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For nearly 30 years, Principles of Medical Biochemistry has integrated medical biochemistry with molecular genetics, cell biology, and genetics to provide complete yet concise coverage that links biochemistry with clinical medicine. The 4th Edition of this award-winning text by Drs. Gerhard Meisenberg and William H. Simmons has been fully updated with new clinical examples, expanded coverage of recent changes in the field, and many new case studies online. A highly visual format helps readers retain complex information, and USMLE-style questions (in print and online) assist with exam preparation.



Just the right amount of detail on biochemistry, cell biology, and genetics - in one easy-to-digest textbook.
Full-color illustrations and tables throughout help students master challenging concepts more easily.
Online case studies serve as a self-assessment and review tool before exams.
Glossary of technical terms, both in print and online.



Clinical Boxes and Clinical Content demonstrate the integration of basic sciences and clinical applications, helping readers make connections between the two. New clinical examples have been added throughout the text.
Student Consult eBook version included with purchase. This enhanced eBook experience includes access -- on a variety of devices -- to the complete text, images, and references from the book.

Principles of Medical Biochemistry

Part ONE



PRINCIPLES OF MOLECULAR STRUCTURE AND



FUNCTION 1



Chapter 1



INTRODUCTION TO BIOMOLECULES



Water Is the Solvent of Life



Water Contains Hydronium Ions and Hydroxyl Ions



Ionizable Groups Are Characterized by Their pK Values



The Blood pH is Tightly Regulated



Acidosis and Alkalosis Are Common in Clinical Practice



Bonds Are Formed by Reactions between Functional Groups



Isomeric Forms Are Common in Biomolecules



Properties of Biomolecules Are Determined by Their Noncovalent



Interactions



Triglycerides Consist of Fatty Acids and Glycerol



Monosaccharides Are Polyalcohols with a Keto Group or an



Aldehyde Group



Monosaccharides Form Ring Structures



Complex Carbohydrates Are Formed by Glycosidic Bonds



Polypeptides Are Formed from Amino Acids



Nucleic Acids Are Formed from Nucleotides



Most Biomolecules Are Polymers



Summary



Chapter 2



INTRODUCTION TO PROTEIN STRUCTURE



Amino Acids Are Zwitterions



Amino Acid Side Chains Form Many Noncovalent



Interactions



Peptide Bonds and Disulfide Bonds Form the Primary Structure of



Proteins



Proteins Can Fold Themselves into Many Shapes



?-Helix and ?-Pleated Sheet Are the Most Common Secondary



Structures in Proteins



Globular Proteins Have a Hydrophobic Core



Proteins Lose Their Biological Activities When Their Higher-Order



Structure Is Destroyed



The Solubility of Proteins Depends on pH and Salt



Concentration



Proteins Absorb Ultraviolet Radiation



Proteins Can Be Separated by Their Charge or Their Molecular



Weight



Abnormal Protein Aggregates Can Cause Disease



Neurodegenerative Diseases Are Caused by Protein Aggregates



Protein Misfolding Can Be Contagious



Summary



Chapter 3



OXYGEN TRANSPORTERS: HEMOGLOBIN AND



MYOGLOBIN



The Heme Group Is the Oxygen-Binding Site of Hemoglobin and



Myoglobin



Myoglobin Is a Tightly Packed Globular Protein



Red Blood Cells Are Specialized for Oxygen Transport



The Hemoglobins Are Tetrameric Proteins



Oxygenated and Deoxygenated Hemoglobin Have Different



Quaternary Structures



Oxygen Binding to Hemoglobin Is Cooperative



2,3-Bisphosphoglycerate Is a Negative Allosteric Effector of



Oxygen Binding to Hemoglobin



Fetal Hemoglobin Has a Higher Oxygen-Binding Affinity than



Does Adult Hemoglobin



The Bohr Effect Facilitates Oxygen Delivery



Most Carbon Dioxide Is Transported as Bicarbonate



Summary 38



Chapter 4



ENZYMATIC REACTIONS 39



The Equilibrium Constant Describes the Equilibrium of the



Reaction



The Free Energy Change Is the Driving Force for Chemical



Reactions



The Standard Free Energy Change Determines the Equilibrium



Enzymes Are Both Powerful and Selective



The Substrate Must Bind to Its Enzyme before the Reaction Can



Proceed



Rate Constants Are Useful for Describing Reaction Rates



Enzymes Decrease the Free Energy of Activation



Many Enzymatic Reactions Can Be Described by Michaelis-Menten



Kinetics



Km and Vmax Can Be Determined Graphically



Substrate Half-Life Can Be Determined for First-Order but Not



Zero-Order Reactions



Kcat/Km Predicts the Enzyme Activity at Low Substrate



Concentration



Allosteric Enzymes Do Not Conform to Michaelis-Menten



Kinetics



Enzyme Activity Depends on Temperature and pH



Different Types of Reversible Enzyme Inhibition Can Be



Distinguished Kinetically



Enzymes Stabilize the Transition State



Chymotrypsin Forms a Transient Covalent Bond during



Catalysis



Summary



Chapter 5



COENZYMES



Enzymes Are Classified According to Their Reaction Type



Adenosine Triphosphate Has Two Energy-Rich Bonds



ATP Is the Phosphate Donor in Phosphorylation Reactions



ATP Hydrolysis Drives Endergonic Reactions



Cells Always Try to Maintain a High Energy Charge



Dehydrogenase Reactions Require Specialized Coenzymes



Coenzyme A Activates Organic Acids



S-Adenosyl Methionine Donates Methyl Groups



Many Enzymes Require a Metal Ion



Summary



Part TWO



GENETIC INFORMATION: DNA, RNA, AND



PROTEIN SYNTHESIS



Chapter 6



DNA, RNA, AND PROTEIN SYNTHESIS



All Living Organisms Use DNA as Their Genetic Databank



DNA Contains Four Bases



DNA Forms a Double Helix



DNA Can Be Denatured



DNA Is Supercoiled



DNA Replication Is Semiconservative



DNA Is Synthesized by DNA Polymerases



DNA Polymerases Have Exonuclease Activities



Unwinding Proteins Present a Single-Stranded Template to the



DNA Polymerases



One of the New DNA Strands Is Synthesized Discontinuously



RNA Plays Key Roles in Gene Expression



The ? Subunit Recognizes Promoters



DNA Is Faithfully Copied into RNA



Some RNAs Are Chemically Modified after Transcription



The Genetic Code Defines the Structural Relationship between mRNA and Polypeptide



Transfer RNA Is the Adapter Molecule in Protein Synthesis



Amino Acids Are Activated by an Ester Bond with the 3' Terminus



of the tRNA



Many Transfer RNAs Recognize More than One Codon



Ribosomes Are the Workbenches for Protein Synthesis



The Initiation Complex Brings Together Ribosome, Messenger



RNA, and Initiator tRNA



Polypeptides Grow Stepwise from the Amino Terminus to the



Carboxyl Terminus



Protein Synthesis Is Energetically Expensive



Gene Expression Is Tightly Regulated



A Repressor Protein Regulates Transcription of the lac Operon



in E. coli



Anabolic Operons Are Repressed by the End Product of the



Pathway



Glucose Regulates the Transcription of Many Catabolic



Operons



Transcriptional Regulation Depends on DNA-Binding



Proteins



Summary



Chapter 7



THE HUMAN GENOME



Chromatin Consists of DNA and Histones



The Nucleosome Is the Structural Unit of Chromatin



Covalent Histone Modifications Regulate DNA Replication and



Transcription



DNA Methylation Silences Genes



All Eukaryotic Chromosomes Have a Centromere, Telomeres, and



Replication Origins



Telomerase Is Required (but Not Sufficient) for Immortality



Eukaryotic DNA Replication Requires Three DNA



Polymerases



Most Human DNA Does Not Code for Proteins



Gene Families Originate by Gene Duplication



The Genome Contains Many Tandem Repeats



Some DNA Sequences Are Copies of Functional RNAs



Many Repetitive DNA Sequences Are (or Were) Mobile



L1 Elements Encode a Reverse Transcriptase



Alu Sequences Spread with the Help of L1 Reverse



Transcriptase



Mobile Elements Are Dangerous



Humans Have Approximately 20,000 Genes



Transcriptional Initiation Requires General Transcription



Factors



Genes Are Surrounded by Regulatory Sites



Gene Expression Is Regulated by DNA-Binding Proteins



Long Non-coding RNAs Play Roles in Gene Expression



mRNA Processing Starts during Transcription



Translational Initiation Requires Many Initiation Factors



mRNA Processing and Translation Are Often Regulated



Small RNA Molecules Inhibit Gene Expression



Mitochondria Have Their Own DNA



Human Genomes Are Very Diverse



Human Genomes Have Many Low-Frequency Copy Number



Variations



Summary



Chapter 8



PROTEIN TARGETING AND PROTEOSTASIS



A Signal Sequence Directs Polypeptides to the Endoplasmic



Reticulum



Glycoproteins Are Processed in the Secretory Pathway



The Endocytic Pathway Brings Proteins into the Cell



Lysosomes Are Organelles of Intracellular Digestion



Autophagy Recycles Cellular Proteins and Organelles



Poorly Folded Proteins Are Either Repaired or Destroyed



Ubiquitin Markes Proteins for Destruction



The Proteostatic System Protects Cells from Abnormal Proteins



Summary



Chapter 9



INTRODUCTION TO GENETIC DISEASES



Four Types of Genetic Disease



Mutations Occur in the Germline and in Somatic Cells



Mutations Are an Important Cause of Poor Health



Small Mutations Lead to Abnormal Proteins



Most Mutations Are Caused by Replication Errors



Mutations Can Be Induced by Radiation and Chemicals



Mismatch Repair Corrects Replication Errors



Missing Bases and Abnormal Bases Need to Be Replaced



Nucleotide Excision Repair Removes Bulky Lesions



Repair of DNA Double-Strand Breaks Is Difficult



Hemoglobin Genes Form Two Gene Clusters



Many Point Mutations in Hemoglobin Genes Are Known



Sickle Cell Disease Is Caused by a Point Mutation in the b-Chain



Gene



SA Heterozygotes Are Protected from Tropical Malaria



?-Thalassemia Is Most Often Caused by Large Deletions



Many Different Mutations Can Cause ?-Thalassemia



Fetal Hemoglobin Protects from the Effects of ?-Thalassemia and



Sickle Cell Disease



Summary



Chapter 10



VIRUSES



Viruses Can Replicate Only in a Host Cell



Bacteriophage T4 Destroys Its Host Cell



DNA Viruses Substitute Their Own DNA for the Host Cell



DNA



? Phage Can Integrate Its DNA into the Host Cell



Chromosome



RNA Viruses Require an RNA-Dependent RNA Polymerase



Retroviruses Replicate Through a DNA Intermediate



Plasmids Are Small "Accessory Chromosomes" or "Symbiotic



Viruses" of Bacteria



Bacteria Can Exchange Genes by Transformation and



Transduction



Jumping Genes Can Change Their Position in the Genome



Summary



Chapter 11



DNA TECHNOLOGY



Restriction Endonucleases Cut Large DNA Molecules into Smaller



Fragments



Large Probes Are Used to Detect Copy Number Variations



Small Probes Are Used to Detect Point Mutations



Southern Blotting Determines the Size of Restriction



Fragments



DNA Can Be Amplified with the Polymerase Chain Reaction



PCR Is Used for Preimplantation Genetic Diagnosis



Allelic Heterogeneity Is the Greatest Challenge for Molecular



Genetic Diagnosis



Normal Polymorphisms Are Used as Genetic Markers



Tandem Repeats Are Used for DNA Fingerprinting



DNA Microarrays Can Be Used for Genetic Screening



DNA Microarrays Are Used for the Study of Gene Expression



DNA Is Sequenced by Controlled Chain Termination



Massively Parallel Sequencing Permits Cost-Efficient



Whole-Genome Genetic Diagnosis



Gene Therapy Targets Somatic Cells



Viruses Are Used as Vectors for Gene Therapy



Retroviruses Can Splice a Transgene into the Cell's Genome



Genome Editing Is Based on the Making and Healing of DNA Double Strand Breaks



Designer Nucleases Are Used for Genome Editing



Antisense Oligonucleotides Can Block the Expression of Rogue



Genes



Genes Can Be Altered in Animals



Tissue-Specific Gene Expression Can Be Engineered into



Animals



Human Germline Genome Editing is Technically Possible



Summary



Part THREE



CELL AND TISSUE STRUCTURE



Chapter 12



BIOLOGICAL MEMBRANES



Membranes Consist of Lipid and Protein



Phosphoglycerides Are the Most Abundant Membrane Lipids



Most Sphingolipids Are Glycolipids



Cholesterol Is the Most Hydrophobic Membrane Lipid



Membrane Lipids Form a Bilayer



The Lipid Bilayer Is a Two-Dimensional Fluid



The Lipid Bilayer Is a Diffusion Barrier



Membranes Contain Integral and Peripheral Membrane



Proteins



Membranes Are Asymmetrical



Membranes Are Fragile



Membrane Proteins Carry Solutes across the Lipid Bilayer



Transport against an Electrochemical Gradient Requires Metabolic



Energy



Active Transport Consumes ATP



Sodium Cotransport Brings Molecules into the Cell



Summary



Chapter 13



THE CYTOSKELETON



The Erythrocyte Membrane Is Reinforced by a Spectrin



Network



Keratins Give Strength to Epithelia



Actin Filaments Are Formed from Globular Subunits



Striated Muscle Contains Thick and Thin Filaments



Myosin Is a Two-Headed Molecule with ATPase Activity



Muscle Contraction Requires Calcium and ATP



The Cytoskeleton of Skeletal Muscle Is Linked to the Extracellular



Matrix



Microtubules Consist of Tubulin



Eukaryotic Cilia and Flagella Contain a 9 + 2 Array of



Microtubules



Cells Form Specialized Junctions with Other Cells and with the



Extracellular Matrix



Summary



Chapter 14



THE EXTRACELLULAR MATRIX



Collagen Is the Most Abundant Protein in the Human Body



Tropocollagen Molecule Forms a Long Triple Helix



Collagen Fibrils Are Staggered Arrays of Tropocollagen



Molecules



Collagen Is Subject to Extensive Posttranslational Processing



Collagen Metabolism Is Altered in Aging and Disease



Many Genetic Defects of Collagen Structure and Biosynthesis Are



Known



Elastic Fibers Contain Elastin and Fibrillin



The Amorphous Ground Substance Contains Hyaluronic Acid



Sulfated Glycosaminoglycans Are Covalently Bound to Core



Proteins



Cartilage Contains Large Proteoglycan Aggregates



Proteoglycans Are Synthesized in the ER and Degraded in



Lysosomes



Mucopolysaccharidoses Are Caused by Deficiency of



Glycosaminoglycan-Degrading Enzymes



Bone Consists of Calcium Phosphates in a Collagenous



Matrix



Basement Membranes Contain Type IV Collagen, Laminin,



and Heparan Sulfate Proteoglycans



Fibronectin Glues Cells and Collagen Fibers Together



Summary



Part FOUR



MOLECULAR PHYSIOLOGY



Chapter 15



EXTRACELLULAR MESSENGERS



Steroid Hormones Are Made from Cholesterol



Progestins Are the Biosynthetic Precursors of All Other Steroid



Hormones



Thyroid Hormones Are Synthesized from Protein-Bound



Tyrosine



T4 Becomes Activiated to T3 in the Target Tissues



Both Hypothyroidism and Hyperthyroidism Are Common



Disorders



Insulin Is Released Together with the C-Peptide



Proopiomelanocortin Forms Several Active Products



Angiotensin Is Formed from Circulating Angiotensinogen



Immunoassays Are Used for Determination of Hormone Levels



Catecholamines Are Synthesized from Tyrosine



Indolamines Are Synthesized from Tryptophan



Histamine Is Produced by Mast Cells and Basophils



Neurotransmitters Are Released at Synapses



Acetylcholine Is the Neurotransmitter of the Neuromuscular



Junction



There Are Many Neurotransmitters



Summary



Chapter 16



INTRACELLULAR MESSENGERS



Receptor-Hormone Interactions Are Noncovalent, Reversible,



and Saturable



Many Neurotransmitter Receptors Are Ion Channels



Steroid and Thyroid Hormones Bind to Transcription Factors



Seven-Transmembrane Receptors Are Coupled to G Proteins



Adenylate Cyclase Is Regulated by G Proteins



Hormones Can Both Activate and Inhibit the cAMP Cascade



Cytoplasmic Calcium Is an Important Intracellular Signal



Phospholipase C Generates Two Second Messengers



Both cAMP and Calcium Regulate Gene Transcription



Muscle Contraction and Exocytosis Are Triggered by Calcium



Atrial Natriuretic Factor Acts through a Membrane-Bound Guanylate Cyclase



Nitric Oxide Stimulates a Soluble Guanylate Cyclase



cGMP Is a Second Messenger in Retinal Rod Cells



Receptors for Insulin and Growth Factors Are Tyrosine-Specific



Protein Kinases



Growth Factors and Insulin Trigger Multiple Signaling



Cascades



Cytokin Receptors Use the JAK-Stat Pathway



Many Receptors Become Desensitized after Overstimulation



Summary



Chapter 17



PLASMA PROTEINS



The Blood pH Is Tightly Regulated



Acidosis and Alkalosis Are Common in Clinical Practice



Plasma Proteins Are Both Synthesized and Destroyed in the



Liver



Albumin Prevents Edema



Albumin Binds Many Small Molecules



Some Plasma Proteins Are Specialized Carriers of Small



Molecules



Deficiency of ?1-Antiprotease Causes Lung Emphysema



Levels of Plasma Proteins Are Affected by Many Diseases



Blood Components Are Used for Transfusions



Blood Clotting Must Be Tightly Controlled



Platelets Adhere to Exposed Subendothelial Tissue



Insoluble Fibrin Is Formed from Soluble Fibrinogen



Thrombin Is Derived from Prothrombin



Factor X Can Be Activated by the Extrinsic and Intrinsic



Pathways



Negative Controls Are Necessary to Prevent Thrombosis



Plasmin Degrades the Fibrin Clot



Heparin and the Vitamin K Antagonists Are Used as



Anticoagulants



Clotting Factor Deficiencies Cause Abnormal Bleeding



Tissue Damage Causes Release of Cellular Enzymes into



Blood



Serum Enzymes Are Used for the Diagnosis of Many Diseases



Summary



Chapter 18



Defense Mechanisms



Lipophilic Xenobiotics Are Metabolized to Water-soluble Products



Cytochrome P-450 Is Involved in Phase I Metabolism



Phase II Metabolism Makes Xenobiotics Water-Soluble for Excretion



Phase III Metabolism Excretes Xenobiotic Metabolites



Drug Metabolizing Enzymes Are Inducible



The Innate Immune System Uses Pattern Recognitino Receptors



Infection Triggers Inflammation



Lymphocytes Possess Antigen Receptors



B Lymphocytes Produce Immunoglobulins



Antiboidies Consist of Two Light Chains and Two Heavy Chains



Different Immunoglobulin Classes Have Different Properties



Adaptive Immune Responses Are Based on Clonal Selection



Immunoglobulin genes Are Rearranged During B-Cell Development



The T-Cell Receptor Recruits Cytosolic Tyrosine Protein Kinases



Mediatros of Inflammation Are Produced form Arachidonic Acid



Prostaglandins Are Synthesized in All Tissues



Prostanoids Participate in Many Physiological Processes



Leukotrienes Are Produced by the Lipoxygenase Pathway



Anti-Inflammatory Drugs Inhibit the Synthesis of Eicosanoids



Summary



Chapter 19



CELLULAR GROWTH CONTROL AND CANCER



The Cell Cycle Is Controlled at Two Checkpoints



Cells Can Be Grown in Culture



Cyclins Play Key Roles in Cell Cycle Control



Retinoblastoma Protein Guards the G1 Checkpoint



Cell Proliferation Is Triggered by Mitogens



Mitogens Regulate Gene Expression



Cells Can Commit Suicide



Cancers Are Monoclonal in Origin



Cancer Is Caused by Activation of Growth-Promoting Genes



and Inactivation of Growth-Inhibiting Genes



Some Retroviruses Contain an Oncogene



Retroviruses Can Cause Cancer by Inserting Themselves Next



to a Cellular Proto-Oncogene



Many Oncogenes Code for Components of Mitogenic Signaling



Cascades



Cancer Susceptibility Syndromes Are Caused by Inherited



Mutations in Tumor Suppressor Genes



Many Tumor Suppressor Genes Are Known



Components of the Cell Cycle Machinery Are Abnormal in Most



Cancers



DNA Damage Causes Either Growth Arrest or Apoptosis



Most Spontaneous Cancers Are Defective in p53 Action



The P13K/Protein Kinase B Pathway Is Activated in Many



Cancers



The Products of Some Viral Oncogenes Neutralize the Products



of Cellular Tumor Suppressor Genes



Tumors Become More Malignant through Darwinian Selection



Intestinal Polyps Are Benign Lesions



Intestinal Polyps Can Evolve into Colon Cancer



Summary



Part FIVE



METABOLISM



Chapter 20



DIGESTIVE ENZYMES



Saliva Contains ?-Amylase and Lysozyme



Protein and Fat Digestion Start in the Stomach



The Pancreas Is a Factory for Digestive Enzymes



Fat Digestion Requires Bile Salts



Some Digestive Enzymes Are Anchored to the Surface of the



Microvilli



Poorly Digestible Nutrients Cause Flatulence



Many Digestive Enzymes Are Released as Inactive



Precursors



Summary



Chapter 21



INTRODUCTION TO METABOLIC PATHWAYS



Alternative Substrates Can Be Oxidized in the Body Metabolic Processes Are Compartmentalized



Free Energy Changes in Metabolic Pathways Are



Additive



Most Metabolic Pathways Are Regulated



Feedback Inhibition and Feedforward Stimulation Are the Most



Important Regulatory Principles



Metabolism Is Regulated to Ensure Homeostasis



Inherited Enzyme Deficiencies Cause Metabolic Diseases



Vitamin Deficiencies, Toxins, and Endocrine Disorders Can Disrupt



Metabolic Pathways



Summary



Chapter 22



GLYCOLYSIS, TRICARBOXYLIC ACID CYCLE, AND



OXIDATIVE PHOSPHORYLATION



Glucose Uptake into the Cells Is Regulated



Glucose Degradation Begins in the Cytoplasm and Ends in the



Mitochondria



Glycolysis Begins with ATP-Dependent Phosphorylations



Most Glycolytic Intermediates Have Three Carbons



Phosphofructokinase Is the Most Important Regulated Enzyme



of Glycolysis



Lactate Is Produced under Anaerobic Conditions



Pyruvate Is Decarboxylated to Acetyl-CoA in the



Mitochondria



The TCA Cycle Produces Two Molecules of Carbon Dioxide for



Each Acetyl Residue



Reduced Coenzymes Are the Most Important Products of the TCA



Cycle



Oxidative Pathways Are Regulated by Energy Charge and



[NADH]/[NAD+] Ratio



TCA Cycle Provides an Important Pool of Metabolic



Intermediates



Antiporters Transport Metabolites across the Inner Mitochondrial



Membrane



The Respiratory Chain Channels Electrons fromNADH



and FADH2 to Molecular Oxygen



Standard Reduction Potential Is the Tendency to Donate



Electrons



The Respiratory Chain Contains Flavoproteins, Iron-Sulfur



Proteins, Cytochromes, Ubiquinone, and Protein-Bound



Copper



The Respiratory Chain Contains Large Multiprotein



Complexes



The Respiratory Chain Creates a Proton Gradient



The Proton Gradient Drives ATP Synthesis



The Efficiency of Glucose Oxidation Is Close to 40%



Oxidative Phosphorylation Is Limited by the Supply of



ADP



Brown Adipose Tissue Contains an Uncoupling Protein



Mutations in Mitochondrial DNA Can Cause Disease



Summary



Chapter 23



Oxygen Deficiency and Oxygen Toxicity



Ischemia Leads to Infarction



Oxidative Phosphorylation Is Inhibited by Many Poisons



Hypoxia Inducible Factor Adjusts Cell Metabolism to Hypoxia



Reactive Oxygen Derivatives Are Formed during Oxidative Metabolism



The Respiratory Chain Is a Major Source of Superoxide



Cells Have Specialized Enzymes to Destroy Reactive Oxygen Species



Free Radical Formation Is Affected by Energy Supply and Energy Consumption



Some Vitamins and Phytochemicals Can Scavange Free Radicals



The NRF2 Transcription Factor Coordinates Defenses against Reactive Oxygen Species



Phagocytic Cells Use Reactive Oxygen Species for Intracellular Killing



Summary



Chapter 24



CARBOHYDRATE METABOLISM



An Adequate Blood Glucose Level Must Be Maintained at All



Times



Gluconeogenesis Bypasses the Three Irreversible Reactions of



Glycolysis



Fatty Acids Cannot Be Converted into Glucose



Glycolysis and Gluconeogenesis Are Regulated by Hormones



Glycolysis and Gluconeogenesis Are Fine Tuned by Allosteric



Effectors and Hormone-Induced Enzyme



Phosphorylations



Fructose-2,6-biphosphate Switches the Liver from Gluconeogenesis to Glycolysis



Glucokinase Is Regulated by Two Regulatory Proteins



Carbohydrate Is Stored as Glycogen



Glycogen Is 0Synthesized from Glucose



Glycogen Is Degraded by Phosphorolytic Cleavage



Glycogen Metabolism Is Regulated by Hormones and



Metabolites



Glycogen Accumulates in Several Enzyme Deficiencies



Fructose Is Channeled into Glycolysis/Gluconeogenesis



Excess Fructose Is Problematic



Excess Galactose Is Channeled into the Pathways of Glucose



Metabolism



The Pentose Phosphate Pathway Supplies NADPH and



Ribose-5-Phosphate



Fructose Is the Principal Sugar in Seminal Fluid



Amino Sugars and Sugar Acids Are Made from Glucose



Summary



Chapter 25



THE METABOLISM OF FATTY ACIDS AND



TRIGLYCERIDES



Fatty Acids Differ in Their Chain Length and Number of



Double Bonds



Chylomicrons Transport Triglycerides from the Intestine to Other



Tissues



Adipose Tissue Is Specialized for the Storage of Triglycerides



Fat Metabolism in Adipose Tissue Is under Hormonal



Control



Fatty Acids Are Transported into the Mitochondrion



?-Oxidation Produces Acetyl-CoA, NADH, and FADH2



Special Fatty Acids Require Special Reactions



The Liver Converts Excess Fatty Acids to Ketone Bodies



Fatty Acids Are Synthesized from Acetyl-CoA



Acetyl-CoA Is Shuttled into the Cytoplasm as Citrate



Fatty Acid Synthesis Is Regulated by Hormones and



Metabolites



AMP-Activated Protein Kinase Adapts Metabolic Pathways to Cellular Energy Status



Most Fatty Acids Can Be Synthesized from Palmitate



Fatty Acids Regulate Gene Expression



Polyunsaturated Fatty Acids Can Be Oxidized



Nonenzymatically



Summary



Chapter 26



THE METABOLISM OF MEMBRANE LIPIDS 000Phosphatidic Acid Is an Intermediate in Phosphoglyceride



Synthesis



Phosphoglycerides Are Remodeled Continuously



Sphingolipids Are Synthesized from Ceramide



Deficiencies of Sphingolipid-Degrading Enzymes Cause Lipid



Storage Diseases



Cholesterol Is the Least Soluble Membrane Lipid



Cholesterol Is Derived from Both Endogenous Synthesis and the



Diet



Cholesterol Biosynthesis Is Regulated at the Level of HMG-CoA



Reductase



Bile Acids Are Synthesized from Cholesterol



Bile Acids Are Subject to Extensive Enterohepatic Circulation



Most Gallstones Consist of Cholesterol



Summary



Chapter 27



LIPID TRANSPORT



Most Plasma Lipids Are Components of Lipoproteins



Lipoproteins Have Characteristic Lipid and Protein



Compositions



Dietary Lipids Are Transported by Chylomicrons



VLDL Is a Precursor of LDL



LDL Is Removed by Receptor-Mediated Endocytosis



Cholesterol Regulates Its Own Metabolism



HDL Is Needed for Reverse Cholesterol Transport



Lipoproteins Can Initiate Atherosclerosis



Lipoproteins Respond to Diet and Lifestyle



Hyperlipoproteinemias Are Grouped into Five Phenotypes



Hyperlipidemias Are Treated with Diet and Drugs



Summary



Chapter 26



AMINO ACID METABOLISM



Amino Acids Can Be Used for Gluconeogenesis and



Ketogenesis



The Nitrogen Balance Indicates the Net Rate of Protein



Synthesis



The Amino Group of Amino Acids Is Released as Ammonia



Ammonia Is Detoxified to Urea



Urea Is Synthesized in the Urea Cycle



Hyperammonemia Can Be Treated with Diet and Drugs



Some Amino Acids Are Closely Related to Common Metabolic



Intermediates



Glycine, Serine, and Threonine Are Glucogenic



Proline, Arginine, Ornithine, and Histidine Are Degraded to



Glutamate



Methionine and Cysteine Are Metabolically Related



Valine, Leucine, and Isoleucine Are Degraded by Transamination



and Oxidative Decarboxylation



Phenylalanine and Tyrosine Are Both Glucogenic and



Ketogenic



Melanin Is Shesized from Tyrosine



Lysine and Tryptophan Have Lengthy Catabolic Pathways



The Liver Is the Most Important Organ of Amino Acid



Metabolism



Glutamine Participates in Renal Acid-Base Regulation



Summary



Chapter 29



METABOLISM OF IRON AND HEME



Iron Is Conserved Very Efficiently in the Body



Iron Uptake by Cells Is Regulated



Dietary Iron Is Absorbed in the Duodenum



Dietary Iron Absorption Is Regulated



Iron Deficiency Is the Most Common Micronutrient Deficiency Worldwide



Bone Marrow and Liver Are the Most Important Sites of Heme



Synthesis



Heme Is Synthesized from Succinyl-Coenzyme A and Glycine



Porphyrias Are Caused by Deficiencies of Heme-Synthesizing



Enzymes



Heme Is Degraded to Bilirubin



Bilirubin Is Conjugated and Excreted by the Liver



Elevations of Serum Bilirubin Cause Jaundice



Many Diseases Can Cause Jaundice



Summary



Chapter 30



THE METABOLISM OF PURINES AND



PYRIMIDINES



Purine Synthesis Starts with Ribose-5-Phosphate



Purines Are Degraded to Uric Acid



Free Purine Bases Can Be Salvaged



Pyrimidines Are Synthesized from Carbamoyl Phosphate and



Aspartate



DNA Synthesis Requires Deoxyribonucleotides



Many Antineoplastic Drugs Inhibit Nucleotide Metabolism



Uric Acid Has Limited Water Solubility



Hyperuricemia Causes Gout



Abnormalities of Purine-Metabolizing Enzymes Can Cause



Gout



Gout Can Be Treated with Drugs



Summary



Chapter 31



MICRONUTRIENTS



Riboflavin Is a Precursor of Flavin Mononucleotide



and Flavin Adenine Dinucleotide



Niacin Is a Precursor of NAD and NADP



Thiamin Deficiency Causes Weakness and Amnesia



Vitamin B6 Plays a Key Role in Amino Acid Metabolism



Pantothenic Acid Is a Building Block of Coenzyme A



Biotin Is a Coenzyme in Carboxylation Reactions



Folic Acid Deficiency Causes Megaloblastic Anemia



Vitamin B12 Requires Intrinsic Factor for Its Absorption



Vitamin C Is a Water-Soluble Antioxidant



Retinol, Retinal, and Retinoic Acid Are the Active Forms of



Vitamin A



Vitamin D Is a Prohormone



Vitamin E Prevents Lipid Oxidation



Many Vitamins and Phytochemicals Are Antioxidants



Vitamin K Is Required for Blood Clotting



Zinc Is a Constituent of Many Enzymes



Copper Participates in Reactions of Molecular Oxygen



Some Trace Elements Serve Very Specific Functions



Summary



Chapter 32



INTEGRATION OF METABOLISM



Insulin Is Released in Response to Elevated Glucose



Insulin Stimulates the Utilization of Nutrients



Protein Synthesis Is Coordinated by the mTOR Complex



Glucagon Maintains the Blood Glucose Level



Catecholamines Mediate the Flight-or-Fight Response



Glucocorticoids Are Released in Chronic Stress



Energy Is Expended Continuously



Stored Fat and Glycogen Are Degraded between Meals



Adipose Tissue Is the Most Important Energy Depot



The Liver Converts Dietary Carbohydrates to Glycogen



and Fat after a Meal



The Liver Maintains the Blood Glucose Level during Fasting



Ketone Bodies Provide Lipid-Based Energy during



Fasting



Obesity Is Common



in All Affluent Countries



Appetite Control Is the Most Important Determinant of Obesity



Obesity Is Related to Insulin Resistance



Diabetes Is Caused by Insulin Deficiency or Insulin



Resistance



In Diabetes, Metabolism Is Regulated as in



Starvation



Diabetes Is Diagnosed with Laboratory Tests



Diabetes Leads to Late Complications



Many Drugs Are Available for Diabetes Treatment



Contracting Muscle Has Three Energy Sources



Catecholamines Coordinate Metabolism during Exercise



Physical Exercise Leads to Adaptive Changes



Ethanol Is Metabolized to Acetyl-CoA in the Liver



Liver Metabolism Is Deranged by Alcohol



Alcoholism Leads to Fatty Liver and Liver Cirrhosis



Most "Diseases of Civilization" Are Caused by Aberrant



Livestyles



Aging Is the Greatest Challenge for Medical Research



Anti-Aging Treatments Are Being Investigated



Summary



ANSWERS TO QUESTIONS



GLOSSARY



CREDITS



EXTRA ONLINE-ONLY CASE STUDIES {more new Cases to be added, to come}



The Mafia Boss



Viral Gastroenteritis



Death in Installments



A Mysterious Death



To Treat or Not to Treat?



Yellow Eyes



An Abdominal Emergency



Shortness of Breath



Itching



Abdominal Pain



Rheumatism



A Bank Manager in Trouble



Kidney Problems



Gender Blender



Man Overboard!



Spongy Bones



Blisters



The Sunburned Child



Too Much Ammonia



ANSWERS TO CASE STUDIES