Chapter 25
Chapter 25
Metabolism and Nutrition
Suggested Lecture Outline
INTRODUCTION
• The food we eat is our only source of energy for performing biological work.
• There are three major metabolic destinations for the principle nutrients. They will be used for energy for active processes, synthesized into structural or functional molecules, or synthesized as fat or glycogen for later use as energy.
METABOLIC REACTIONS
• Metabolism refers to all the chemical reactions in the body.
• Catabolism includes all chemical reactions that break down complex organic molecules while anabolism refers to chemical reactions that combine simple molecules to form complex molecules.
• The chemical reactions of living systems depend on transfer of manageable amounts of energy from one molecule to another. This transfer is usually performed by ATP (Figure 25.1).
ENERGY TRANSFER
• All molecules (nutrient molecules included) have energy stored in the bonds between their atoms.
Oxidation-Reduction Reactions
• Oxidation is the removal of electrons from a molecule and results in a decrease in the energy content of the molecule. Because most biological oxidations involve the loss of hydrogen atoms, they are called dehydrogenation reactions.
• When a substance is oxidized, the liberated hydrogen atoms do not remain free in the cell but are transferred immediately by coenzymes to another compound.
• Reduction is the opposite of oxidation, that is, the addition of electrons to a molecule and results in an increase in the energy content of the molecule.
Coenzymes
• Two coenzymes are commonly used by living cells to carry hydrogen atoms: nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD).
• An important point to remember about oxidation-reduction reactions is that oxidation is usually an energy-releasing reaction.
Mechanisms of ATP Generation
• Phosphorylation is
– bond attaching 3rd phosphate group contains stored energy
• Mechanisms of phosphorylation
– within animals
• substrate-level phosphorylation in cytosol
• oxidative phosphorylation in mitochondria
– in chlorophyll-containing plants or bacteria
• photophosphorylation.
Phosphorylation in Animal Cells
• In cytoplasm (1)
• In mitochondria (2, 3 & 4)
CARBOHYDRATE METABOLISM
• During digestion, polysaccharides and disaccharides are converted to monosaccharides (primarily glucose)
– absorbed through capillaries in villi
– transported to the liver via the hepatic portal vein
• Liver cells convert much of the remaining fructose and practically all of the galactose to glucose
– carbohydrate metabolism is primarily concerned with glucose metabolism.
Carbohydrate Review
• In GI tract
– polysaccharides broken down into simple sugars
– absorption of simple sugars (glucose, fructose & galactose)
• In liver
– fructose & galactose transformed into glucose
– storage of glycogen (also in muscle)
• In body cells --functions of glucose
– oxidized to produce energy
– conversion into something else
– storage energy as triglyceride in fat
Fate of Glucose
• Since glucose is the body’s preferred source for synthesizing ATP, the fate of absorbed glucose depends on the energy needs of body cells.
• If the cells require immediate energy, glucose is oxidized by the cells to produce ATP.
Fate of Glucose
• Glucose can be used to form amino acids, which then can be incorporated into proteins.
• Excess glucose can be stored by the liver and skeletal muscles as glycogen, a process called glycogenesis.
• If glycogen storage areas are filled up, liver cells and fat cells can convert glucose to glycerol and fatty acids that can be used for synthesis of triglycerides (neutral fats) in the process of lipogenesis.
Glucose Movement into Cells
• Glucose absorption in the GI tract is accomplished by secondary active transport (Na+ - glucose symporters).
• Glucose movement from blood into most other body cells occurs via facilitated diffusion transporters (Gly-T molecules). Insulin increases the insertion of Gly-T molecules into the plasma membranes, thus increasing the rate of facilitated diffusion of glucose.
• Glucose is trapped in the cell when it becomes phosphorylated.
– Concentration gradient remains favorable for more glucose to enter
Glucose Movement into Cells
• In GI tract and kidney tubules
– Na+/glucose symporters
• Most other cells
– GluT facilitated diffusion transporters
– insulin increases the insertion of GluT transporters in the membrane of most cells
– in liver & brain, always lots of GluT transporters
• Glucose 6-phosphate forms immediately inside cell (requires ATP) thus, glucose is “hidden” when it is in the cell.
– Concentration gradient remains favorable for more glucose to enter.
Glucose Catabolism
Glucose Oxidation
• Cellular respiration
– 4 steps are involved
– glucose + O2 produces
H2O + energy + CO2
• Anaerobic respiration
– called glycolysis (1)
– formation of acetyl CoA (2)
is transitional step to Krebs cycle
• Aerobic respiration
– Krebs cycle (3) and electron transport chain (4)
Glycolysis
• Glycolysis refers to the breakdown of the six-carbon molecule, glucose, into two three-carbon molecules of pyruvic acid.
– 10 step process occurring in cell cytosol
– use two ATP molecules, but produce four, a net gain of two (Figure 25.3).
Glycolysis in Ten Steps
Glycolysis of Glucose & Fate of Pyruvic Acid
• Breakdown of six-carbon glucose molecule into 2 three-carbon molecules of pyruvic acid
– Pyruvic acid is converted to acetylCoA, which enters the Kreb’s Cycle.
– The Kreb’s Cycle will require NAD+
• NAD+ will be reduced to the high-energy intermediate NADH.
Glycolysis of Glucose & Fate of Pyruvic Acid
When O2 falls short in a cell
– pyruvic acid is reduced to lactic acid
• coupled to oxidation of NADH to NAD+
• NAD+ is then available for further glycolysis
– lactic acid rapidly diffuses out of cell to blood
– liver cells remove lactic acid from blood & convert it back to pyruvic acid
Pyruvic Acid
• The fate of pyruvic acid depends on the availability of O2.
Formation of Acetyl Coenzyme A
• Pyruvic acid enters the mitochondria with help of transporter protein
• Decarboxylation
– pyruvate dehydrogenase converts 3 carbon pyruvic acid to 2 carbon fragment acetyle group plus CO2.
Formation of Acetyl Coenzyme A
• 2 carbon fragment (acetyl group) is attached to Coenzyme A to form Acetyl coenzyme A, which enter Krebs cycle
– coenzyme A is derived from pantothenic acid (B vitamin).
Krebs Cycle
• The Krebs cycle is also called the citric acid cycle, or the tricarboxylic acid (TCA) cycle. It is a series of biochemical reactions that occur in the matrix of mitochondria (Figure 25.6).
Krebs Cycle
Krebs Cycle
• The large amount of chemical potential energy stored in intermediate substances derived from pyruvic acid is released step by step.
• The Krebs cycle involves decarboxylations and oxidations and reductions of various organic acids.
• For every two molecules of acetyl CoA that enter the Krebs cycle, 6 NADH, 6 H+, and 2 FADH2 are produced by oxidation-reduction reactions, and two molecules of ATP are generated by substrate-level phosphorylation (Figure 25.6).
• The energy originally in glucose and then pyruvic acid is primarily in the reduced coenzymes NADH + H+ and FADH2.
Krebs Cycle (Citric Acid Cycle)
• The oxidation-reduction & decarboxylation reactions occur in matrix of mitochondria.
– acetyl CoA (2C) enters at top & combines with a 4C compound
– 2 decarboxylation reactions peel 2 carbons off again when CO2 is formed
Krebs Cycle
• Potential energy (of chemical bonds) is released step by step to reduce the coenzymes (NAD+èNADH & FADèFADH2) that store the energy
Review:
• Glucoseè 2 acetyl CoA molecules
• each Acetyl CoA
molecule that enters the Krebs
cycle produces
– 2 molecules of C02
– 3 molecules of NADH + H+
– one molecule of ATP
– one molecule of FADH2
Review
• Figure 25.7 summarizes the eight reactions of the Krebs cycle.
Electron Transport Chain
• The electron transport chain involves a sequence of electron carrier molecules on the inner mitochondrial membrane, capable of a series of oxidation-reduction reactions.
• As electrons are passed through the chain, there is a stepwise release of energy from the electrons for the generation of ATP.
• In aerobic cellular respiration, the last electron receptor of the chain is molecular oxygen (O2). This final oxidation is irreversible.
• The process involves a series of oxidation-reduction reactions in which the energy in NADH + H+ and FADH2 is liberated and transferred to ATP for storage.
Electron Transport Chain
• Pumping of hydrogen is linked to the movement of electrons passage along the electron transport chain.
• It is called chemiosmosis (Figure 25.8.)
• Note location.
Chemiosmosis
• H+ ions are pumped from matrix into space between inner & outer membrane
• High concentration of H+ is maintained outside of inner membrane
• ATP synthesis occurs as H+ diffuses through a special H+ channels in the inner membrane
Electron Transport Chain
• The carrier molecules involved include flavin mononucleotide, cytochromes, iron-sulfur centers, copper atoms, and ubiquinones (also coenzyme Q).
Electron Carriers
• Flavin mononucleotide (FMN) is derived from riboflavin (vitamin B2)
• Cytochromes are proteins with heme group (iron) existing either in reduced form (Fe+2) or oxidized form (Fe+3)
• Iron-sulfur centers contain 2 or 4 iron atoms bound to sulfur within a protein
• Copper (Cu) atoms bound to protein
• Coenzyme Q is nonprotein carrier mobile in the lipid bilayer of the inner membrane
Steps in Electron Transport
• Carriers of electron transport chain are clustered into 3 complexes that each act as a proton pump (expelling H+)
• Mobile shuttles (CoQ and Cyt c) pass electrons between complexes.
• The last complex passes its electrons (2H+) to oxygen to form a water molecule (H2O)
Proton Motive Force & Chemiosmosis
• Buildup of H+ outside the inner membrane creates + charge
– The potential energy of the electrochemical gradient is called the proton motive force.
• ATP synthase enzymes within H+ channels use the proton motive force to synthesize ATP from ADP and P
Summary of Aerobic Cellular Respiration
• The complete oxidation of glucose can be represented as follows:
• C6H12O6 + 6O2 => 36 or 38ATP + 6CO2 +6H2O
• During aerobic respiration, 36 or 38 ATPs can be generated from one molecule of glucose.
– Two of those ATPs come from substrate-level phosphorylation in glycolysis.
– Two come from substrate-level phosphorylation in the Krebs cycle.
Review
• Table 25.1 summarizes the ATP yield during aerobic respiration.
• Figure 25.8 summarizes the sites of the principal events of the various stages of cellular respiration.
Glycogenesis & Glycogenolysis
• Glycogenesis
– glucose storage as glycogen
– 4 steps to glycogen
formation in liver or
skeletal muscle
– stimulated by insulin
• Glycogenolysis
– glucose release
Glycogenesis & Glycogenolysis
• Glycogenesis
– glucose storage as glycogen
• Glycogenolysis
– glucose release
– not a simple reversal of steps
– Phosphorylase enzyme is activated by glucagon (pancreas) & epinephrine (adrenal gland)
– Glucose-6-phosphatase enzyme is only in hepatocytes so muscle can not release glucose into the serum.
Carbohydrate Loading
• Long-term athletic events (marathons) can exhaust glycogen stored in liver and skeletal muscles
• Eating large amounts of complex carbohydrates (pasta & potatoes) for 3 days before a marathon maximizes glycogen available for ATP production
• Useful for athletic events lasting for more than an hour.
Gluconeogenesis
• Gluconeogenesis is the conversion of protein or fat molecules into glucose (Figure 25.12).
Gluconeogenesis
• Glycerol (from fats) may be converted to glyceraldehyde-3-phosphate and some amino acids may be converted to pyruvic acid. Both of these compounds may enter the Krebs cycle to provide energy.
• Gluconeogenesis is stimulated by cortisol, thyroid hormone, epinephrine, glucagon, and human growth hormone.
Transport of Lipids by Lipoproteins
• Most lipids are transported in the blood in combination with proteins as lipoproteins (Figure 25.13).
Transport of Lipids by Lipoproteins
• Four classes of lipoproteins are chylomicrons, very low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs).
Lipoproteins
• Chylomicrons form in small intestinal mucosal cells and contain exogenous (dietary) lipids. They enter villi lacteals, are carried into the systemic circulation into adipose tissue where their triglyceride fatty acids are released and stored in the adipocytes and used by muscle cells for ATP production.
• VLDLs contain endogenous triglycerides. They are transport vehicles that carry triglycerides synthesized in hepatocytes to adipocytes for storage. VLDLs are converted to LDLs.
• LDLs carry about 75% of total blood cholesterol and deliver it to cells throughout the body. When present in excessive numbers, LDLs deposit cholesterol in and around smooth muscle fibers in arteries.
• HDLs remove excess cholesterol from body cells and transport it to the liver for elimination.
Classes of Lipoproteins
• Chylomicrons (2 % protein)
– form in intestinal mucosal cells
– transport exogenous (dietary) fat
• apo C-2 activates enzyme that releases the fatty acids from the chylomicron for absorption by adipose & muscle cells; liver processes what is left
• VLDLs (10% protein)
– transport endogenous triglycerides (from liver) to fat cells
– converted to LDLs
• LDLs (25% protein) --- “bad cholesterol”
– carry 75% of blood cholesterol to body cells
– apo B100 is docking protein for receptor-mediated endocytosis of the LDL into a body cell
• HDLs (40% protein) --- “good cholesterol”
– carry cholesterol from cells to liver for elimination
Cholesterol
• There are two sources of cholesterol in the body: food we eat and liver synthesis.
• For adults, desirable levels of blood cholesterol are
– TC (total cholesterol) under 200 mg/dl
– LDL under 130 mg/dl
– HDL over 40 mg/dl.
– Normally, triglycerides are in the range of 10-190 mg/dl.
• Among the therapies used to reduce blood cholesterol level
– Exercise
– Diet
– Drugs that inhibit the synthesis of cholesterol
Fate of Lipids,
• Some lipids may be oxidized to produce ATP.
• Some lipids are stored in adipose tissue.
• Other lipids are used as structural molecules or to synthesize essential molecules. Examples include
– phospholipids of plasma membranes
– lipoproteins that transport cholesterol
– thromboplastin for blood clotting
– myelin sheaths to speed up nerve conduction
– cholesterol used to synthesize bile salts and steroid hormones.
Review
• The various functions of lipids in the body may be reviewed in Table 2.7.
Triglyceride Storage
• Triglycerides are stored in adipose tissue, mostly in the subcutaneous layer.
• Adipose cells contain lipases that catalyze the deposition of fats from chylomicrons and hydrolyze neutral fats into fatty acids and glycerol.
– 50% subcutaneous, 12% near kidneys, 15% in omenta, 15% in genital area, 8% between muscles
• Fats in adipose tissue are not inert. They are catabolized and mobilized constantly throughout the body.
Lipid Catabolism: Lipolysis
• Triglycerides are split into fatty acids and glycerol (a process called lipolysis) under the influence of hormones such as epinephrine, norepinephrine, and glucocorticoids and released from fat deposits. Glycerol and fatty acids are then catabolized separately (Figure 25.14).
Lipid Catabolism: Lipolysis
• Glycerol can be converted into glucose by conversion into glyceraldehyde-3-phosphate.
• In beta oxidation, carbon atoms are removed in pairs from fatty acid chains. The resulting molecules of acetyl coenzyme A enter the Krebs cycle.
Lipid Catabolism: Ketogenesis
• As a part of normal fatty acid catabolism two acetyl CoA molecules can form acetoacetic acid which can then be converted to beta-hydroxybutyric acid and acetone.
• These three substances are known as ketone bodies and their formation is called ketogenesis (Figure 25.14).
– heart muscle & kidney cortex prefer to use acetoacetic acid for ATP production
Lipid Anabolism: Lipogenesis
• The conversion of glucose or amino acids into lipids is called lipogenesis. The process is stimulated by insulin (Figure 25.14).
• The intermediary links in lipogenesis are glyceraldehyde-3-phosphate and acetyl coenzyme A.
Clinical Application
• Blood ketone levels are usually very low
– many tissues use ketone for ATP production
– An excess of ketone bodies, called ketosis, may cause acidosis or abnormally low blood pH.
• Fasting, starving or high fat meal with few carbohydrates results in excessive beta oxidation & ketone production
– acidosis (ketoacidosis) is abnormally low blood pH
– sweet smell of ketone body acetone on breath
– occurs in diabetic since triglycerides are used for ATP production instead of glucose & insulin inhibits lipolysis
PROTEIN METABOLISM
• During digestion, proteins are hydrolyzed into amino acids. Amino acids are absorbed by the capillaries of villi and enter the liver via the hepatic portal vein.
Fate of Proteins
• Amino acids, under the influence of human growth hormone and insulin, enter body cells by active transport.
• Inside cells, amino acids are synthesized into proteins that function as enzymes, transport molecules, antibodies, clotting chemicals, hormones, contractile elements in muscle fibers, and structural elements. They may also be stored as fat or glycogen or used for energy. (Table 2.8)
Protein Catabolism
• Amino acids can be converted to substances that can enter the Krebs cycle.
– Deamination
– Decarboxylation
– Hydrogenation
– (Figure 25.13).
• Amino acids can be converted into
– Glucose
– fatty acids
– ketone bodies
Protein Catabolism
• Liver cells convert amino acids into substances that can enter the Krebs cycle
– deamination removes the amino group (NH2)
• converts it to ammonia (NH3) & then urea
• urea is excreted in the urine
• Converted substances enter the Krebs cycle to produce ATP.
Protein Anabolism
– involves the formation of peptide bonds between amino acids to produce new proteins.
– stimulated by human growth hormone, thyroxine, and insulin.
– carried out on the ribosomes of almost every cell in the body, directed by the cells’ DNA and RNA.
Amino Acids
• Of the 20 amino acids in your body, 10 are referred to as essential amino acids. These amino acids cannot be synthesized by the human body from molecules present within the body. They are synthesized by plants or bacteria. Food containing these amino acids are “essential” for human growth and must be a part of the diet.
• Nonessential amino acids can be synthesized by body cells by a process called transamination. Once the appropriate essential and nonessential amino acids are present in cells, protein synthesis occurs rapidly.
Clinical Application: PKU
• Phenylketonuria (PKU) is a genetic error of protein metabolism characterized by elevated blood and urine levels of the amino acid phenylalanine.
– caused by a mutation in the gene that codes for the enzyme phenylalanine hydrolylase.
– This enzyme is needed to convert phenylalanine to tyrosine.
– Tyrosine
