Textbook of biochemistry

Tags: Clinical Correlations, amino acids, DNA, proteins, metabolism, Protein Structure, Deficiency, Protein, pH, tertiary structure, Pyrimidine Nucleotide Metabolism, amino acid sequence, Recombinant DNA, Aminolevulinic acid synthase, Protein Metabolism, Oxygen, Respiratory acidosis, Respiratory system, Cytochromes P450, Posttranslational Modifications, Physiological Functions, Cytochrome P450 Electron Transport, Niemann Pick Disease, Heme Biosynthesis, Ceruloplasmin Deficiency, enzymatic processes, Amino Acid Metabolism, Retinitis Pigmentosa, Gas Transport, Heme Metabolism, Urea synthesis, phenylalanine metabolism, nucleotides, Urea Cycle, Prostaglandins, nitric oxide synthase gene, Carbon Dioxide, Prekallikrein Deficiency, RNA polymerase III, Iron Absorption, Respiratory alkalosis, Epithelial Transport, Absorption, Metabolizing Enzymes, Metabolic acidosis, Iron Metabolism, RNA processing, Primary Structure of Proteins, Amino Acid Composition of Proteins, Proteolytic enzymes, Editor John Wiley York Outline, biological molecules, Structure Function, Chaperone proteins, quaternary structure, biological function, amino acid sequence homology, amino acid composition, Textbook of Biochemistry With Clinical Correlations, Eukaryotic Cell Structure, Lysosomes function, Eukaryotic Cells, amino acid, plasma membrane, water molecules, Thomas M. Devlin, Functional Role, DNA Sequencing, Posttranslational Modification, Messenger RNA, RNA precursors, Messenger RNA Synthesis, Complementary DNA synthesis, Recombinant DNA technology, mRNA synthesis, Protein Synthesis, Primary Structure, Complement Proteins, conjugate acid and base, Amino Acid Analysis, Functional Roles, oxygen binding site, protein folding pathway, chemical properties, Complementary DNA
Content: Textbook of Biochemistry With Clinical Correlations, Fourth Edition, 1997 Thomas M. Devlin, Editor John Wiley York Outline with Key Concepts & Comments Added by Franklin R. Leach Chapter 1 Eukaryotic cell structure 1.1 Overview: Cells and Cellular Compartments 1.1.1 Cells are organized chemical systems. 1.2 Cellular Environment: Water and Solutes 1,2,1 Hydrogen bonds form between water molecules 1.2.2 Water has unique solvent properties ­ life is based on water as solvent 1.2.3. Some molecules ionize to form cations and anions 4.5.3 Weak electrolytes partially dissociate 1.25Water is a weak electrolyte with pH of 7.0 1.2.6 Many biological molecules are acids or bases 1.2.7 The Henderson-Hasselbalch equation defines the relationship between pH and concentrations of conjugate acid and base pH = pK' + log [base}/[acid] 1.2.8 Buffering is important in the control of pH. 1.2.9 The buffer capacity depends on the [acid] and [base]. 1.3 Organization and Composition of Eukaryotic Cells 1.3.1Cell membranes being semipermeable protect the cell. 1.4 functional role of Subcellular Organelles and Membranes 1.4.1 The plasma membrane is the cell boundary. 1.4.2 DNA and RNA synthesis occur in the nucleus. 1.4.3.The endoplasmic reticulum is the site of many kinds of synthesis. 1.4.4 The Golgi apparatus sequesters and processes proteins.
1.4.5 Mitochondria are the energy factories of the cell. 1.4.6 Lysosomes function in intracellular digestion. 1.4.7 Peroxisomes contain oxidative enzymes and metabolize hydrogen peroxide. 1.4.8 The cytoskeleton organizes the cell's contents. 1.4.9 The cytosol contains soluble components, is gel-like, and also has loser organization. 1.5 The cell is a complex organization where both structure and function are important. Clinical Correlations cc 1.1 Blood Bicarbonate Concentration in metabolic acidosis cc 1.2 Mitochondrial Diseases cc 1.3 Lysosomal Enzymes and Gout cc 1.4 Lysosomal Acid Lipase Deficiency cc 1.5 Zellweger Syndrome and the Absence of Functional Peroxisomes Chapter 2 Proteins I: Composition and Structure 2.1 Functional Roles of Proteins in Humans 2.1.1 Proteins are important biochemiCal Polymers to both structure and function. 2.2 Amino Acid Composition of Proteins 2.2.1 Proteins are linear polymers of _-amino acids. 2.2.2 Common amino acids have a common structure H RC-COOH NH2 2.2.3 The side chain (R) defines the structure as thus the chemical nature of the particular amino acid. 2.2.4 Most amino acids have an asymmetric center and are optically active. 2.2.5 Amino acids are polymerized into peptides and proteins. 2.2.6 Many amino acid derivatives are found in protein. They are posttranslationaly modified. 2.3 Charge and Chemical Properties of Amino Acids and Proteins 2.3.1 The ionization of amino acids and proteins are important in their biological function. 2.3.2 The ionic form of an amino acid is determined by pH. 2.3.3 At the isoelectrical point the molecule has a charge of 0. 2.3.4 Titration experiments can characterize ionization behavior of amino acids. 2.3.5 The charge influence movement in an electrical field.
2.3.6 At the pI the molecule doesn't move. 2.3.7 Amino acid R-groups can be polar or nonpolar. 2.3.8 Amino acids are chemically reactive. 2.4 Primary Structure of Proteins 2.4.1 Insulin is an illustration. 2.5 Higher Levels of Protein Organization 2.5.1 Proteins have secondary structure. Coiled _-helical structure. Flat _-sheets. Additional organization features. 2.5.2 Proteins fold into a 3-D tertiary structure. 2.5.3 There can be families of proteins with common structural parameters. 2.5.4 When multiple protein chains interact there is quaternary structure. 2.6 Other Types of Proteins 2.6.1 Examples of fibrous proteins are collagen, elastin, _-keratin, and tropomysin. Collagen is found in all human tissues and organs. Table 2.10 shows the amino acid composition of collagen. Collagen has long stretches where glycine occurs every third residue. A diagram of collagen is in Figure 2.38. There are covalent cross-links in collagen. Elastin has allysine-generated cross-links. 2.6.2 Lipoproteins are comlexes of lipids and proteins. 2.6.3 Glycoproteins contain carbohydrates and protein. 2.7 Folding of Proteins from Randomized to Unique Structures: Protein Stability 2.7.1 A possible pathway for protein folding pathway is presented. This is currently a very active research area. 2.7.2 Chaperone proteins assist in the folding process. 2.7.3 Noncovalent forces aid in folding and stability. 2.7.4 Denaturation of proteins leads to a loss of structure. 2.8 dynamic aspects of Protein Structure 2.8.1 Proteins are constantly in motion and are not in the static structure revealed by x-ray crystallography. 2.9 Methods for Characterization, Purification, and Study of Protein Structure and Organization 2.9.1 Proteins can be separated on the basis of charge. 2.9.2 Proteins can be separated on the basis of mass or size. 2.9.3 Proteins can be separated on the basis of chemical properties. 2.9.4 The amino acid sequence of a protein can be determined. 2.9.5 The 3-D structures of proteins can be determined by x-ray crystallograpphic methods. 2.9.6 Proteins can be characterized spectroscopically.
Clinical Correlations cc 2.1 Plasma Proteins in Diagnosis of Disease cc 2.2 Differences in Primary Structure of Insulins Used in Treatment of Diabetes Mellitus cc 2.3 A Nonconservative Mutation Occurs in Sickle Cell Anemia cc 2.4 Symptoms of Diseases of Abnormal Collagen Synthesis cc 2.5 Hyperlipidemias cc 2.6 Hypolipoproteinemias cc 2.7 Glycosylated Hemoglobin, HbA1c cc 2.8 Use of Amino Acid Analysis in Diagnosis of Disease Chapter 3 Proteins II: Structure Function Relationships in Protein Families 3.1 Overview 3.2 Antibody Molecules: The Immunoglobulin Superfamily 3.2.1 Immunogloblin molecules have four peptide chains. 3.2.2 The are both constant and variable regions. 3.2.3 Immunoglobulins in a single class contain common homologous regions. 3.2.4 Repeating amino acid sequences and homologous 3-D domains occur within an antibody. 3.2.5 There are two antigen-binding sites per antibody molecule. 3.2.6 The immunoglobulin fold is a tertiary structure found in a large family of proteins with different functions. 3.3 Proteins with a Common Catalytic Mechanism: Serine Proteases 3.3.1 Proteolytic enzymes are classified by catalytic mechanisms. 3.3.2 Serine proteases have remarkable specificity. 3.3.3 Serine proteases are synthesized as zymogens. 3.3.4 Serpins are natural inhibitors of serine proteases. 3.3.5 The serine proteases have similar structure/function relations. 3.3.6 There is amino acid sequence homology. 3.3.7 Tertiary structures are similar. 3.4 DNA-binding proteins 3.4.1 There are three major structural motifs for DNA-binding proteins. 3.4.2 DNA-binding proteins bind several ways to DNA. 3.5 Hemoglobin and Myoglobin 3.5.1 Human hemoglobin occurs in several forms. 3.5.2 A heme prosthetic group is at the oxygen binding site. 3.5.3 X-ray crystallography has defined the structures of hemoglobin and myoglobin. 3.5.4 Table 3.9 compares amino acid sequence of hemoglobin and myglobin. 3.5.5 A simple equilibrium defines oxygen binding to myoglobin. 3.5.6 The re is cooperativity in oxygen binding to hemoglobin. 3.5.7 The affinity of the T conformational state for oxygen is greater than that of the R conformatIon. 3.5.8 The Bohr effect involves dissociation of proton on binding an oxygen.
Clinical Correlations cc 3.1 The Complement Proteins cc 3.2 Functions of Different Antibody Classes cc 3.3 Immunization cc 3.4 Fibrin Formation in a Myocardial Infarct and the Action of Recombinant Tissue Plasminogen Activator (rtPA) cc 3.5 Involvement of Serine Proteases in Tumor Cell Metastasis
Chapter 4 Enzymes: Classification, Kinetics, and Control
4.1 General Concepts
4.1.1 Enzymes are special proteins that catalyze reactions.
4.1.2 Can have no protein cofactors.
4.2 Classification of Enzymes
4.2.1 Class 1 Oxidoreductases
4.2.2. Class 2 Transferases
4.2.3 Class 3 Hydrolases
4.2.4 Class 4 Lyases
4.2.5 Class 5 Isomerases
4.2.6 Class 6 Ligases
4.3 Kinetics
4.3.1 Kinetics studies the rate of change of reactants to products.
4.3.2 The rate equation is eq. 4.2. Reactions can be characterized bases on order Most reactions are reversible.
4.3.3 Enzymes can be saturated with substrate. Specific activity is enzyme units per mg protein. The enzyme binds the substrate. The Michaelis-Menten equation is eq 4.12.
velocity. KM is the substrate concentration that gives half maximum The equation can be linearlized The equation can be transformed in several ways.
4.3.4 An enzyme catalyzes both forward and reverse directions of a reversible
4.3.5 Multisubstrate reactions follow either a ping-pong or sequential
4.4 Coenzymes: Structure and Function
4.4.1 Coenzymes provide additional organic structures for catalytic function.
4.4.2 Adenosine triphosphate can serve as a phosphate donor or a modulator
of activity.
4.4.3 NAD+ and NADP+ are hydrogen-carrying coenzymes derived from
4.4.4 FMN and FAD are hydrogen-carrying coenzymes derived from
4.4.5 Metal ions can serve various functions as cofactors. Metals can have a structural role. Metals can function in redox reactions.
4.5 Inhibition of Enzymes
4.5.1 Competitive inhibitors can be reversed by increased [substrate].
4.5.2 Noncompetitve inhibitors do not prevent substrate binding.
4.5.3 Reversible inhibition leads to covalent modification of an enzyme. Many drugs inhibit enzyme action. Sulfa drugs compete with PABA. Methotrexate competes with folates. Nonclassical inhibitors that upon an enzyme's action
become a highly reactive species. Fluorouracil and 6-mercaptopurine are other significant
purine/pyrimidine inhibitors
4.6 Allosteric Control of Enzyme Activity
4.6.1 Allosteric inhibitors bind at sites different from substrate binding sites.
4.6.2 Allosteric enzymes exhibit sigmodial kinetics.
4.6.3 Cooperativity explains interaction between ligand sites in an oligomer
4.6.4 Regulatory subunits modulate the activity of catalytic subunits.
4.7 Enzyme Specificity: The Active Site
4.7.1 Complementarity of substrate and enzyme explains substrate secificity.,
4.7.2 Not all enzymes can distinguish between two isomers.
4.8 Mechanism of Catalysis
4.8.1 Enzymes decrease activation energy. Acid-base mechanisms can be used catalytically. Strain in the substrate can be introduced. Covalent bonds are sometimes formed during catalysis. Transition states can be stabilized. A decrease in entropy can function in catalysis.
4.8.2 Abzymes are artificially synthesized antibodies with catalytic activity.
4.8.3 Enviornmental factor can influence catalysis. Temperature pH
4.9 Clinical Applications of Enzymes
4.9.1 Coupled assays often involve changes that be monitored
4.9.2 Clinical analyzers use immobilized enzymes as reagents.
4.9.3 Enyme-linked immunoassays employ enzymes as indicators.
4.9.4 Isozymes are diagnostically important.
4.9.5 Some enzymes can be used as therapeutic agents..
4.9.6 Enzymes linked to insoluble matrices are used as chemical reactors.
4.10 Regulation of Enzyme Activity
Clinical Correlations
cc 4.1 A Case of Gout Demonstrates Two Phases in the Mechanism of Enzyme Action cc 4.2 The Physiological Effect of Changes in Enzyme Km Value cc 4.3 Mutation of a Coenzyme Binding Site Results in Clinical Disease cc 4.4 A Case of Gout Demonstrates the Difference Between an Allosteric and the Substrate- Binding Site cc 4.5 Thermal Lability of Glucose 6 Phosphate Dehydrogenase Results in Hemolytic Anemia cc 4.6 Alcohol Dehydrogenase Isoenzymes with Different pH Optima cc 4.7 Identification and Treatment of an Enzyme Deficiency cc 4.8 Ambiguity in the Assay of Mutated Enzymes Chapter 5 Biological Membranes: Structure and Membrane Transport 5.1 Overview 5.1.1 Membranes are important boundaries. 5.2 chemical composition of Membranes 5.2.1 Lipids are a major component of membranes. 5.2.2 Glycerophospholipids are the most abundant lipids of membranes. 5.2.3 Sphingolipids are also present in membranes. 5.2.4 Most membranes contain cholesterol. 5.2.5 The lipid compositions of various membranes differ. 5.2.6 Membrane proteins are classified by their easy of removal. 5.2.7 Carbohydrates of membranes are present as glycoprotein or glycolipids. 5.3 Micelles and Liposomes 5.3.1 Lipids form vesicular structures. 5.3.2 Liposomes have a membrane structure similar to that of a biological membrane. 5.4 Structure of Biological Membranes 5.4.1 The fludi mosaic model shown in Fig 5.21 explains membrane structure. 5.4.2 Integral membrane proteins are immersed in the lipid bilayer. 5.4.3 Perippheral membrane proteins have various modes of attachment. 5.4.4 Human erythrocytes are ideal for studying membrane structure. 5.4.5 Lipids are distributed in an asymmetric manner in membranes. 5.4.6 Proteins and lipids can diffuse in membranes. 5.5 Movement of Molecules Through Membranes 5.5.1 Some molecules can freely diffuse through membranes. 5.5.2 Movement of molecules across membranes can be facilitated. There can be membrane channels. Transporters can function in transport. Transport can be by group translocation. 5.5.3 Membrane Transport systems have common properties. 5.5.4 There are four common steps in transport. Recognition Translocation Release Recovery 5.5.5 Energetics of membrane transport systems. Passive Active 5.6 Channels and Pores 5.6.1 Channels and pores in membranes function differently. 5.6.2 Opening and closing of channels are controlled. Sodium channel Nicotinic-acetylcholine channel 5.6.3 Examples of pores are gap functions and nuclear pores. 5.7 Passive Mediated Transport Systems 5.7.1 Glucose transport is facilitated. 5.7.2 Cl- and HCO3- are transported by an antiport mechanism. 5.7.3 Mitochondria contain a number of transport systems. 5.8 Active Mediated Transport Systems 5.8.1 Translocation of Na+ and K+ is a primary active transport system. 5.8.2 All plasma membranes contain a Na+,K+-activated ATPase. 5.8.3 Erythrocyte ghosts are used to study Na+,K+ -activated translocation. 5.8.4 Ca2+ translocation is another example of a primary active transport system. 5.8.5 Na+-dependent transport of glucose and amino acids are secondary active transport systems. 5.8.6 Group translocation involves Chemical Modification of the substrate transported. 5.8.7 Summary of transport systems. 5.9 Ionophores Clinical Correlations cc 5.1 Liposomes as Carriers of Drugs and Enzymes cc 5.2 Abnormalities of Cell Membrane Fluidity in Disease States cc 5.3 Cystic Fibrosis and the Cl- Channel cc 5.4 Diseases Due to Loss of Membrane Transport Systems Chapter 6 Bioenergetics and Oxidative Metabolism 6.1 Energy Producing and Energy Utilizing Systems 6.1.1 ATP links energy producing and utilization. 6.2 Thermodynamic Relationships and Energy Rich Components 6.2.1 free energy is energy that is available for useful work. 6.2.2 The caloric value of dietary substances is shown in Tale 6.2. 6.2.3 Compounds are classified on the basis of energy release on hydrolysis of specific groups. 6.2.4 Free-energy changes can be determined in coupled enzyme reactions. 6.2.5 High-energy bond energies of various groups can be transferred from one compound to another. 6.3 Sources and Fates of Acetyl Coenzyme A 6.3.1 Metabolic sources and fates of pyruvate ­ an important cross-road.
6.3.2 Pyruvate dehydrogenase is a multienzyme complex. 6.3.3 Pyruvate dehydrogenase is strictly regulated. In bacteria the pryvuate dehydrogenase complex is regulated by products and substrates. In animals there is a covalent modification/demodification. 6.3.4 Acetyl CoA is used by several different pathways. 6.4 The Tricarboxylic Acid Cycle 6.4.1 The reactions of the tricarboxylic acid cycle are shown in Fig. 6.19. 6.4.2 Conversion of the acetyl group of acetyl CoA to CO2 and H2O conserves energy. 6.4.3 The activity of the tricarboxylic acid cycle is crefully regulated. 6.5 Structure and Compartmentation of the Mitochondrial Membranes 6.5.1 Inner and outer mitochondrial membranes have different compositions and functions. 6.5.2 Mitochondrial inner membranes contain substrate transport systems. 6.5.3 Substrate shuttles transport reducing equivalents across the inner mitochondrial membrane. 6.5.4 Acetyl units are transported by citrate. 6.5.5 Transport of adenine nucleotides and phosphate There is an adenine nucleotide translocator. Phosphate is transport by an exchanger. 6.5.6 Mitochondria have a specific calcium transport mechanism. 6.6 Electron Transfer 6.6.1 Redox reactions 6.6.2 Free-energy changes in redox reactions. 6.6.3 Mitochondrial electron transport is a multicomponent system. NAD-linked dehydrogenase Flavin-linked dehydrogenase Iron-sulfur centers Cytochromes Coenzyme Q 6.6.4 The mitochondrial ele4ctron transport chain is located in the inner membrane in a specific sequence. 6.6.5 Electron transport can be inhibited at specific sites. 6.6.6 Electron transport is reversible. 6.6.7 Oxidative phosphorylation is coupled to electron transport. 6.7 Oxidative Phosphorylation 6.7.1 The chemiosmotic-coupling mechanism involves the generation of a proton gradient and reversal of an ATP-dependent proton pump. Clinical Correlations cc 6.1 Pyruvate Dehydrogenase Deficiency cc 6.2 Fumarase Deficiency cc 6.3 Mitochondrial Myopathies cc 6.4 Subacute Necrotizing Encephalopathy cc 6.5 Cyanide Poisoning
cc 6.6 Hypoxic Injury Chapter 7 Carbohydrate Metabolism I: Major Metabolic Pathways and Their Control 7.1 Overview 7.1.1 Gucose is either the start or end of the major carbohydrate metabolic pathways. 7.1.2 Glycolysis ­ glucose utilization. 7.1.3 Gluconeogeneis ­ glucose synthesis. 7.1.4 your brain needs 100 g of glucose per day ­ it is the major energy source. 7.2 Glycolysis 7.2.1 Glycolysis occurs in all human cells. The overall reaction gl;ucose ­­> 2 pyruvate ­­>2 actyel CoA glucose + 6O2 + 38 ADP3- + 38 Pi2- ­­> 6CO2 + 6 H2O + 38 ATP47.2.1.3 Glucose is metabolized differently in various cells. 7.3 The Glycolytic Pathway 7.3.1 See Fig. 7.6 7.3.2 Glycolysis occurs in three stages (other authors divide into two stages). Stage 1 primes the glucose molecule. Stage 2 splits a phosphorylated intermediate. Stage 3 involves redox reactions and the synthesis of ATP. 7.3.3 A balance of reduction of NAD+ and reoxidation of NADH is required ­ role of lactic dehydrogenase. 7.3.4 NADH generated during glycolysis can be reoxidized via substrate shuttle systems. 7.3.5 Shuttles are important in other redox pathways. 7.3.6 Two shuttle pathways yield different amounts of ATP NADH ­ 3 Flavin ­ 2 7.3.7 Glycolysis can be inhibited at different stages. 7.4 Regulation of the Glycolytic Pathway 7.4.1 The regulatory enzymes are hexokinase, 6-phosphofructo-1kinase and pyruvate kinase. See Fig 7.13. 7.4.2 Hexokinase and glucokinase have different properties. See Fig. 7.14 7.4.3 6-Phosphofructo-1-kinase is the major regulatory site. Crossover theorem explains regulating of 6-phosphofructo-1kinase by ATP and AMP. Intracellular pH can regulate 6-phosphofructo-1-kinase. Intracellular citrate levels regulate 6-phosphfructo-1-kinase by cAMP and fructose 2,6-bisphophate. cAMP activates protein kinase A. 6-Phosphofructo-2-kinase and fructose 2,6-bisphosphase are domains of a bifunctional polypeptide regulated by phosphorylation/dephosphorylation.. See Fig 7.23. The heart contains a different isozyme of the bifunctional enzyme. 7.4.4 Pyruvate kinase is a regulated enzyme of glycolysis. 7.5 Gluconeogenesis 7.5.1 Glucose is required for survival. 7.5.2 The Cori and alanine cycles are paths for lactate and alanine return to the liver for gluconeogenesis. 7.5.3 Pathway of glucose synthesis from lactate includes lactic dehydrogenase and pyruvate kinase and requires 6 ATPs. 7.5.4 Pyruvate carboxylase and phosphoenolpyruvate carboxykinase also function in gluconeogeneis. 7.5.5 Gluconeogenesis uses many glycolytic enzymes but in the reverse direction. 7.5.6 Glucose can from synthesized from the carbon chains of glucogenic amino acids (all except leucine and lysine). 7.5.7 Glucose can be synthesized from odd-chain fatty acids via propionyl CoA. 7.5.8 Glucose can be synthesized from other sugars. Fructose Galactose Mannose 7.5.9 Gluconeogenesis requires expenditure of 6 ATPs per glucose formed. 7.5.10 Gluconeogenesis is regulated at the glucose 6-phosphatase, phosphofructokinase, and pyvuate carboxylase steps. These are catalyzed by enzymes that aren't a part of glycolysis. 7.5.11 Glucagon and insulin are hormones that regulate the balance of gluconeogenesis and glycolysis. 7.5.12 Ethanol ingestion inhibits gluconeogenesis. 7.6 Glycogenolysis and Glycogenesis 7.6.1 Glycogen, a storage form of glucose, serves as a ready source of energy. 7.6.2 Glycogen phosphorylase catalyzed the removal of one glucose unit as glucose 1-phosphate from glycogen. 7.6.2 The debranching enzyme is required for complete hydrolysis of glycogen. 7.6.3 Synthesis of glycogen requires unique enzymes. Glycogen synthase 7.6.4 There are special features of glycogen degradation and synthesis. We store glycogen because it is a good fuel reserve. Glycogenin, a protein, is required as a primer for glycogen synthesis. Glycogen limits its own synthesis. 4.5.4 Glycogen synthesis and degradation are highly regulated processes. Regulation of glycogen phosphorylase. See Fig. 7.57. The cascade that regulates glycogen phosphorylase amplifies a small signal into a very large effect. Regulation of glycogen synthase is shown in Fig. 7.58. Regulation of phosphoprotein phosphatases which functions for the removal of phosphates from proteins is part of the scheme. 4.5.5 Effector control of glycogen metabolism There is negative feedback control by glycogen. Phosphorylase functions as a glucose receptor in liver. Glucagon stimulates glycogen degradation in the liver. Epinephrine stimulates glycogen degradation in the liver. Epinephrine stimulates glycogen degradtion in heart and skeletal muscle. There is neural control of glycogen degradation in skeletal muscle. Insulin stimulates glycogen synthesis in muscle and liver. Clinical Correlations cc 7.1 Alcohol and Barbiturates cc 7.2 arsenic poisoning cc 7.3 Fructose Intolerance cc 7.4 Diabetes Mellitus cc 7.5 Lactic Acidosis cc 7.6 Pickled Pigs and Malignant Hyperthermia cc 7.7 Angina Pectoris and Myocardial Infarction cc 7.8 Pyruvate Kinase Deficiency and Hemolytic Anemia cc 7.9 Hypoglycemia and Premature Infants cc 7.10 Hypoglycemia and alcohol intoxication cc 7.11 Glycogen Storage Diseases Chapter 8 Carbohydrate Metabolism II: Special Pathways 8.1 Overview 8.1.1 Pentose phosphate pathway is also known as the hexose monophopsphate shunt or the 6-phosphogluconate pathway. 8.1.2 The various carbons of sugars can be shuffled via reactions in carbohydrate interconversions. 8.2 Pentose Phosphate Pathway 8.2.1 There are two phases in the pentose phosphate pathway. 8.2.2. First, glucose 6-phosphate is oxidized and decarboxylated to a pentose phosphate. 8.2.3 Then the interconversions of the pentose phosphates lead to glycolytic intermediates. 8.2.4 Glucose 6-phosphate can be completely oxidized to carbon dioxide. 8.2.5 The pentose phosphate pathway produces NADPH. 8.3 Sugar Interconversions and Nucleotide Sugar Formation
8.3.1 Isomerization and phoshporylation are common reactions for interconverting carbohydrates. 8.3.2 Nucleotide-linked sugars are intermediates in many sugar transformations. 8.3.3 Epimerization interconverts glucose and galactose. 8.3.4 Glucuronic acid is formed by oxidation of UDP-glucose. 8.3.5 Decarboxylation, oxidoreduiction, and transamination of sugars produce necessary produts. 8.3.6 Sialic acids are derived from N-acetylglucosamine. 8.4 Biosynthesis of Complex Carbohydrates 8.4.1 Glucosyltransferases specifically transfer to other carbohydrate containing molecules. 8.5 Glycoproteins 8.5.1 Glycoproteins contain variable amount of carbohydrate. 8.5.2 Carbohydrates are covalently linked to glycoproteins by N- or O- glycosyl bonds. 8.5.3 Synthesis of N-linked glycoproteins involves dolichol phosphate. 8.6 Proteoglycans 8.6.1 Hyaluronate is a copolymer of N-acetylglucosamine and glucuronic acid. 8.6.2 Chondroitin sulfates are the most abundant glycosaminoglycans. 8.6.3 Dermatan sulfate contains L-iduronic acid. 8.6.4 Heparin and heparan sulfate differ from other glycosaminoglycans 8.6.5 Kertan sulfate exists in two forms. 8.6.6 The biosynthesis of chondroitin sulfate is typical of glycosaminoglycan formatin. Clinical Correlations cc 8.1 Glucose 6 Phosphate Dehydrogenase: Genetic Deficiency or Presence of Genetic Variants inErythrocytes cc 8.2 Essential Fructosuria and Fructose Intolerance: Deficiency of Fructokinase and Fructose 1 PhosphateAldolase cc 8.3 Galactosemia: Inability to Transform Galactose into Glucose cc 8.4 Pentosuria: Deficiency of Xylitol Dehydrogenase cc 8.5 Glucuronic Acid: Physiological Significance of Glucuronide Formation cc 8.6 Blood Group Substances cc 8.7 Aspartylglycosylaminuria: Absence of 4 L Aspartylglycosamine Amidohydrolase cc 8.8 Heparin Is an Anticoagulant cc 8.9 Mucopolysaccharidoses Chapter 9 Lipid Metabolism I: Utilization and Storage of Energy in Lipid Form 9.1 Overview 9.1.1 Triacylglycerols are more efficient and qunatitative more important storage form of energy than glycogen. 9.2 Chemical Nature of Fatty Acids and Acylglycerols 9.2.1 Fatty acids are alkyl chains terminating in a carboxyl group.
9.2.2 Nomenclature of fatty acids. See Table 9.1. 9.2.3 Most fatty acids in humans occur as traiacylglycerols. 9.2.4 The hydrophobic nature of lipids is important to their biological function. 9.3 Sources of Fatty Acids 9.3.1 Most fatty acids are supplied in the diet. 9.3.2 Palmitate can be synthesized from acetylCoA. 9.3.3 Formation of malonyl CoA is the commitment step of fatty acid synthesis. 9.3.4 The reaction sequence of fatty acid synthesis is shown in Fig. 9.7. 9.3.5 Mammalian fatty acid synthase is a multifunctional polypeptide. 9.3.6 Stoichiometry ­ 8 acetyl CoAs, 7 ATPs, 14 NADPHs, and 14 protons are used to make palmitate. 9.3.7 Acetyl CoA must be transported from mitochondria to the cytosol for palmitate synthesis. 9.3.8 Palmitate is the precursor of other fatty acids. Elongation reactions add carbons. Desaturation reactions removed hydrogens. A series of reactions is involved in the synthesis and modification of polyunsaturated fatty acids. Hydroxy fatty acids are formed in nerve tissue. 9.3.9 Fatty acid synthesis can produce fatty acids other than palmitate. 9.3.10 Fatty acyl CoAs may be reduced to fatty alcohols. 9.4 Storage of Fatty Acids as Triacylglycerols 9.4.1 Triacylglycerols are synthesized from fatty acyl ColAs and glycerol 3-phsphate in most tissues. 9.4.2 Mobilization of triacylglycerols requires hydrolysis. 9.5 Methods of Interorgan Transport of Fatty Acids and Their Primary Products 9.5.1 Lipid-based energy is transported in the blood in different forms. Plasma lipoproteins can tracylglycerols and other lipids. Fatty acids can be bound to serum albumin. Ketone bodies are a lipid-based energy source used in starvation. 9.5.2 Lipases must hydrolyze blood triacylglycerols for their fatty acids to become available to tissues. 9.6 Utilization of Fatty Acids for Energy Production 9.6.1 -Oxidation of straight-chain fatty acids is the major energy-producing process. Fatty acids are activated by conversion to fatty acyl CoA. Carnitine carries acyl groups across the mitochondrial membrane. -Oxidation is a sequence of four reactions. 9.6.2 Comparison of the b-oxidation scheme with palmitate biosynthesis. See table 9.4. 9.6.3 Some fatty acids require modification of -oxidation for metabolism. Proprionyl CoA is produced by oxidation of odd-chain fatty acids. Oxidation of unsaturated fatty acids requires additional enzymes. Some fatty acids undergo -oxidation. -Oxidation gives rise to a dicarboxylic acid. 9.6.4 Ketone bodies are formed from acetyl CoA. HMG CoA is an intermediate in the synthesis of acetoacetate from acetyl CoA. Acetoacetate forms both D--hydroxybutyrate and acetone. Utilization of ketone bodies by nonhepatic tissues requires formation of acetoacetyl CoA. Starvation and certain pathological conditions lead to ketosis. 9.6.5 Peroxisomal oxidation of fatty acids serves many functions. Clinical Correlations cc 9.1 Obesity cc 9.2 Leptin and Obesity cc 9.3 Genetic Abnormalities in Lipid Energy Transport cc 9.4 Genetic Deficiencies in Carnitine or Carnitine Palmitoyl Transferase cc 9.5 Genetic Deficiencies in the Acyl CoA Dehydrogenases cc 9.6 Refsum's Disease cc 9.7 Diabetic Ketoacidosis Chapter 10 Lipid Metabolism II: Pathways of Metabolism of Special Lipids 10.1 Overview 10.2 Phospholipids 10.2.1 Phospholipids contain 1,2-diacylglycerol and a base connected by a phosphodiester bridge. 10.2.2 Phospholipids in membranes have various functions. Dipalmitoyllecithin is necessary for normal lung function. Inositides play a role in signal transduction. Phosphatidylinositol serves to anchor glycoproteins to the plasma membrane. 10.2.3 Biosynthesis of phospholipids. Phosphatidic acid is synthesized from -glycerophosphate and fatty acyl CoA. Specific phospholipids are synthesized by addition of a base to diacylglycerol. The asymmetric distribution of fatty acids in phospholipids is due to remodeling reactions. Plasmalogens are synthesized from fatty alcohol. 10.3 Cholesterol 10.3.1 Cholesterol, an alicyclic compound, is widely distributed in free and esterified forms. 10.3.2 Cholesterol is a membrane component and precursor of bile salts and steroid hormones.
10.3.3 Cholesterol is synthesized from acetyl CoA. Mevalonic acid is a key intermediate. Mevalonic acid is a precursor of farnesyl pyrophosphate. Cholesterol is formed from farnesyl pyrophosphate via squalene.
10.3.4 Cholesterol biosynthesis is carefully regulated.
10.3.5 Plasma cholesterol is in a dynamic state.
10.3.6 Cholesterol is excreted primarily as bile acids.
10.3.7 Vitamin D is synthesized from an intermediate of cholesterol
biosynthesis ­ dehydrocholesterol.
10.4 Sphingolipids
10.4.1 Biosynthesis of sphingosine
10.4.2 Ceramides are fatty acid amide derivatives of sphingosine.
10.4.3 Sphingomyelin is the only sphingolipid containing phosphorus. Sphingomyelin is synthesized from a ceramide and
10.4.4 Glycosphingolipids usually have a galactose or glucose unit. Cerebrosides are glycosylceramides. Sulfatide is a sulfuric acid ester of galactocerebroside. Globosides are ceramide oligosacchrides. Gangliosides contain sialic acid.
10.4.5 Sphingolipidoses are lysomal storage disease with defect in the
catabolic pathway for sphingolipids. Diagnostic enzyme assays for sphingolipidoses.
10.5 Prostaglandins and Thromboxanes
10.5.1 Prostaglandins and thromboxanes are derivatives of twenty-carbon,
monocarboxylic acids.
10.5.2 Synthesis of prostaglandins involvess a cyclooxygenase.
` Prostaglandin production is inhibited by steroidal and
nonsteroidal anti-inflammatory agents.
10.5.3 Prostaglandins exhibit many physiological effects.
10.6 Lipoxygenase and Oxyeicosatetraenoic Acids
10.6.1 Monohydroperoxyeicostetraenoic acids are produts of
lipoxygenase action.
10.6.2 Leukotrienes and hydroxyeicostertraenoic acids are hormones
derived from HPETEs.
10.6.3 Leukotrienes and HETEs affect several physiological processes.
Clinical Correlations cc 10.1 Respiratory Distress Syndrome cc 10.2 Treatment of Hypercholesterolemia cc 10.3 Atherosclerosis cc 10.4 Diagnosis of Gaucher's Disease in an Adult
Chapter 11 Amino Acid Metabolism
11.1 Overview
11.1 Human have "forgotten" how to synthesize 10 different amino acids. These must be supplied in the diet. They are listed in Table 11.2 Incorporation of Nitrogen into Amino Acids 11.2.1 Most amino acids are obtained from the diet. It is cheaper to import than manufacture. 11.2.2 Amino groups are transferred between different amino acids using keto acid intermediates and vitamin B6 coenzymes. 11.2.3 Pyridoxal phosphate is the cofactor for aminotransferases. 11.2.4 Glutamte dehydrogenase incorporates and produces ammonia. 11.2.5 Free ammonia is incorporated into and produced from glutamine. 11.2.6 The amide group of asparagine is derived from glutamine. 11.2.7 Amino acid oxidases remove amino groups. 11.3 Transport of Nitrogen to Liver and Kidney 11.3.1 Protein is degraded on a regular basis. 11.3.2 Amino acids are transported from muscle after proteolysis. 11.3.3 Ammonia is released in the liver and kidney. 11.4 Urea Cycle 11.4.1 The nitrogens of urea come from ammonia and aspartate. 11.4.2 The synthesis of urea requires five enzymes Carbamoyl phosphate synthetase I Ornithine transcarbamoylase Argininosuccinate synthetase Argininosuccinate lyase. Arginase. 11.4.3 Urea synthesis is regulated by an allosteric effector (N-acetylglutamate) and enzyme induction. 11.4.4 Metabolic disorders of urea synthesis have serious results. 11.5 Synthesis and Degradation of Individual Amino Acids 11.5.1 Glutamate is a precursor of glutahione and -aminobutyrate. 11.5.2 Arginine is also synthesized in intestines. 11.5.3 Ornithine and proline are both synthesized from glutamate. 11.5.4 Serine and glycine are synthesized from 3-phosphoglycerate. 11.5.5 Tetrahydrofolate is a cofactor in many reactions of amino acids as a one-carbon carrier. 11.5.6 Threonine is usually metabolism to lactate. 11.5.7 Phenylalanine and tyrosine Tyrosine is the first intermediate in phenylalanine metabolism. Dopamine, epinephrine, and norepinephrine are derivatives of tyrosine. Tyrosine is involved in synthesis of melanin, thyroid hormone, and quinoproteins. 11.5.8 Methionine and cysteine Methionoine is an essential amino acid. Cysteine is made from serine. Methionine first reacts with ATP. S-Adenosylmethioine is a methyl groups donor. AdoMet is the precursor of spermidine and spermine. Metabolism of cysteine produces sulfur-containg compounds. 11.5.9 Tryptophan (See Fig. 11.66) Tryptophan is a precursor of NAD. Pyridoxal phosphate has a prominent role in tryptophan metabolism. Kynurenine gives rise to neurotransmitters. Serotonin and melatonin are tryptophan derivatives. Tryptophan induces sleep. Initial reaction of BCAA (branched chain) metabolism are shared. Pathways of valine and isoleucine metabolism are similar. The leucine pathway differs from those of the other two branched-chain amino acids. Propionyl CoA is metabolized to succinyl CoA. 11.5.10 Lysine Carnitine is derived from lysine 11.5.11 Histidine Urinary formiminoglutamate is diagnostic for folate deficieny. Histiamine, carnosine, and anserine are produced from histidine. Creatine 11.5.12 Glutahtionine Glutathione is synthesized from three amino acids. The -glutamyl cycle transports amino acids. Glutathione concentration affects the response to toxins. Clinical Correlations cc 11.1 Carbamoylphosphate Synthetase and N-Acetylglutamate Synthetase Deficiencies cc 11.2 Deficiencies of Urea Cycle Enzymes cc 11.3 Nonketotic Hyperglycinemia cc 11.4 Folic Acid Deficiency cc 11.5 Phenylketonuria cc 11.6 Disorders of Tyrosine Metabolism cc 11.7 Parkinson's Disease cc 11.8 Hyperhomocysteinemia and Atherogenesis cc 11.9 Other Diseases of Sulfur Amino Acids cc 11.10 Diseases of Metabolism of Branched Chain Amino Acids cc 11.11 Diseases of Propionate and Methylmalonate Metabolism cc 11.12 Diseases Involving Lysine and Ornithine cc 11.13 Histidinemia cc 11.14 Diseases of Folate Metabolism Chapter 12 Purine and Pyrimidine Nucleotide Metabolism 12.1 Overview
12.1.1 The author of this chapter limited his discussion to only humans. 12.2 Metabolic Functions of Nucleotides 12.2.1 Roles of nucleotidetides Energy metabolism Monomeric units of nucleic acids Regulators Precursors Components of coenzymes (This is a subclass of 4) Activated intermediates (Similar to1) Allosteric effectors (I consider this a subclass of 3) 12.2.2 The distribution of nucleotides vary with cell type. 12.3 Chemistry of Nucleotides 12,3,1 Properties of nucleotides Absorb UV light RNA digested by base. 12.4 Metabolism of Purine Nucleotides 12.4.1 The purine nucleotides are synthesized by a series of reactions to form IMP. See fig 12.7. 12.4.2 IMP is the common precursor for AMP and GMP. See Fig. 12.10/ 12.4.3 Purine nucleotide synthesis is highly regulated. 12.4.4 Purine bases and nucleotides can be salvaged to reform nucleotides. 12.4.5 Purine nucleotides can be interconverted to maintain the appropriate balance of adenine and guanine nucleotides. 12.4.6 GTP is a precursor of tetrahydrobiopterin. 12.4.7 The end product of purine degradation in humans is uric acid. 12.4.8 Uric acid is formed by xanthine oxidase action. 12.5 Metabolism of Pyrimidine Nucleotides 12.5.1 Pyrimidine nucleotides are synthesized by a series of reaction leading to UMP. See Fig 12.17. 12.5.2 Pyrimidine nucleotide synthesis in humans is regulated at the level of carbamoyl phosphate synthetase II. 12.5.3 Pyrimidine bases are salvaged to reform nucleotides. 12.6 Deoxyribonucleotide Formation 12.6.1 Deoxyribonucleotides are formed by reduction of ribonucleotide diphopsphates. 12.6.2 Deoxythymidylate synthesis requires N5,N10-methylene tetrahydrofolate. 12.6.3 Pyrimidine interconversions emphasize deoxyribopyrimidine nucleotiside and nucleotides. 12.6.4 Pyrimidne nucleotides are degraded to -amino acids. 12.7 Nucleoside and Nucleotide Kinases 12.7.1 ATP can donate a phosphate to form the other NTPs. 12.8 Nucleotide Metabolizing Enzymes as a Function of the Cell Cycle and Rate of Cell Division 12.8.1 Enzymes of purine and pyrimidine nucleotide synthesis are elevated during the S phase of the cell cycle.
12.9 Nucleotide Coenzyme Synthesis 12.9.1 FAD see Fig. 12.33. 12.9.2 CoA see Fig. 12.34. 12.10 Synthesis and Utilization of 5-Phosphoribosyl-1-pyrophosphate 12.10.1 De novo synthesis of purines. Synthesis of 5-phosphoribosylamine. 12.10.2 Salvage of purine bases 12.10.3 De novo synthesis of pyrimidines. 12.10.4 Salvage of pyrimdines. 12.10.5 Synthesis of NAD+. 12.11 Compounds that Interfere with Cellular Purine and Pyrimidine Nucleotide Metabolism: Chemotherapeutic Agents 12.11.1 Antimetabolites are often structural analogs of bases or nucleosides. 12.11.2 Antifolates inhibit formation of tetrahydrofolate. 12.11.3 Glutamine anatgonists inhibit enzymes that utilize glutamine as nitrogen donors. 12.11.4 Other agents inhibit cell growth by interfering with nucleotide metabolism. 12.11.5 Purine and pyrimidine analogs can be antivirals. 12.11.6 Resistance against these agents can develop. Clinical Correlations cc 12.1 Gout cc 12.2 Lesch-Nyhan Syndrome cc 12.3 Immunodeficiency Diseases Associated with Defects in Purine Nucleoside Degradation cc 12.4 Hereditary Orotic Aciduria Chapter 13 Metabolic Interrelationships 13.1 Overview 13.1.1.Interrelationship examined in this chapter. 13.1.2 Feed-starve cycle 13.1.3 ATP cycle 13.2 Starve-Feed Cycle 13.2.1 In the well-fed state the diet supplies the energy requirement. See Fig. 13.2. 13.2.2 In the early fasting state hepatic glycoenolysis is an important source of blood glucose. 13.2.3 The fasting state requires gluconeogenesis from amino acids and glycerol. 13.2.4 In the early refed state, fat is metabolized normally, but normal glucose metabolism is slowly reestablished. See Fig. 13.6. 13.2.5 Other interorgan metabolic interactions Gut and kidney function together in the synthesis of arginine from glutamine. Liver provides glutathione for other tissues. Kidney and liver provide carnitine for other tissues. 13.2.6 Energy requirements, reserves, and caloric homeostasis 13.2.7 Glucose homeostasis has five stages. See Fig. 13.10. 13.3 Mechanisms Involved in Switching the Metabolism of Liver Between the Well-Fed State and the Starved State 13.3.1 Substrate availability controls many metabolic pathways. 13.3.2 Negative and positive allosteric effectors regulate key enzymes. 13.2.3 Covalent modificaiton and demodification regulates key enzymes. 13.2.4 Changes in levels of key enzymes are a longer term adaptive mechanism. 13.4 Metabolic Interrelationships of Tissues in Various Nutritional and Hormonal States 13.4.1 Staying in the well-fed state results in obesity and insulin resistance. 13.4.2 Noninsulin-dependent diabetes mellitus 13.4.3 Insulin-dependent diabetes mellitus 13.4.4 Aerobic and anaerobic exercise use different fuels. 13.4.5 Changes in pregnancy are related to fetal requirements and hormonal changes. 13.4.6 Lactation requires synthesis of lactose, triacyglycerol, and protein 13.4.7 Stress and injury lead to metabolic changes. 13.4.8 Liver disease causes major metabolic derangements. 13.4.9 In renal disease nitrogenous wastes accumulate. 13.4.10 Oxidation of ethanol in liver alters the NAD+/NADH ratio. 13.4.11 In acid-base regulation, glutamine plays a pivotal role. 13.4.12 The colon salvages energy from the diet. Clinical Correlations cc 13.1 Obesity cc 13.2 Protein Malnutrition cc 13.3 Starvation cc 13.4 Reye's Syndrome cc 13.5 Hyperglycemic, Hyperosmolar Coma cc 13.6 Hyperglycemia and Protein Glycosylation cc 13.7 Noninsulin-Dependent Diabetes Mellitus cc 13.8 Insulin-Dependent Diabetes Mellitus cc 13.9 Complications of Diabetes and the Polyol Pathway cc 13.10 Cancer Cachexia Chapter 14 DNA I: Structure and Conformation 14.1 Overview 14.1.1 DNA can transform cells. 14.1.2 DNA's information capacity is enormous. 14.2 Structure of DNA 14.2.1 Nucleotides joined by phosphodiester bonds form polynucleoties. 14.2.2 Nucleases hydrolyze phosphodiester bonds.
14.2.3 Periodicity leads to secondary structure/ Forces that determine polynucleotide confomation. Stacked Hydrophobic Dipole-induced dipole interactions DNA double helix 14.2.4 Many factors stabilize DNA structure. Denaturation Renaturation Hybridization DNA probes Heteroduplexes 14.3 Types of DNA Structure 14.3.1 Size of DNA is highly variable. Techniques for determining DNA size 14.3.2 DNA may b3 linear or circular Double-stranded circles Single-stranded DNA 14.3.3 Circular DNA is a superhelix. Geometric description of superhelical DNA. Topoisomerases 14.3.4 Alternative DNA conformations DNA bending Cruciform DNA Triple-standed DNA Four-stranded DNA. Slipped DNA. 14.3.5 Nucleoproteins of eukaryotes contain histones and nonhistone proteins. Nucleosomes and polynucelosomes. Polynucleosome packing into higher structures. 14.3.6 Nucleoproteins of prokaryotes are similar to those of eukaryotes. 14.4 DNA Structure and Function 14.4.1 Restriction endonuclease and palindromes 14.4.2 Most prokaryotic DNA codes for specific proteins. 14.4.3 Only a small percentage of eukaryotic DNA codes for structural genes. 14.4.4 Repeated sequences Single-copy DNA Moderately reiterated DNA Highlky reiterated DNA Inverted repeat DNA 14.4.5 Mitochondrial DNA. Clinical Correlations cc 14.1 DNA Vaccines cc 14.2 Diagnostic Use of Probes in Medicine cc 14.3 Topoisomerases in Treatment of Cancer
cc 14.4 Hereditary Persistence of Fetal Hemoglobin cc 14.5 Therapeutic Potential of Triplex DNA Formation cc 14.6 Expansion of DNA Triple Repeats and Human Disease cc 14.7 Mutations of Mitochondrial DNA: Aging and Degenerative Diseases
Chapter 15 DNA II: Repair, Synthesis, and Recombination
15.1 Overview
15.2 Formation of the Phosphodiester Bond in Vivo
15.2.1 DNA-dependent DNA polymerase of E. coli. Synthetic activity. Proofreading activity Structure of polymerases
15.2.2 Eukaryotic DNA polymerases
15.3 Mutation and Repair of DNA
15.3.1 Mutations are stable change in DNA structure. Chemical modificaion of bases. Radiation damage DNA polymerase errors Stretching of the double helix.
15.3.2 DNA is repaired rather than degraded.
. Excision repair in E. coli. Excision repair in eukaryotes. Mismatch repair Mechanism that reverse damage Postreplication repair. SOS postreplication repair.
1.5 DNA Replication
15.4.1 Complementary strands are basic to the mechanism of replication. Replication is semiconservative. A primer is required. Both strands of DNA serve as templates concurrently. Synthesis is discontinuous. Macroscopic synthesis is as a rule bidirectional Strands must unwind and separate.
1.5.6 Eschericia coli provides the basic model for replication of DNA> Initiation and progression of DNA synthesis. Termination of DNA synthesis. Rolling circle model for replication.
1.5.7 Eukaryotic DNA replication. Role eukaryotic DNA polymerases Initiation of eukaryotic DNA replication.
1.5.8 DNA replication at the end of linear chromosomes. Prokaryotic replication Eukaryotic replication: telomerases.
1.5.9 DNA can be synthesized using an RNA template.
1.5.10 DNA replication, repair, and transcription are closely coordinated. 1.6 DNA Recombination 15.5.1 Homologous recombination. Enzymes and proteins that catalyze homologous recombination 1.6.6 Site-specific recombination. 1.6.7 Transposition. 1.7 Sequencing of Nucleotides in DNA 15.6.1 Restriction maps give the sequence of segm,ents of DNA. Clinical Correlations cc 15.1 Mutations and the Etiology of Cancer cc 15.2 Defects in Nucleotide Excision Repair and Hereditary Diseases cc 15.3 DNA Ligase Activity and Bloom Syndrome cc 15.4 DNA Repair and Chemotherapy cc 15.5 Mismatch DNA Repair and Cancer cc 15.6 Telomerase Activity in Cancer and Aging cc 15.7 Inhibitors of Reverse Transcriptase in Treatment of AIDS cc 15.8 Immunoglobulin Genes Are Assembled by Recombination cc 15.9 Transposons and Development of Antibiotic Resistance cc 15.10 DNA Amplification and Development of Drug Resistance cc 15.11Nucleotide Sequence of the Human Genome Chapter 16 RNA: Structure, Transcription, and Processing 16.1 Overview 16.1. The central dogma. DNA ­>RNA­>protein 16.2 Structure of RNA 16.2.1 RNA is a polymer of ribonucleoside 5'-monophosphates. 16.2.2. Secondary structure of RNA involves intramolecular base pairing. 16.2.3 RNA molecules have tertiary structure. 16.3 Types of RNA 16.3.1 Transfer RNA has two roles: accepting activated amino acids and recognizing codons in mRNA. 16.3.2 Ribosomal RNA is part of the protein synthesis apparatus. 16.3.3 Messenger RNAs carry the information for the primary structure of proteins. 16.3.4 Mitochondria contain unique RNA species. 16.3.5 RNA in ribonucleoprotein particles 16.3.6 Some RNAs have catalytic activity. 16.3.7 RNAs can form binding sites for other molecules. 16.4 Mechanisms of Transcription 16.4.1 The initial process of RNA synthesis is transcription. 16.4.2 The template for RNA synthesis is DNA. 16.4.3 RNA polymerase catalyzes the transcription process. 16.4.4 The steps of transcription in prokaryotes have been determined. Initiation Elongation Termination 16.4.5 Transcription in eukaryotes involves many additional molecular events. The nature of active chromatin. Enhancers Transcription of ribosomal RNA genes. Transcription by RNA polymerase II. Promoters for mRNA synthesis Transcription by RNA polymerase III 16.5 Posttranscriptional Processing 16.5.1 Transfer RNA precursors are modified by cleavage, additions, and base modification. Cleavage Additions Modified nucleosides 16.5.2 Ribosomal RNA processing releases the various RNAs from a longer polymer. 16.5.3 Messenger RNA processing requires maintenance of the coding sequence. Blocking of the 5' terminus and poly(A) synthesis Removal of introns from mRNA precursors. Mutations in splicing signals cause human disease. Alternate pre-mRNA splicing can lead to multiple proteins being made from a single DNA coding sequence. 16.6 Nucleases and RNA Turnover Clinical Correlations cc 16.1 Staphylococcal Resistance to Erythromycin cc 16.2 Antibiotics and Toxins that Target RNA Polymerase cc 16.3 Fragile X Syndrome: A Chromatin Disease? cc 16.4 Involvement of Transcriptional Factors in Carcinogenesis cc 16.5 Thalassemia Due to Defects in Messenger RNA Synthesis cc 16.6 Autoimmunity in connective tissue Disease Chapter 17 Protein Synthesis: Translation and Posttranslational Modifications 17.1 Overview 17.2 Components of the Translational Apparatus 17.2.1 Messenger RNA is the carrier of genetic information from DNA. 17.2.2 Ribosomes are workbenches for protein biosynthesis. 17.2.3 Transfer RNA and activating enzymes act as a bilingual translator molecule. 17.2.4 The genetic code uses a four-letter alphabet of nucleotides. 17.2.5 Condons in mRNA are three-letter words. Punctuation: AUG is start and UAG, UAA, and UGA are stops.
17.2.6 Codon-anticodon interactions permit reading of mRNA. Breaking the genetic code. Mutations 17.2.7 Aminoacylation of tRNA activates amino acids for protein synthesis. Specificity and fidelity of aminoacylation reactions. 17.3 Protein Biosynthesis 17.3.1 Translation is directional and colinear with mRNA. 17.3.2 Initiation of protein synthesis is a comp9lex process. 17.3.3 Elongation is the stepwise formation of peptide bonds. 17.3.4 Termination of polypeptide synthesis requires a stop codon. 17.3.5 Translation has significant energy cost. 17.3.6 Protein synthesis in mitochondria differs slightly. 17.3.7 Some antibiotics and toxins inhibit protein biosynthesis. 17.4 Protein Maturation: Modification, Secretion, and Targeting 17.4.1 Proteins for export follow the secretory pathway. 17.4.2 Glycosylation of proteins occurs in the endoplasmic reticulum and Golgi apparatus. 17.5 Organelle Targeting and Biogenesis 17.5.1 Sorting of proteins targeted for lysosomes occurs in the secretory pathway. 17.5.2 Import of protein by mitochondria requires specific signals. 17.5.3 Targeting to other organelles requires specific signals. 17.6 Further Posttranslational Protein Modifications 17.6.1 Insulin biosynthesis involves partial proteolysis. 17.6.2 Proteolysis leads to zymogen activation. Amino acids can be modified after incorporation into proteins. See Table 17.10. 17.6.3 Collagen biosynthesis requires many posttranslational modifications. Procollagem formation occurs in the endoplasmic reticulum and Golgi appartus. Collagen maturation occurs extracellularly. 17.7 Regulation of Translation 17.8 Protein Degradation and Turnover 17.8.1 Intracelluar digestion of some proteins occurs in lysosomes. 17.8.2 Ubiquitin is a marker for an ATP-dependent proteolysis. Clinical Correlations cc 17.1 Missense Mutation: Hemoglobin cc 17.2 Disorders of Terminator Codons cc 17.3 Thalassemia cc 17.4 Mutation in Mitochondrial Ribosomal RNA Results in Antibiotic-Induced Deafness cc 17.5 I Cell Disease cc 17.6 Familial Hyperproinsulinemia cc 17.7 Absence of Posttranslational Modification: Multiple Sulfatase Deficiency cc 17.8 .Defects in Collagen Synthesis
cc 17.9 Deletion of a Codon, Incorrect Posttranslational Modification, and Premature Protein Degradation: Cystic Fibrosis Chapter18 Recombinant DNA and Biotechnology 18.1 Overview Sophisticated techniques that will be increasingly used in medicine. 18.2 The Polymerase Chain Reaction 18.2.1 Gives rapid production of large amounts of DNA from minute starting substrate. 18.3 Restriction Endonuclease and Restriction Maps 18.3.1 Restriction endonucleases permit selective hydrolysis of DNA to genomic restriction maps. 18.3.2 Restriction maps permit the routine preparation of defined seqments of DNA. 18.4 DNA Sequencing 18.4.1 Chemical cleavage method: Maxam-Gilbert procedure 18.4.2 Interrupted enzymatic synthesis method: Sanger procedure. 18.5 Recombinant DNA and Cloning 18.5.1 DNA from different sources can be ligated to form a new DNA species: recombinant DNA. 18.5.2 Recombinant DNA vectors can be produced in significant quantities by cloning. 18.5.3 DNA can be inserted into vector DNA in a specific direction: directional cloning. 18.5.4 Bacteria can be transformed with recombinant DNA. 18.5.5 It is necessary to be able to select transformed bacteria. 18.5.6 Recombinanat DNA molecules in a gene library. 18.5.7 PCR may circumvent the need to clone DNA. 18.6 Selection of Specific Cloned DNA in Libraries 18.6.1 Loss of antibiotic resistance is used to select transformed bacteria. 18.6.2 -Complementation for selecting bacteria carrying recombinant plasmids. 18.7 Techniques for Detection and Identification of Nucleic Acids 18.7.1 Nucleic acids can serve as probes for specific DNA or RNA sequences. 18.7.2 Southern blot technique is useful for identifying DNA fragments. 18.7.3 Single-strand conformation polymorphism. 18.8 Complementary DNA and Complementary DNA Libraries 18.8.1 mRNA is used as a template for DNA synthesis using reverse transcriptase. 18.8.2 Desired mRNA is a sample can be enriched by separation techniques. 18.8.3 Complementary DNA synthesis. 18.8.4 Total cellular RNA may be used as a template for DNSA synthesis using RT-PCR. 18.9 Bacteriophage, Cosmid, and Yeast Cloning Vectors
18.9.1 Bacteriophage as cloning vectors. 18.9.2 Screening bacteriophage libraries. 18.9.3 Cloning DNA fragments into cosmid and yeast artificial chromosome vectors. 18.10 Techniques to Further Analyze Long Stretches of DNA 18.10.1 Subcloning permits definition of large segments of DNA. 18.10.2 Chromosome walking is a technique to define gene arrangement in long stretches of DNA. 18.11 Expression Vectors and Fusion Proteins 18.11.1 Foreign genes can be expressed in bacteria allowing synthesis of their encoded proteins. 18.12 Expression Vectors in Eukaryotic Cells 18.12.1 DNA elements required for expression of vectors in mammalian cells. 18.12.2 Transfected eukaryotic cells can be selected by utilizing mutant cells that require specific nutrients. 18.12.3 Foreign genes can be expressed in eukaryotic cells by utilizing virus transformed cells. 18.13 Site Directed Mutagenesis 18.13.1 Role of flanking regions in DNA can be evaluated by deletion and insertion mutations. 18.13.2 Site-directed mutagenesis of a single nucleotide. 18.14 Applications of Recombinant DNA Technologies 18.14.1 Antisense nucleic acids hold promise as research tools and in therapy 18.14.2 Normal genes can be introduced into cells with a defective gene in gene therapy. 18.14.3 Transgenic animals 18.14.4 Recombinant DNA in agricultural will have significant commercial impact. 18.15 Concluding Remarks Clinical Correlations cc 18.1Polymerase Chain Reaction and Screening for Human Immunodeficiency Virus cc 18.2 Restriction Mapping and Evolution cc 18.3 Direct Sequencing of DNA for Diagnosis of Genetic Disorders cc 18.4 Multiplex PCR Analysis of HGPRTase Gene Defects in Lesch-Nyhan Syndrome cc 18.5 Restriction Fragment Length Polymorphisms Determine the Clonal Origin of Tumors cc 18.6 Site-Directed Mutagenesis of HSV IgD cc 18.7 Normal Genes Can be Introduced into Cells with Defective Genes in Gene Therapy cc 18.8 Transgenic Animal Models Chapter 19 Regulation of Gene Expression 19.1 Overview 19.2 Unit of Transcription in Bacteria: The Operon 19.2.1 Partial genetic map of E. coli. See fig. 19.1. 19.3 Lactose Operon of E. coli
19.3.1 Repressor of the lactose operon is a diffusible protein. 19.3.2 Operator sequence of the lactose operon is contiguous on DNA with a promoter and three structural genes. See Fig. 19.4. 19.3.3 Promoter sequence of lactose operon contains recognition sites for RNA polymerase and a regulator protein. 19.3.4 Catabolite activator protein binds at a site on the lactose promotor. 19.4 Tryptophan Operon of E. coli 19.4.1 The tryptophan operon is controlled by a repressor protein. 19.4.2 The tryptophan operon has a second control site: the attenuator site. 19.4.3 Transcription attenuation is a mechanism of control in operons for amino acid biosynthesis. 19.5 Other Bacterial Operons 19.5.1 Synthesis of ribosomal proteins is regulated in a coordinated manner. 19.5.2 The stringent response controls synthesis of rRNAs and tRNAs. 19.6 Bacterial Transposons 19.6.1 Transposons are mobile segments of DNA. 19.6.2 The Tn3 transposon contains three structural genes. 19.7 Inversion of Genes in Salmonella 19.8 Organization of Genes in Mammalian DNA 19.8.1 Only a small fraction of eukaryotic DNA codes for proteins. 19.8.2 Eukaryotic genes usually contain interventing sequences (introns). 19.9 Repetitive DNA sequences in Eukaryotes 19.9.1 The importance of highly repetitive sequences is unknown. 19.9.2 A variety of repeating units are defined as moderately repetitive sequences. 19.10 Genes for Globin Proteins 19.10.1 Recombinant DNA technology has been used to clone genes for many eukaryotic processes. 19.10.2 Sickle cell anemia is due to a single base pair change. 19.10.3 Thalassemias are caused by mutations in genes for the or subunits of globin. 19.11 Genes for Human Growth Hormone-like Proteins 19.12 Mitochondrial Genes. See Fig. 19.27. 19.13 Bacterial Expression of Foreign Genes 19.13.1 Recombinant bacteria can synthesize human insulin. 19.13.2 Recombinant bacteria can synthesis human growth hormone. 19.14 Introduction of Rat Growth Hormone Gene into Mice Clinical Correlations cc 19.1 Transmissible Multiple Drug Resistances cc 19.2 Duchenne/Becker Muscular Dystrophy and the Dystrophin Gene cc 19.3 Prenatal Diagnosis of Sickle Cell Anemia cc 19.4 Prenatal Diagnosis of Thalassemia cc 19.5 Leber Hereditary Optic Neuropathy (LHON) cc 19.6 Huntington Disease and Unstable Trinucleotide Expansions
Chapter 20 Biochemistry of Hormones I: Polypeptide Hormones 20.1 Overview 20.1.1 Hormones bind to their cognate receptor. 20.1.2 There are peptide, amino acid, and steroid hormones. 20.1.3 The signals of many hormones are amplified by a cascade system involving second messengers. 20.2 Hormones and the Hormonal Cascade System 20.2.1 A cascade amplification system is shown in Fig. 20.2 Hypthalmic interrelationships are shown in Fig. 20.3. 20.2.2 Polypeptide hormones of the anterior pituitary are shown in Fig. 20.4. 20.3 Major Polypeptide Hormones and Their Actions 20.3.1 Table 20.2 summaries the important polypeptide hormones. 20.4 Genes and Formation of Polypeptide Hormones 20.4.1 Propiomelanocortin is a precursor polypeptide for eight hormones. See. Fig. 20.5. 20.4.2 Many polypeptide hormones are encoded together in a single gene. 20.4.3 Multiple copies of a hormone can be encoded on a single gene. 20.5 Synthesis of Amino Acid-Derived Hormones 20.5.1 Epinephrine is synthesized from phenylalanine/tyrosine. 20.5.2 The synthesis of thyroid hormone requires incorporation of iodine into a tyrosine of thyroglobulin. 20.6 Inactivation and Degradation of Hormones 20.7 Cell Regulation and Hormone Secretion 20.7.1 G-proteins serve as cellular transducers of hormone signals. See Fig. 20.17. 20.7.2 cAMP activates a protein kinase a pathway. 20.7.3 Inositiol triphosphate formation leads to release of calcium from intracellular stores. 20.7.4 Diacylglycerol activates protein kinase C pathway. 20.8 Cyclic Hormonal Cascade Systems 20.8.1 Melatonin and serotonin synthesis are controlled by light and dark cycles 20.8.2 The ovarian cycle is controlled by gonadotropin-releasing hormone. Absence of fertilization. 20.8.3 Fertilization 20.9 Hormone-Receptor Interactions 20.9.1 Scatchard analysis permits determination of the number of receptorbinding sites and association constant for ligand. 20.9.2 Some hormone-receptor interactions involve multiple hormone subunits. 20.10 Structure of Receptors: -Adrenergic Receptor 20.11 Internalization of Receptors 20.11.1 Clathrin forms a lattice structure to direct internalization of hormone-receptor complexes from the plasma membrane.
20.12 Intracellular Action: Protein Kinases 20.12.1 Insulin receptor: transduction through tyrosine kinase 20.12.2 Activity of vasopressin: protein kinase A. 20.12.3 Gonadotropin-releasing hormone (GnRH): Protein kinase C 20.12.4 Activity of atrial natriuretic factor (ANF): protein kinase G. 20.13 Oncogenes and Receptor Functions 20.13.1 The known oncogenes are summarized in Table 20.9. Clinical Correlations cc 20.1 Testing Activity of the Anterior Pituitary cc 20.2 Hypopituitarism cc 20.3 Lithium Treatment of Manic Depressive Illness: The Phosphatidylinositol Cycle Chapter 21 Biochemistry of Hormones II: Steroid Hormones 21.1 Overview 21.2 Structures of Steroid Hormones 21.2.1 The major steroid hormones of humans are listed in Table 21.1. 21.3 Biosynthesis of Steroid Hormones 21.3.1 Steroid hormones are synthesized from cholesterol. 21.4 Metabolic Inactivation of Steroid Hormones 21.5 Cell-Cell Communication and Control of Synthesis and Release of Steroid Hormones 21.5.1. Steroid hormone synthesis is controlled by specific hormones. Aldosterone. Estradiol Vitamin D3 21.6 Transport of Steroid Hormones in Blood 21.6.1 Steroid hormones are bound to specific proteins or albumin in blood. 21.7 Steroid Hormone Receptors 21.7.1 Steroid hormones bind to specific intracellular protein receptors. 21.7.2 Some steroid receptors are part of the cErbA family of protooncogenes. 21.8 Receptor Activation: Upregulation and Downregulation 21.8.1 Steroid receptors can be upregulated or downregulated depending on exposure to hormone. 21.9 A Specific Example of Steroid Hormone Action at Cell Level: Programmed Death Clinical Correlations cc 21.1 Oral Contraception cc 21.2 Apparent Mineralocorticoid Excess Syndrome cc 21.3 Programmed Cell Death in the Ovarian Cycle
Chapter 22 Molecular Cell Biology 22.1 Overview 22.2 Nervous Tissue: Metabolism and Function 22.2.1 ATP and transmembrane electrical potential in neurons. 22.2.2 Neuron-neuron interaction occurs through synapses. 22.2.3 Synthesis, storage, and release of neurotransmitters. Listed in Table 22.1. Proteins listed in Table 22.2 22.3.4 Termination of signals at synaptic junctions. Acetylcholine Catecholamines Serotonin (5-hydroxytryptamine) 4-Aminobutyrate 22.3.5. Neuropeptides are derived from precursor proteins. 22.3 The Eye: Metabolism and Vision 22.3.1 The cornea derives ATP from aerobic metabolism. 22.3.2 Lens consists mostly of water and proteins. 22.3.3 The retina derives ATP from anaerobic glycolysis. 22.3.4 Visual transduction involves photochemical, biochemical, and electric events. The biochemical events of the visual cycle are shown in Fig. 22.24. 22.3.5 Photoreceptor cells are rods and cones. 22.3.6 Color vision originates in the cones. 22.3.7 Other physical and chemical differences between rods and cones. 22.4 Muscle Contraction 22.4.1 Skeletal muscle contraction follows an electrical to chemical to mechanical path. 22.4.2 Myosin forms the thick filament of muscle. 22.4.3 Actin, tropomyosin, and troponin are thin filament proteins. 22.4.4 Muscle contraction requires Ca2+ interaction. 22.4.5 Energy for muscle contraction is supplied by ATP hydrolysis. 22.4.6 Model for skeletal muscle contraction is shown in Fig. 22.34. 22.4.7 Calcium regulates smooth muscle contraction. 22.5 Mechanism of Blood Coagulation 22.5.1 Clot formation is a membrane-mediated process. 22.5.2 Reactions of the intrinsic pathway. 22.5.3 Reactions of the extrinsic pathway. 22.5.4 Thrombin converts fibrinogen to fibrin. 22.5.5 Major roles of thrombin. 22.5.6 Formation of a platelet plug. 22.5.7 Properties of some of the proteins involved in coagulation. 22.5.8 Role of vitamin K in protein carboxylase reactions. 22.5.9 Control of the synthesis of Gla-proteins. 22.5.10 Dual role of thrombin in promoting coagulation and clot dissolution.
22.5.11 The allosteric role of thrombin in controlling coagulation. 22.5.12 Inhibitors of the plasma serineproteinases. 22.5.13 Fibrinolysis requires plaminogen and tissue plasminogen activator to produce plasmin. Clinical Correlations cc 22.1 Lambert Eaton Myasthenic Syndrome cc 22.2 Myasthenia Gravis: A Neuromuscular Disorder cc 22.3 Macula Degeneration Other Causes of Loss of Vision cc 22.4 Niemann Pick Disease and Retinitis Pigmentosa cc 22.5 Retinitis Pigmentosa Resulting from a de Novo Mutation in the Gene Codingfor Peripherin cc 22.6 Chromosomal Location of Genes for Vision cc 22.7 Troponin Subunits as Markers for Myocardial Infarction cc 22.8 Voltage Gated Ion Channelopathies cc 22.9 Intrinsic Pathway Defects Prekallikrein Deficiency cc 22.10 Classic Hemophilia cc 22.11 Thrombosis and Defects of the Protein C Pathw Chapter 23 Biotransformations: The Cytochromes P450 23.1 Overview 23.1.1 A family of heme proteins. 23.2 Cytochrome P450: Nomenclature and Overall Reaction 23.2.1 Endoplasmic reticulum or microsomes. 23.3 Cytochrome P450: Multiple Forms 23.3.1 Multiplicity of genes produces many forms of cytochrome P450. Substrate specificity Induction of cytochrome P450 Polymorphisms. 23.4 Inhibitors of Cytochrome P450 23.5 Cytochrome P450 Electron Transport Systems 23.5.1 NADH-adrenodoxin reductase is the flavoprotein donor in mitochondria. 23.6 Physiological Functions of Cytochromes P450 23.6.1 Cytochrome P450 participate in synthesis of steroid hormones and oxygenation of eicosanoids. 23.6.2 Cytochrome P450 oxidize exogenous lipophilic substrates. 23.7 Other Hemoprotein and Flavoprotein-Mediated Oxygenations: The Nitric Oxide Synthases 23.7.1 Three distinct nitric oxide synthase gene products display diverse physiological functions. 23.7.2 Structural aspects of nitric oxide synthases. Clinical Correlations cc 23.1 Consequences of Induction of Drug Metabolizing Enzymes cc 23.2 Genetic Polymorphisms of Drug-Metabolizing Enzymes
cc 23.3 Deficiency of Cytochrome P450 21 Hydroxylase cc 23.4 Steroid Hormone Production During Pregnancy cc 23.5 Clinical Aspects of Nitric Oxide Production Chapter 24 Iron and Heme Metabolism 24.1 Iron Metabolism: Overview 24.1.1 Two oxidation state 2+ and 3+. 24.2 Iron-Containing Proteins 24.2.2 Transferrin transports iron in serum 24.2.3 Lactoferrin binds iron in milk. 24.2.4 Ferritin is a protein involved in the storage of iron. 24.2.5 Other nonheme iron-containing proteins are involved in enzymatic processes. 24.3 Intestinal Absorption of Iron 24.3.1 Major site is the small intestines. 24.4 Molecular Regulation of Iron Utilization 24.4.1 Iron regulatory proteins. 24.4.2 stem-loop structure 24.5 Iron Distribution and Kinetics 24.6 Heme Biosynthesis 24.6.1 Enzymes in heme biosynthesis occur in both mitochondria and cytosol 24.6.1 Aminolevulinic acid synthase 24.6.2 ALA dehydratase 24.6.3 Porphobilinogen deaminase 24.6.4 Uroporphyrinogen decarboxylase. 24.6.5 Coproporphyrinogen oxidase. 24.6.6 Protoporphyrinogen oxidase. 24.6.7 Ferochelatase 24.6.2 ALA synthase catalyzes the rate-limiting step of heme biosynthesis. 24.7 Heme Catabolism 24.7.1 Bilirubin is conjugated to form bilirubin diglucuronide in liver. See Fig. 24.13. 24.7.2 Intravascular hemolysis requires scavenging of iron. Clinical Correlations cc 24.1 Iron Overload and Infection cc 24.2 Duodenal Iron Absorption cc 24.3 Mutant Iron-Responsive Element cc 24.4 Ceruloplasmin Deficiency cc 24.5 Iron-Deficiency Anemia cc 24.6 Hemochromatosis and Iron-Fortified Diet cc 24.7 Acute Intermittent Porphyria cc 24.8 Neonatal Isoimmune Hemolysis cc 24.9 Bilirubin UDP-Glucuronosyltransferase Deficiency cc 24.10 Elevation of Serum Conjugated Bilirubin
Chapter 25 Gas Transport and pH Regulation 25.1 Introduction to Gas Transport 25.2 Need for a Carrier of Oxygen in the Blood 25.2.1 Respiratory system anatomy affects blood gas concentration. 25.2.2 A physiological oxygen crrier must have unusual properties. 25.2.3 The steep part of the curve lies in the physiological range. 25.3 Hemoglobin and Allosterism: Effect of 2,3 Bisphosphoglycerate 25.4 Other Hemoglobins 25.5 Physical Factors that Affect Oxygen Binding 25.5.1 High temperature weakens hemoglobin's oxygen affinity. 25.5.2 Low pH weakens hemoglobin's oxygen affinity. 25.6 Carbon Dioxide Transport 25.6.1 Blood CO2 is present in three major forms. 25.6.2 Bicarbonate formation. 25.6.3 Carbaminohemoglobin formation. 25.6.4 Two processes regulate [H+] derived from CO2 transport. Buffering mechanism 25.6.5 HCO3- distribution between plasma and erythrocytes. 25.7 Interrelationships Among Hemoglobin, Oxygen, Carbon Dioxide, Hydrogen Ion, and 2,3 Bisphosphoglycerate 25.8 Introduction to pH Regulation 25.9 Buffer Systems of Plasma, Interstitial Fluid, and Cells 25.10 The Carbon Dioxide-Bicarbonate Buffer System 25.10.1 The chemistry of the system 25.10.2 The carbon dioxide-bicarbonate buffer system is an open system. 25.10.3 Graphical representation: the pH-bicarbonate diagram. See Fig. 25.18. 25.11 Acid-Base Balance and Its Maintenance 25.11.1 The kidney plays a critical role in acid-base balance. 25.11.2 Urine formation occurs primarily in the nephron. 25.11.3 The three fates of excreted H+. 25.11.4 Total acidity of the urine. 25.12 Compensatory Mechanisms 25.12.1 Principles of compensation. three states of compensation defined Compensated. Uncompensated Partially compensated. 1.2.8 Specidic compensatory processes Respiratory acidosis. Respiratory alkalosis. Metabolic acidosis. Metabolic alkalosis 1.3 Alternative Measures of Acid-Base Imbalance
25.14 The Significance of Na+ and Cl- in Acid-Base Imbalance Clinical Correlations cc 25.1 Diaspirin Hemoglobin cc 25.2 Cyanosis cc 25.3 Chemically Modified Hemoglobins: Methemoglobin and Sulfhemoglobin cc 25.4 Hemoglobins with Abnormal Oxygen Affinity cc 25.5 The Case of the Variable Constant cc 25.6 The Role of Bone in Acid-Base Homeostasis cc 25.7 Acute Respiratory Alkalosis cc 25.8 Chronic Respiratory Acidosis cc 25.9 Salicylate Poisoning cc 25.10 Evaluation of Clinical Acid-Base Data cc 25.11 Metabolic Alkalosis Chapter 26 Digestion and Absorption of Basic Nutritional Constituents 26.1 Overview 26.1.1 Importance ­ thus look at the infomericals and popular books. 26.1.2 Gastrointestinal organs have multiple functions in digestion. See Fig. 26.1 26.2 Digestion: General Considerations 26.2.1 The pancreas supplies enzymes for intestinal digestion. 26.2.2 Digestive enzymes are secreted as proenzymes. 26.2.3 Regulation of secretion occurs through secretagogues. neurotransmitters, hormones, pharmacological agents, and some bacterial toxins. See Table 26.3 for the physiological ones. 26.3 Epithelial Transport 26.3.1 Solute transport may be transcellular or paracellular. 26.3.2 NaCl absorption has both active and passive components. 26.3.3 NaCl secretion depends on contraluminal Na+,K+-ATPase. 26.3.4 Concentration gradients or electrical potential drive transport of nutrients. 26.3.5 Gastric parietal cells secrete HCl. 26.4 Digestion and Absorption of Proteins 26.4.1 Mixture of peptidasses assures efficient protein digestion. See Table 26.6. 26.4.2 Pepsins catalyze gastric digestion of protein 26.4.3 Pancreatic zymogens are activated in the small intestine. 26.4.4 Intestinal peptidases digest small peptides. 26.4.5 Free amino acids and dipeptides are absorbed by carrier-mediated transport. 26.4.6 Fetus and neonate can absorb intact proteins. 26.5 Digestion and Absorption of Carbohydrates
26.5.1 Do- and polysaccharides require hydrolysis. 26.5.2 Monosaccharides are absorbed by carrier-mediated transport. 26.6 Digestion and Absorption of Lipids 26.6.1 Lipid digestion requires overcoming the limited water solubility of lipids. 26.6.2 Lipids are digested by gastric and pancreatic lipases. 26.6.3 Bile acid micelles solubilize lipids during digestion. 26.6.4 Most absorbed lipids are incorporated into chylomicrons 26.7 Bile Acid Metabolism Clinical Correlations cc 26.1 Cystic Fibrosis cc 26.2 Bacterial Toxigenic Diarrheas and Electrolyte Replacement Therapy cc 26.3 Neutral Amino Aciduria (Hartnup Disease) cc 26.4 Disaccharidase Deficiency cc 26.5 Cholesterol Stones cc 26.6 A--Lipoproteinemia Chapter 27 Principles of Nutrition I: Macronutrients 27.1 Overview 27.1.1 Under nutrition 27.1.2 Over nutrition 27.1.3 Optimal nutrition 27.2 Energy Metabolism 27.2.1 The energy content of food is measured in kilocalories. 27.2.2 The energy expenditure is influenced by four factors. Surface area Age Sex Activity level 27.3 Protein Metabolism 27.3.1 Dietary protein serves many roles including energy production. 27.3.2 Nitrogen balance relates intake of nitrogen to its excretion. 27.3.3 essential amino acids must be present in the diet. 27.3.4 Protein sparing is related to the dietary content of carbohydrate and fat. 27.3.5 Normal adult protein requirements depend on diet. 0.8 g/kg per day 58 g for a 160-lb man. 27.3.6 Protein requirement increases during growth and recovery from illness. 27.4 Protein-Energy Malnutrition 27.5 Excess Protein-Energy Intake 27.5.1 Obesity has dietary and genetic components. 27.5.2 Metabolic consequences of obesity have significant health implications. 27.6 Carbohydrates 27.7 Fats
27.8 Fiber 27.9 Composition of Macronutrients in the Diet 27.9.1 Composition of the diet affect serum cholesterol. 27.9.2 Effects of refined carbohydrate in the diet are not straightforward. 27.9.3 Mixed vegetable and animal proteins meet nutritional protein requirements. 27.9.4 An increase in fiber from varied sources is desirable. 27.9.5 Current recommendations are for a "prudent diet". See Fig. 27.3. Clinical Correlations cc 27.1 Vegetarian Diets and Protein-Energy Requirements cc 27.2 Low-Protein Diets and Renal Disease cc 27.3 Providing Adequate Protein and Calories for the Hospitalized Patient cc 27.4 Carbohydrate Loading and Athletic Endurance cc 27.5 High-Carbohydrate versus High-Fat Diets for Diabetics cc 27.6 Polyunsaturated Fatty Acids and risk factors for heart disease cc 27.7 Metabolic Adaptation: The Relationship between Carbohydrate Intake and Serum Triacylglycerols Chapter 28 Principles of Nutrition II: Micronutrients 28.1 Overview 28.1.1 Micronutrients are important. 28.2 Assessment of Malnutrition 28.2.1 Dietary intake studies. 28.2.2 Biochemical assays. 28.2.3 Clinical symptoms 28.3 Recommended Dietary Allowances 28.3.1 Ideal average 28.3.2 Healthy people 28.3.3 Knowledge is changing. 28.3.4 Optimal levels not defined. 28.4 Fat-Soluble Vitamins 28.4.1 Vitamin A is derived from plant carotenoids. 28.4.2 Vitamin D synthesis in the body requires sunlight. 28.4.3 Vitamin E is a mixture of tocopherols. 28.4.4 Vitamin K is a quinone derivative. 28.5 Water-Soluble Vitamins 28.6 Energy-Releasing Water-Soluble Vitamins 28.6.1 Thiamine (vitamin B1) forms the coenzyme TPP (thiamine pyrophosphate). 28.6.2 Riboflavin is part of FAD and FMN. 28.6.3 Niacin is part of NAD+ and NADP+. 28.6.4 Pyridoxine (vitamin B6) forms the coenzyme pyridoxal phosphate. 28.6.5 Pantothenic acid and biotin are also energy-releasing vitamins 28.7 Hematopoietic Water-Soluble Vitamins
28.7.1 Folic acid functions as tetrahydrofolate in one-carbon metabolism. 28.7.2 Vitamin B12 (cobalamine) contains cobalt in a tetrapyrrole ring. 28.8 Other Water-Soluble Vitamins 28.8.1 Ascorbic acid functions in reduction and hydroxylation reactions. 28.8.2 Lipoic acid function in -keto acid metabolism. 28.9 Macrominerals 28.9.1 Calcium has many physiological roles. 28.9.2 Magnesium is another important macromineral. 28.10 Trace Minerals 28.10.1 Iron is efficiently reutilized. 28.10.2 Iodine is incorporated into thyroid hormones. 28.10.3 Zinc is a cofactor for many enzymes. 28.10.4 Copper is also a cofactor for important enzymes. 28.10.5 Chromium is a component of glucose tolerance factor. 28.10.6 Selenium is a scavenger of peroxides. 28.10.7 Manganese, molybdenum, fluoride, and boron are other trace elements. 28.11 The American Diet: Fact and Fallacy 28.12 Assessment of Nutritional Status in clinical practice Clinical Correlations cc 28.1 Nutritional Considerations for Cystic Fibrosis cc 28.2 Renal Osteodystrophy cc 28.3 Nutritional Considerations in the born cc 28.4 Anticonvulsant Drugs and Vitamin Requirements cc 28.5 Nutritional Considerations in the Alcoholic cc 28.6 Vitamin B6 Requirements for Users of oral contraceptives cc 28.7 Diet and Osteoporosis cc 28.8 Nutritional Considerations for Vegetarians cc 28.9 Nutritional Needs of Elderly Persons

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