asymmetric 8.3 Membrane Proteins Integral membrane proteins span the bilayer An a helix can cross the bilayer A transmembrane ß sheet forms a barrel Lipid-linked proteins are anchored in the membrane 8.4 The Fluid Mosaic Model Membrane glycoproteins face the cell exterior 9 Membrane Transport 9.1 The Thermodynamics of Membrane Transport Ion movements alter membrane potential Membrane proteins mediate transmembrane ion movement 9.2 Passive Transport Porins are ß barrel proteins Ion channels are highly selective Box 9.A Pores Can Kill Gated channels undergo conformational changes Aquaporins are water-specific pores Some transport proteins alternate between conformations 9.3 Active Transport The Na,K-ATPase changes conformation as it pumps ions across the membrane ABC transporters mediate drug resistance Secondary active transport exploits existing gradients 9.4 Membrane Fusion Box 9.B Antidepressants Block Serotonin Transport SNAREs link vesicle and plasma membranes Endocytosis is the reverse of exocytosis Box 9.C Exosomes 10 Signaling 10.1 General Features of Signaling Pathways A ligand binds to a receptor with a characteristic affinity Box 10.A Bacterial Quorum Sensing Most signaling occurs through two types of receptors The effects of signaling are limited 10.2 G Protein Signaling Pathways G protein–coupled receptors include seven transmembrane helices The receptor activates a G protein Adenylate cyclase generates the second messenger cyclic AMP Cyclic AMP activates protein kinase A Signaling pathways are also switched off The phosphoinositide signaling pathway generates two second messengers Calmodulin mediates some Ca2+ signals 10.3 Receptor Tyrosine Kinases The insulin receptor dimer binds one insulin The receptor undergoes autophosphorylation Box 10.B Cell Signaling and Cancer 10.4 Lipid Hormone Signaling Eicosanoids are short-range signals Box 10.C Aspirin and Other Inhibitors of Cyclooxygenase 11 Carbohydrates 11.1 Monosaccharides Most carbohydrates are chiral compounds Cyclization generates a and ß anomers Monosaccharides can be derivatized in many different ways 11.2 Polysaccharides Lactose and sucrose are the most common disaccharides Starch and glycogen are fuel-storage molecules Cellulose and chitin provide structural support Box 11.A Cellulosic Biofuel Bacterial polysaccharides form a biofilm 11.3 Glycoproteins Oligosaccharides are N-linked or O-linked Oligosaccharide groups are biological markers Box 11.B The ABO Blood Group System Proteoglycans contain long glycosaminoglycan chains Bacterial cell walls are made of peptidoglycan Part 3 Metabolism 12 Metabolism and Bioenergetics 12.1 Food and Fuel Cells take up the products of digestion Box 12.A Dietary Guidelines Monomers are stored as polymers Fuels are mobilized as needed 12.2 Metabolic Pathways Some major metabolic pathways share a few common intermediates Many metabolic pathways include oxidation–reduction reactions Metabolic pathways are complex Box 12.B The Transcriptome, the Proteome, and the Metabolome Human metabolism depends on vitamins 12.3 Free Energy Changes in Metabolic Reactions The free energy change depends on reactant concentrations Unfavorable reactions are coupled to favorable reactions Free energy can take different forms Box 12.C Powering Human Muscles Regulation occurs at the steps with the largest free energy changes 13 Glucose Metabolism 13.1 Glycolysis Reactions 1–5 are the energy-investment phase of glycolysis Reactions 6–10 are the energy-payoff phase of glycolysis Box 13.A Catabolism of Other Sugars Pyruvate is converted to other substances Box 13.B Alcohol Metabolism 13.2 Gluconeogenesis Four gluconeogenic enzymes plus some glycolytic enzymes convert pyruvate to glucose Gluconeogenesis is regulated at the fructose bisphosphatase step 13.3 Glycogen Synthesis and Degradation Glycogen synthesis consumes the free energy of UTP Glycogen phosphorylase catalyzes glycogenolysis 13.4 The Pentose Phosphate Pathway The oxidative reactions of the pentose phosphate pathway produce NADPH Isomerization and interconversion reactions generate a variety of monosaccharides A summary of glucose metabolism 13.5 Clinical Connection: Disorders of Carbohydrate Metabolism Glycogen storage diseases aff ect liver and muscle 14 The Citric Acid Cycle 14.1 The Pyruvate Dehydrogenase Reaction The pyruvate dehydrogenase complex contains multiple copies of three different enzymes Pyruvate dehydrogenase converts pyruvate to acetyl-CoA 14.2 The Eight Reactions of the Citric Acid Cycle 1. Citrate synthase adds an acetyl group to oxaloacetate 2. Aconitase isomerizes citrate to isocitrate 3. Isocitrate dehydrogenase releases the first CO2 4. a-Ketoglutarate dehydrogenase releases the second CO2 5. Succinyl-CoA synthetase catalyzes substrate-level phosphorylation 6. Succinate dehydrogenase generates ubiquinol 7. Fumarase catalyzes a hydration reaction 8. Malate dehydrogenase regenerates oxaloacetate 14.3 Thermodynamics of the Citric Acid Cycle The citric acid cycle is an energy-generating catalytic cycle The citric acid cycle is regulated at three steps The citric acid cycle probably evolved as a synthetic pathway Box 14.A Mutations in Citric Acid Cycle Enzymes 14.4 Anabolic and Catabolic Functions of the Citric Acid Cycle Citric acid cycle intermediates are precursors of other molecules Anaplerotic reactions replenish citric acid cycle intermediates Box 14.B The Glyoxylate Pathway 15 Oxidative Phosphorylation 15.1 The Thermodynamics of Oxidation–Reduction Reactions Reduction potential indicates a substance’s tendency to accept electrons The free energy change can be calculated from the change in reduction potential 15.2 Mitochondrial Electron Transport Mitochondrial membranes define two compartments Complex I transfers electrons from NADH to ubiquinone Other oxidation reactions contribute to the ubiquinol pool Complex III transfers electrons from ubiquinol to cytochrome c Complex IV oxidizes cytochrome c and reduces O2 Box 15.A Free Radicals and Aging 15.3 Chemiosmosis Chemiosmosis links electron transport and oxidative phosphorylation The proton gradient is an electrochemical gradient 15.4 ATP Synthase ATP synthase rotates as it translocates protons The binding change mechanism explains how ATP is made The P:O ratio describes the stoichiometry of oxidative phosphorylation Box 15.B Uncoupling Agents Prevent ATP Synthesis The rate of oxidative phosphorylation depends on the rate of fuel catabolism 16 Photosynthesis 16.1 Chloroplasts and Solar Energy Pigments absorb light of different wavelengths Light-harvesting complexes transfer energy to the reaction center 16.2 The Light Reactions Photosystem II is a light-activated oxidation–reduction enzyme The oxygen-evolving complex of Photosystem II oxidizes water Cytochrome b6f links Photosystems I and II A second photooxidation occurs at Photosystem I Chemiosmosis provides the free energy for ATP synthesis 16.3 Carbon Fixation Rubisco catalyzes CO2 fixation Box 16.A The C4 Pathway The Calvin cycle rearranges sugar molecules The availability of light regulates carbon fixation Calvin cycle products are used to synthesize sucrose and starch 17 Lipid Metabolism 17.1 Lipid Transport 17.2 Fatty Acid Oxidation Fatty acids are activated before they are degraded Each round of ß oxidation has four reactions Degradation of unsaturated fatty acids requires isomerization and reduction Oxidation of odd-chain fatty acids yields propionyl-CoA Some fatty acid oxidation occurs in peroxisomes 17.3 Fatty Acid Synthesis Acetyl-CoA carboxylase catalyzes the first step of fatty acid synthesis Fatty acid synthase catalyzes seven reactions Other enzymes elongate and desaturate newly synthesized fatty acids Box 17.A Fats, Diet, and Heart Disease Fatty acid synthesis can be activated and inhibited Box 17.B Inhibitors of Fatty Acid Synthesis Acetyl-CoA can be converted to ketone bodies 17.4 Synthesis of Other Lipids Triacylglycerols and phospholipids are built from acyl-CoA groups Cholesterol synthesis begins with acetyl-CoA A summary of lipid metabolism 18 Nitrogen Metabolism 18.1 Nitrogen Fixation and Assimilation Nitrogenase converts N2 to NH3 Ammonia is assimilated by glutamine synthetase and glutamate synthase Transamination moves amino groups between compounds Box 18.A Transaminases in the Clinic 18.2 Amino Acid Biosynthesis Several amino acids are easily synthesized from common metabolites Amino acids with sulfur, branched chains, or aromatic groups are more diff icult to synthesize Box 18.B Glyphosate, the Most Popular Herbicide Amino acids are the precursors of some signaling molecules Box 18.C Nitric Oxide 18.3 Amino Acid Catabolism Amino acids are glucogenic, ketogenic, or both Box 18.D Diseases of Amino Acid Metabolism 18.4 Nitrogen Disposal: The Urea Cycle Glutamate supplies nitrogen to the urea cycle The urea cycle consists of four reactions 18.5 Nucleotide Metabolism Purine nucleotide synthesis yields IMP and then AMP and GMP Pyrimidine nucleotide synthesis yields UTP and CTP Ribonucleotide reductase converts ribonucleotides to deoxyribonucleotides Thymidine nucleotides are produced by methylation Nucleotide degradation produces uric acid or amino acids 19 Regulation of Mammalian Fuel Metabolism 19.1 Integration of Fuel Metabolism Organs are specialized for different functions Metabolites travel between organs Box 19.A The Intestinal Microbiome Contributes to Metabolism 19.2 Hormonal Control of Fuel Metabolism Insulin is released in response to glucose Insulin promotes fuel use and storage Glucagon and epinephrine trigger fuel mobilization Additional hormones influence fuel metabolism AMP-dependent protein kinase acts as a fuel sensor 19.3 Disorders of Fuel Metabolism The body generates glucose and ketone bodies during starvation Box 19.B Marasmus and Kwashiorkor Obesity has multiple causes Diabetes is characterized by hyperglycemia The metabolic syndrome links obesity and diabetes 19.4 Clinical Connection: Cancer Metabolism Aerobic glycolysis supports biosynthesis Cancer cells consume large amounts of glutamine Part 4 Genetic Information 20 DNA Replication and Repair 20.1 The DNA Replication Machinery Replication occurs in factories Helicases convert double-stranded DNA to single-stranded DNA DNA polymerase faces two problems DNA polymerases share a common structure and mechanism DNA polymerase proofreads newly synthesized DNA An RNase and a ligase are required to complete the lagging strand 20.2 Telomeres Telomerase extends chromosomes Box 20.A HIV Reverse Transcriptase Is telomerase activity linked to cell immortality? 20.3 DNA Damage and Repair DNA damage is unavoidable Repair enzymes restore some types of damaged DNA Base excision repair corrects the most frequent DNA lesions Nucleotide excision repair targets the second most common form of DNA damage Double-strand breaks can be repaired by joining the ends Recombination also restores broken DNA molecules 20.4 Clinical Connection: Cancer as a Genetic Disease Tumor growth depends on multiple events DNA repair pathways are closely linked to cancer 20.5 DNA Packaging DNA is negatively supercoiled Topoisomerases alter DNA supercoiling Eukaryotic DNA is packaged in nucleosomes 21 Transcription and RNA 21.1 Initiating Transcription What is a gene? DNA packaging affects transcription DNA also undergoes covalent modification Transcription begins at promoters Transcription factors recognize eukaryotic promoters Enhancers and silencers act at a distance from the promoter Box 21.A DNA-Binding Proteins Prokaryotic operons allow coordinated gene expression 21.2 RNA Polymerase RNA polymerases have a common structure and mechanism RNA polymerase is a processive enzyme Transcription elongation requires a conformational change in RNA polymerase Transcription is terminated in several ways 21.3 RNA Processing Eukaryotic mRNAs receive a 5' cap and a 3' poly(A) tail Splicing removes introns from eukaryotic RNA mRNA turnover and RNA interference limit gene expression rRNA and tRNA processing includes the addition, deletion, and modification of nucleotides RNAs have extensive secondary structure 22 Protein Synthesis 22.1 tRNA and the Genetic Code The genetic code is redundant tRNAs have a common structure tRNA aminoacylation consumes ATP Some synthetases have proofreading activity tRNA anticodons pair with mRNA codons Box 22.A The Genetic Code Expanded 22.2 Ribosome Structure The ribosome is mostly RNA Three tRNAs bind to the ribosome 22.3 Translation Initiation requires an initiator tRNA The appropriate tRNAs are delivered to the ribosome during elongation The peptidyl transferase active site catalyzes peptide bond formation Box 22.B Antibiotic Inhibitors of Protein Synthesis Release factors mediate translation termination Translation is efficient in vivo 22.4 Post-Translational Events Chaperones promote protein folding The signal recognition particle targets some proteins for membrane translocation Many proteins undergo covalent modification GLOSSARY ODD-NUMBERED SOLUTIONS INDEX