Chapter 4 Cellular Metabolism Hole’s Human Anatomy and Physiology Twelfth Edition Shier w Butler w Lewis Chapter 4 Cellular Metabolism Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

4.2: Metabolic Processes Metabolic processes – all chemical reactions that occur in the body There are two (2) types of metabolic reactions: Anabolism Larger molecules are made from smaller ones Requires energy Catabolism Larger molecules are broken down into smaller ones Releases energy

Anabolism Anabolism provides the materials needed for cellular growth and repair Dehydration synthesis Type of anabolic process Used to make polysaccharides, triglycerides, and proteins Produces water Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. CH2OH CH2OH CH2OH CH2OH O O O O H H H H H H H H H H H H H2O O HO OH H OH HO OH H OH HO OH H OH H OH H OH H OH H OH H OH Monosaccharide + Monosaccharide Disaccharide + Water

Anabolism + + H O H O H C OH HO C (CH2)14 CH3 H C O C (CH2)14 CH3 O O Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. H O H O H C OH HO C (CH2)14 CH3 H C O C (CH2)14 CH3 O O H2O H C OH HO C (CH2)14 CH3 H C O C (CH2)14 CH3 H2O H2O O O H C OH HO C (CH2)14 CH3 H C O C (CH2)14 CH3 H H Glycerol + 3 fatty acid molecules Fat molecule (triglyceride) + 3 water molecules Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Peptide bond H H H H H O O R R H O H O H H H O O N C C N C C N N C C C C N N C C C C OH OH H2O H O H H O H H H R R R R H H H H Amino acid + Amino acid Dipeptide molecule + Water

Catabolism Catabolism breaks down larger molecules into smaller ones Hydrolysis A catabolic process Used to decompose carbohydrates, lipids, and proteins Water is used to split the substances Reverse of dehydration synthesis Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. CH2OH CH2OH CH2OH CH2OH O O O O H H H H H H H H H H H H H2O O HO OH H OH HO OH H OH HO OH H OH H OH H OH H OH H OH H OH Monosaccharide + Monosaccharide Disaccharide + Water

Catabolism + + H O H O H C OH HO C (CH2)14 CH3 H C O C (CH2)14 CH3 O O Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. H O H O H C OH HO C (CH2)14 CH3 H C O C (CH2)14 CH3 O O H2O H C OH HO C (CH2)14 CH3 H C O C (CH2)14 CH3 H2O H2O O O H C OH HO C (CH2)14 CH3 H C O C (CH2)14 CH3 H H Glycerol + 3 fatty acid molecules Fat molecule (triglyceride) + 3 water molecules Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Peptide bond H H H H H O O R R H O H O H H H O O N C C N C C N N C C C C N N C C C C OH OH H2O H O H H O H H H R R R R H H H H Amino acid + Amino acid Dipeptide molecule + Water

4.3: Control of Metabolic Reactions Enzymes Control rates of metabolic reactions Lower activation energy needed to start reactions Most are globular proteins with specific shapes Not consumed in chemical reactions Substrate specific Shape of active site determines substrate Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Substrate molecules Product molecule Active site Enzyme molecule Enzyme-substrate complex Unaltered enzyme molecule (a) (b) (c)

Enzyme Action Metabolic pathways Enzyme names commonly: Series of enzyme-controlled reactions leading to formation of a product Each new substrate is the product of the previous reaction Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Substrate 1 Enzyme A Substrate 2 Enzyme B Substrate 3 Enzyme C Substrate 4 Enzyme D Product Enzyme names commonly: Reflect the substrate Have the suffix – ase Examples: sucrase, lactase, protease, lipase

Cofactors and Coenzymes Make some enzymes active Non-protein component Ions (magnesium, zinc, etc.) or coenzymes Coenzymes Organic molecules that act as cofactors Vitamins

Factors That Alter Enzymes Heat Radiation Electricity Chemicals Changes in pH

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Regulation of Metabolic Pathways Limited number of regulatory enzymes Negative feedback Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Inhibition Rate-limiting Enzyme A Substrate 1 Substrate 2 Enzyme B Substrate 3 Enzyme C Substrate 4 Enzyme D Product

4.4: Energy for Metabolic Reactions Energy is the capacity to change something; it is the ability to do work . Common forms of energy: Heat Light Sound Electrical energy Mechanical energy Chemical energy

ATP Molecules Each ATP molecule has three parts: An adenine molecule A ribose molecule Three phosphate molecules in a chain Third phosphate attached by high-energy bond When the bond is broken, energy is transferred When the bond is broken, ATP becomes ADP ADP becomes ATP through phosphorylation Phosphorylation requires energy released from cellular respiration Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. P P P Energy transferred from cellular respiration used to reattach phosphate Energy transferred and utilized by metabolic reactions when phosphate bond is broken P P P P

4.5: Cellular Respiration Occurs in a series of reactions: Glycolysis Citric acid cycle (or Kreb’s Cycle) Electron transport system Chemical bonds are broken to release energy We burn glucose in a process called oxidation

Cellular Respiration Produces: Carbon dioxide Water ATP (chemical energy) Heat Includes: Anaerobic reactions (without O2) - produce little ATP Aerobic reactions (requires O2) - produce most ATP

Glycolysis Series of ten reactions Breaks down glucose into 2 pyruvic acid molecules Occurs in cytosol Anaerobic phase of cellular respiration Yields two ATP molecules per glucose molecule Summarized by three main phases or events: Phosphorylation Splitting Production of NADH and ATP

Glycolysis Event 1 - Phosphorylation Two phosphates added to glucose Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Event 1 - Phosphorylation Two phosphates added to glucose Requires ATP Phase 1 priming Glucose Carbon atom P Phosphate 2 ATP 2 ADP Fructose-1,6-diphosphate P P Phase 2 cleavage Event 2 – Splitting (cleavage) 6-carbon glucose split into two 3-carbon molecules Dihydroxyacetone phosphate Glyceraldehyde phosphate P P Phase 3 oxidation and formation of ATP and release of high energy electrons P 2 NAD+ 4 ADP 2 NADH + H+ 4 ATP 2 Pyruvic acid O2 O2 2 NADH + H+ 2 NAD+ To citric acid cycle and electron transport chain (aerobic pathway) 2 Lactic acid

Glycolysis Event 3 – Production of NADH and ATP Hydrogen atoms are released Hydrogen atoms bind to NAD+ to produce NADH NADH delivers hydrogen atoms to electron transport system if oxygen is available ADP is phosphorylated to become ATP Two molecules of pyruvic acid are produced Two molecules of ATP are generated Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Phase 1 priming Glucose Carbon atom P Phosphate 2 ATP 2 ADP Fructose-1,6-diphosphate P P Phase 2 cleavage Dihydroxyacetone phosphate Glyceraldehyde phosphate P P Phase 3 oxidation and formation of ATP and release of high energy electrons P 2 NAD+ 4 ADP 2 NADH + H+ 4 ATP 2 Pyruvic acid O2 O2 2 NADH + H+ 2 NAD+ To citric acid cycle and electron transport chain (aerobic pathway) 2 Lactic acid

Anaerobic Reactions If oxygen is not available: Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. If oxygen is not available: Electron transport system cannot accept new electrons from NADH Pyruvic acid is converted to lactic acid Glycolysis is inhibited ATP production is less than in aerobic reactions Phase 1 priming Glucose Carbon atom P Phosphate 2 ATP 2 ADP Fructose-1,6-diphosphate P P Phase 2 cleavage Dihydroxyacetone phosphate Glyceraldehyde phosphate P P Phase 3 oxidation and formation of ATP and release of high energy electrons P 2 NAD+ 4 ADP 2 NADH + H+ 4 ATP 2 Pyruvic acid O2 O2 2 NADH + H+ 2 NAD+ To citric acid cycle and electron transport chain (aerobic pathway) 2 Lactic acid

Aerobic Reactions If oxygen is available: Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. If oxygen is available: Pyruvic acid is used to produce acetyl CoA Citric acid cycle begins Electron transport system functions Carbon dioxide and water are formed 34 molecules of ATP are produced per each glucose molecule Glucose High energy electrons (e–) and hydrogen ions (H+) 2 ATP Pyruvic acid Pyruvic acid Cytosol Mitochondrion High energy electrons (e–) and hydrogen ions (h+) CO2 Acetyl CoA Oxaloacetic acid Citric acid High energy electrons (e–) and hydrogen ions (H+) 2 CO 2 2 ATP Electron transport chain 32-34 ATP O 2 2e – + 2H + H 2 O

Citric Acid Cycle Begins when acetyl CoA combines with oxaloacetic acid to produce citric acid Citric acid is changed into oxaloacetic acid through a series of reactions Cycle repeats as long as pyruvic acid and oxygen are available Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Pyruvic acid from glycolysis Cytosol Carbon atom + P Phosphate NAD CO 2 Mitochondrion CoA Coenzyme A NADH + H + Acetic acid CoA Acetyl CoA (replenish molecule) Oxaloacetic acid Citric acid (finish molecule) (start molecule) NADH + H + CoA NAD + Malic acid Isocitric acid NAD + For each citric acid molecule: One ATP is produced Eight hydrogen atoms are transferred to NAD+ and FAD Two CO2 produced Citric acid cycle CO 2 NADH + H + Fumaric acid -Ketoglutaric acid CO 2 CoA FADH 2 NAD + FAD NADH + H + Succinic acid Succinyl-CoA CoA ADP + P ATP

Electron Transport System NADH and FADH2 carry electrons to the ETS ETS is a series of electron carriers located in cristae of mitochondria Energy from electrons transferred to ATP synthase ATP synthase catalyzes the phosphorylation of ADP to ATP Water is formed Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. ATP synthase ADP + P ATP Energy NADH + H+ Energy 2H+ + 2e– FADH2 Energy NAD+ 2H+ + 2e– FAD Electron transport chain 2e– 2H+ O 2 H2O

Summary of Cellular Respiration Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Glucose Glycolysis The 6-carbon sugar glucose is broken down in the cytosol into two 3-carbon pyruvic acid molecules with a net gain of 2 ATP and release of high-energy electrons. High-energy electrons (e–) 1 Glycolysis 2 A T P Cytosol Pyruvic acid Pyruvic acid Citric Acid Cycle The 3-carbon pyruvic acids generated by glycolysis enter the mitochondria. Each loses a carbon (generating CO2 and is combined with a coenzyme to form a 2-carbon acetyl coenzyme A (acetyl CoA). More high-energy electrons are released. 2 High-energy electrons (e–) CO 2 Acetyl Co A 3 Each acetyl CoA combines with a 4-carbon oxaloacetic acid to form the 6-carbon citric acid, for which the cycle is named. For each citric acid, a series of reactions removes 2 carbons (generating 2 CO2’s), synthesizes 1 ATP, and releases more high-energy electrons. The figure shows 2 ATP, resulting directly from 2 turns of the cycle per glucose molecule that enters glycolysis. Oxaloacetic acid Citric acid Citric acid cycle Mitochondrion High-energy electrons (e–) 2 CO 2 2 A T P Electron Transport Chain The high-energy electrons still contain most of the chemical energy of the original glucose molecule. Special carrier molecules bring the high-energy electrons to a series of enzymes that convert much of the remaining energy to more ATP molecules. The other products are heat and water. The function of oxygen as the final electron acceptor in this last step is why the overall process is called aerobic respiration. Electron transport chain 4 32–34 A T P 2e – and 2H + O 2 H 2 O

Carbohydrate Storage Carbohydrate molecules from foods can enter: Catabolic pathways for energy production Anabolic pathways for storage

Carbohydrate Storage Excess glucose stored as: Glycogen (primarily by liver and muscle cells) Fat Converted to amino acids Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Carbohydrates from foods Hydrolysis Monosaccharides Catabolic pathways Anabolic pathways Energy + CO2 + H2O Glycogen or Fat Amino acids

Summary of Catabolism of Proteins, Carbohydrates, and Fats Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Food Food Proteins (egg white) Proteins (egg white) Carbohydrates (toast, hashbrowns) Carbohydrates (toast, hashbrowns) Fats (butter) Fats (butter) 1 1 Breakdown of large macromolecules to simple molecules Breakdown of large macromolecules to simple molecules Amino acids Amino acids Simple sugars (glucose) Simple sugars (glucose) Glycerol Glycerol Fatty acids Fatty acids Glycolysis Glycolysis ATP ATP Pyruvic acid Pyruvic acid 2 2 Breakdown of simple molecules to acetyl coenzyme A accompanied by production of limited ATP and high energy electrons Breakdown of simple molecules to acetyl coenzyme A accompanied by production of limited ATP and high energy electrons Acetyl coenzyme A Acetyl coenzyme A Citric acid cycle Citric acid cycle CO2 CO2 3 3 Complete oxidation of acetyl coenzyme A to H2O and CO2 produces high energy electrons (carried by NADH and FADH2), which yield much ATP via the electron transport chain ATP ATP High energy electrons carried by NADH and FADH2 High energy electrons carried by NADH and FADH2 Electron transport chain Electron transport chain ATP ATP 2e– and 2H+ 2e– and 2H+ –NH2 –NH2 CO2 CO2 ½ O2 ½ O2 H2O H2O Waste products Waste products © Royalty Free/CORBIS. © Royalty Free/CORBIS.

4.6: Nucleic Acids and Protein Synthesis Instruction of cells to synthesize proteins comes from a nucleic acid, DNA Genetic information – instructs cells how to construct proteins; stored in DNA Gene – segment of DNA that codes for one protein Genome – complete set of genes Genetic Code – method used to translate a sequence of nucleotides of DNA into a sequence of amino acids. Each amino acid is represented by a triplet code

Structure of DNA Two polynucleotide chains Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Two polynucleotide chains Hydrogen bonds hold nitrogenous bases together Bases pair specifically (A-T and C-G) Forms a helix DNA wrapped about histones forms chromosomes (a) Hydrogen bonds P G C P Thymine (T) Adenine (A) P T P Cytosine (C) Guanine (G) P C G P P G C P P A P G C Nucleotide strand A G C T C G Segment of DNA molecule A (b) Globular histone proteins Chromatin Metaphase chromosome (c)

Animation: DNA Structure Please note that due to differing operating systems, some animations will not appear until the presentation is viewed in Presentation Mode (Slide Show view). You may see blank slides in the “Normal” or “Slide Sorter” views. All animations will appear after viewing in Presentation Mode and playing each animation. Most animations will require the latest version of the Flash Player, which is available at http://get.adobe.com/flashplayer.

DNA Replication Hydrogen bonds break between bases Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. A T Hydrogen bonds break between bases Double strands unwind and pull apart New nucleotides pair with exposed bases Controlled by DNA polymerase C G G C C G Original DNA molecule T A C G C G T A A T C G A T Region of replication G C C G G T A T A T A T T A A Newly formed DNA molecules G C G C T A T A C G C G C G C G T A A

Animation: DNA Replication Please note that due to differing operating systems, some animations will not appear until the presentation is viewed in Presentation Mode (Slide Show view). You may see blank slides in the “Normal” or “Slide Sorter” views. All animations will appear after viewing in Presentation Mode and playing each animation. Most animations will require the latest version of the Flash Player, which is available at http://get.adobe.com/flashplayer.

RNA Molecules Messenger RNA (mRNA): Making of mRNA (copying of DNA) is transcription Transfer RNA (tRNA): Carries amino acids to mRNA Carries anticodon to mRNA Translates a codon of mRNA into an amino acid Ribosomal RNA (rRNA): Provides structure and enzyme activity for ribosomes

RNA Molecules Messenger RNA (mRNA): Delivers genetic information from nucleus to the cytoplasm Single polynucleotide chain Formed beside a strand of DNA RNA nucleotides are complementary to DNA nucleotides (exception – no thymine in RNA; replaced with uracil) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. DNA RNA S P A U P S S P T A P S S P Direction of “reading” code G C P S S P C G P S S P G C P S

Animation: Stages of Transcription Please note that due to differing operating systems, some animations will not appear until the presentation is viewed in Presentation Mode (Slide Show view). You may see blank slides in the “Normal” or “Slide Sorter” views. All animations will appear after viewing in Presentation Mode and playing each animation. Most animations will require the latest version of the Flash Player, which is available at http://get.adobe.com/flashplayer.

Animation: How Translation Works Please note that due to differing operating systems, some animations will not appear until the presentation is viewed in Presentation Mode (Slide Show view). You may see blank slides in the “Normal” or “Slide Sorter” views. All animations will appear after viewing in Presentation Mode and playing each animation. Most animations will require the latest version of the Flash Player, which is available at http://get.adobe.com/flashplayer.

Protein Synthesis Cytoplasm 3 Translation begins as tRNA anticodons Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cytoplasm 3 Translation begins as tRNA anticodons recognize complementary mRNA codons, thus bringing the correct amino acids into position on the growing polypeptide chain DNA double helix Amino acids attached to tRNA Nucleus T A T A 6 tRNA molecules can pick up another molecule of the same amino acid and be reused G C G C 2 mRNA leaves the nucleus and attaches to a ribosome A T A T Polypeptide chain Messenger RNA G C DNA strands pulled apart A T A T T U A C G G G C T A G G C G G C C C G 5 At the end of the mRNA, the ribosome releases the new protein C G T U A T A C C G G C C C G A T G C G C C G A A T G C A A T Nuclear pore 4 As the ribosome moves along the mRNA, more amino acids are added Amino acids represented A T C C G C G G G C T A G G C 1 DNA information is copied, or transcribed, into mRNA following complementary base pairing A C C G U Codon 1 Methionine A A T G C G G G C T A G G C G G C C C G G Codon 2 Glycine A T T U A C C C G C C G U G C A A T C Codon 3 Serine A T T U A C C G G G C G T A A A T Messenger RNA DNA strand C Codon 4 Alanine C C G G C A C G G C A T A C G C Codon 5 Threonine G C A T G Transcription (in nucleus) G C Translation (in cytoplasm) G G C C Codon 6 Alanine C G A U A G C G G Codon 7 Glycine C

Protein Synthesis 1 2 1 The transfer RNA molecule Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 2 1 The transfer RNA molecule for the last amino acid added holds the growing polypeptide chain and is attached to its complementary codon on mRNA. Growing polypeptide chain 3 4 Next amino acid 5 6 Transfer RNA Anticodon U G C C G U A U G G G C U C C G C A A C G G C A G G C A A G C G U 1 2 3 4 5 6 7 Codons 1 Peptide bond 2 2 A second tRNA binds complementarily to the next codon, and in doing so brings the next amino acid into position on the ribosome. A peptide bond forms, linking the new amino acid to the growing polypeptide chain. Growing polypeptide chain 3 4 Next amino acid 5 6 Transfer RNA Anticodon U G C C G U A U G G G C U C C G C A A C G G C A G G C A A G C G U Messenger RNA 1 2 3 4 5 6 7 Codons 1 2 Next amino acid 3 The tRNA molecule that brought the last amino acid to the ribosome is released to the cytoplasm, and will be used again. The ribosome moves to a new position at the next codon on mRNA. A 3 4 5 7 6 Transfer RNA U G C C C G C G U A U G G G C U C C G C A A C G G C A G G C A A G C G U Messenger RNA 1 2 3 4 5 6 7 Ribosome 1 2 4 A new tRNA complementary to the next codon on mRNA brings the next amino acid to be added to the growing polypeptide chain. 3 4 5 Next amino acid 6 7 Transfer RNA C G U C C G A U G G G C U C C G C A A C G G C A G G C A A G C G U Messenger RNA 1 2 3 4 5 6 7

Animation: Protein Synthesis Please note that due to differing operating systems, some animations will not appear until the presentation is viewed in Presentation Mode (Slide Show view). You may see blank slides in the “Normal” or “Slide Sorter” views. All animations will appear after viewing in Presentation Mode and playing each animation. Most animations will require the latest version of the Flash Player, which is available at http://get.adobe.com/flashplayer.

4.7: Changes in Genetic Information Only about 1/10th of one percent of the human genome differs from person to person Mutations – change in genetic information Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Code for glutamic acid Mutation Code for valine Result when: Extra bases are added or deleted Bases are changed P P T T S S Direction of “reading” code P P T A S S P P C C S S May or may not change the protein (a) (b) Repair enzymes correct the mutations

Code for Glutamic acid Mutation Code for valine P P T T S S P P T A S Fig. 4.25 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Code for Glutamic acid Mutation Code for valine P P T T S S Direction of “reading” code P P T A S S P P C C S S (a) (b)

Inborn Errors of Metabolism Occurs from inheriting a mutation that then alters an enzyme This creates a block in an otherwise normal biochemical pathway

ALA dehydratase deficiency Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. STARTING MATERIALS Enzyme #1 INTERMEDIATE #1 Enzyme #2 ALA dehydratase deficiency INTERMEDIATE #2 Enzyme #3 acute intermittent porphyria INTERMEDIATE #3 Enzyme #4 congenital erythropoietic porphyria INTERMEDIATE #4 Enzyme #5 porphyria cutanea tarda INTERMEDIATE #5 Enzyme #6 coproporphyria INTERMEDIATE #6 Enzyme #7 porphyria variegata INTERMEDIATE #7 Enzyme #8 erythropoietic protoporphyria HEME

Important Points in Chapter 4: Outcomes to be Assessed 4.1: Introduction Define metabolism. Explain why protein synthesis is important. 4.2: Metabolic Processes Compare and contrast anabolism and catabolism. Define dehydration synthesis and hydrolysis. 4.3: Control of Metabolic Reactions Describe how enzymes control metabolic reactions. List the basic steps of an enzyme-catalyzed reaction. Define active site.

Important Points in Chapter 4: Outcomes to be Assessed Define a rate-limiting enzyme and indicate why it is important in a metabolic pathway. 4.4: Energy for Metabolic Reactions Explain how ATP stores chemical energy and makes it available to a cell. State the importance of the oxidation of glucose. 4.5: Cellular Respiration Describe how the reactions and pathways of glycolysis, the citric acid cycle, and the electron transport chain capture the energy in nutrient molecules. Discuss how glucose is stored, rather than broken down.

Important Points in Chapter 4: Outcomes to be Assessed 4.6: Nucleic Acids and Protein Synthesis Define gene and genome. Describe the structure of DNA, including the role of complementary base pairing. Describe how DNA molecules replicate. Define genetic code. Compare DNA and RNA. Explain how nucleic acid molecules (DNA and RNA) carry genetic information. Define transcription and translation. Describe the steps of protein synthesis.

Important Points in Chapter 4: Outcomes to be Assessed 4.7: Changes in Genetic Information Compare and contrast mutations and SNPs. Explain how a mutation can cause a disease. Explain two ways that mutations originate. List three types of genetic changes. Discuss two ways that DNA is protected against mutation.