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Metabolism Marcus Cueno, RN
Metabolism
• Functions of food – source of energy – essential nutrients – stored for future use
• Metabolism is all the chemical reactions of the body
– some reactions produce the energy stored in ATP that other reactions consume
– all molecules will eventually be broken down and recycled or excreted from the body
Catabolism and Anabolism
• Catabolic reactions breakdown complex organic compounds
– providing energy (exergonic) – glycolysis, Krebs cycle and electron transport
• Anabolic reactions synthesize complex molecules from small molecules
– requiring energy (endergonic)
• Exchange of energy requires use of ATP (adenosine triphosphate) molecule. ATP Molecule & Energy • Each cell has about 1 billion ATP molecules that last for less than one minute • Over half of the energy released from ATP is converted to heat Energy Transfer
• Energy is found in the bonds between atoms
• Oxidation is a decrease in the energy content of a molecule
• Reduction is the increase in the energy content of a molecule
• Oxidation-reduction reactions are always coupled within the body
– whenever a substance is oxidized, another is almost simultaneously reduced.
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Oxidation and Reduction
• Biological oxidation involves the loss of (electrons) hydrogen atoms
– dehydrogenation reactions require coenzymes to transfer hydrogen atoms to another compound
– common coenzymes of living cells that carry H+ • NAD (nicotinamide adenine dinucleotide ) • NADP (nicotinamide adenine dinucleotide phosphate ) • FAD (flavin adenine dinucleotide )
• Biological reduction is the addition of electrons (hydrogen atoms) to a molecule
– increase in potential energy of the molecule 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--In 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
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Fate of Glucose
• ATP production during cell respiration – uses glucose preferentially
• Converted to one of several amino acids in many different cells throughout the body
• Glycogenesis
– hundreds of glucose molecules combined to form glycogen for storage in liver & skeletal muscles
• Lipogenesis (triglyceride synthesis) – converted to glycerol & fatty acids within liver & sent to fat cells
Glucose Movement into Cells • In GI tract and kidney tubules, Na+/glucose symporters • Most other cells, GluT facilitated diffusion transporters move glucose into cells
– insulin increases number 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 hidden in cell
• Concentration gradient favorable for more glucose to enter Glucose Catabolism
• 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 of Glucose & Fate of Pyruvic Acid • Breakdown of six-carbon glucose molecule into 2 three-carbon molecules of pyruvic
acid – 10 step process occurring in cell cytosol – produces 4 molecules of ATP after input of 2 ATP – utilizes 2 NAD+ molecules as hydrogen acceptors
• If O2 shortage in a cell – pyruvic acid is reduced to lactic acid so that NAD+ will be still available for further glycolysis
– rapidly diffuses out of cell to blood – liver cells remove it from blood & convert it back to pyruvic acid
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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 (CO2 produced)
– pyruvic acid was oxidized so that NAD+ becomes NADH • 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 (Citric Acid Cycle)
• Series of oxidation-reduction & decarboxylation reactions occurring in matrix of mitochondria
• It finishes the same as it starts (4C) – 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
• Energy stored in bonds is released step by step to form several reduced coenzymes (NADH & FADH2) that store the energy
• In summary: each Acetyl CoA molecule that enters the Krebs cycle produces – 2 molecules of C02
• one reason O2 is needed – 3 molecules of NADH + H+ – one molecule of ATP – one molecule of FADH2
• Remember, each glucose produced 2 acetyl CoA molecules
The Electron Transport Chain
• Series of integral membrane proteins in the inner mitochondrial membrane capable of oxidation/reduction
• Each electron carrier is reduced as it picks up electrons and is oxidized as it gives up electrons
• Small amounts of energy released in small steps
• Energy used to form ATP by chemiosmosis Chemiosmosis • Small amounts of energy released as substances are passed along inner membrane • Energy used to pump H+ ions 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+ channel in inner
membrane
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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 proton pump (expel H+)
• Mobile shuttles pass electrons between complexes
• Last complex passes its electrons (2H+) to a half of O2 molecule to form a water molecule (H2O)
Proton Motive Force & Chemiosmosis
• Buildup of H+ outside the inner membrane creates + charge – electrochemical gradient potential energy is called proton motive force
• ATP synthase enzyme within H+ channel uses proton motive force to synthesize ATP from ADP and P
Summary of Cellular Respiration • Glucose + O2 is broken down into CO2 + H2O + energy used to form 36 to 38 ATPs
– 2 ATP are formed during glycolysis – 2 ATP are formed by phosphorylation during Krebs cycle – electron transfers in transport chain generate 32 or 34 ATPs from one glucose molecule
• Summary in Table 25.1 • Points to remember
– ATP must be transported out of mitochondria in exchange for ADP • uses up some of proton motive force
– Oxygen is required or many of these steps can not occur 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
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Glycogenesis & Glycogenolysis
• Glycogenesis – glucose storage as glycogen – 4 steps to glycogen formation in liver or skeletal muscle
– stimulated by insulin
• Glycogenolysis – glucose release not a simple reversal of steps
– enzyme phosphorylase splits off a glucose molecule by phosphorylation to form glucose 1-phosphate
– enzyme only in hepatocytes so muscle can’t release glucose – enzyme activated by glucagon (pancreas) & epinephrine (adrenal)
Gluconeogenesis
• Liver glycogen runs low if fasting, starving or not eating carbohydrates forcing formation from other substances – lactic acid, glycerol & certain amino acids (60% of available)
• Stimulated by cortisol (adrenal) & glucagon (pancreas) – cortisol stimulates breakdown of proteins freeing amino acids – thyroid mobilizes triglycerides from adipose tissue
Transport of Lipids by Lipoproteins
• Most lipids are nonpolar and must be combined with protein to be tranported in blood
• Lipoproteins are spheres containing hundreds of molecules – outer shell polar proteins (apoproteins) & phospholipids
– inner core of triglyceride & cholesterol esters
• Lipoprotein categorized by function & density
• 4 major classes of lipoproteins – chylomicrons, very low-density, low-density & high-density lipoproteins
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Classes of Lipoproteins
• Chylomicrons (2 % protein) – form in intestinal epithelial cells to transport 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 triglycerides formed in liver to fat cells
• 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 • if cells have insufficient receptors, remains in blood and more likely to deposit cholesterol in artery walls (plaque)
• HDLs (40% protein) --- “good cholesterol” – carry cholesterol from cells to liver for elimination
Blood Cholesterol
• Sources of cholesterol in the body – food (eggs, dairy, organ meats, meat) – synthesized by the liver
• All fatty foods still raise blood cholesterol – liver uses them to create cholesterol – stimulate reuptake of cholesterol containing bile normally lost in the feces
• Desirable readings for adults – total cholesterol under 200 mg/dL; triglycerides 10-190 mg/dL – LDL under 130 mg/dL; HDL over 40 mg/dL – cholesterol/HDL ratio above 4 is undesirable risk
• Raising HDL & lowering cholesterol can be accomplished by exercise, diet & drugs
Fate of Lipids
• Oxidized to produce ATP
• Excess stored in adipose tissue or liver • Synthesize structural or important molecules
– 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.
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Triglyceride Storage
• Adipose tissue removes triglycerides from chylomicrons and VLDL and stores it
– 50% subcutaneous, 12% near kidneys, 15% in omenta, 15% in genital area, 8% between muscles
• Fats in adipose tissue are ever-changing – released, transported & deposited in other adipose
• Triglycerides store more easily than glycogen
– do not exert osmotic pressure on cell membranes
– are hydrophobic Lipid Catabolism: Lipolysis & Glycerol
• Triglycerides are split into fatty acids & glycerol by lipase – glycerol
• if cell ATP levels are high, converted into glucose • if cell ATP levels are low, converted into pyruvic acid which enters aerobic pathway to ATP production
Lipolysis & Fatty acids • Beta oxidation in mitochondria removes 2 carbon units from fatty acid & forms acetyl
coenzyme A • Liver cells form acetoacetic acid from 2 carbon units & ketone bodies from
acetoacetic acid (ketogenesis) – heart muscle & kidney cortex prefer to use acetoacetic acid for ATP production
Lipid Anabolism: Lipogenesis
• Synthesis of lipids by liver cells = lipogenesis – from amino acids
• converted to acetyl CoA & then to triglycerides – from glucose
• from glyceraldehyde 3-phosphate to triglycerides
• Stimulated by insulin when eat excess calories Ketosis
• Blood ketone levels are usually very low – many tissues use ketone for ATP production
• 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
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Fate of Proteins
• Proteins are broken down into amino acids
– transported to the liver
• Usage – oxidized to produce ATP – used to synthesize new proteins • enzymes, hemoglobin, antibodies, hormones, fibrinogen, actin, myosin, collagen, elastin & keratin
– excess converted into glucose or triglycerides • no storage is possible
• Absorption into body cells is stimulated by insulinlike growth factors (IGFs) & insulin Protein Catabolism
• Breakdown of protein into amino acids
• 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 excreted in the urine
• Converted substances enter the Krebs cycle to produce ATP Protein Anabolism
• Production of new proteins by formation of peptide bonds between amino acids – 10 essential amino acids are ones we must eat because we can not synthesize them
– nonessential amino acids can be synthesized by transamination (transfer of an amino group to a substance to create an amino acid)
• Occurs on ribosomes in almost every cell
• Stimulated by insulinlike growth factor, thyroid hormone, insulin, estrogen & testosterone
• Large amounts of protein in the diet do not cause the growth of muscle, only weight-bearing exercise
Phenylketonuria (PKU)
• Genetic error of protein metabolism that produces elevated blood levels of amino acid phenylalanine
– causes vomiting, seizures & mental retardation
– normally converted by an enzyme into tyrosine which can enter the krebs cycle
• Screening of newborns prevents retardation – spend their life with a diet restricting phenylalanine – restrict Nutrasweet which contains phenylalanine
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Key Molecules at Metabolic Crossroads
• Glucose 6-phosphate, pyruvic acid and acetyl coenzyme A play pivotal roles in metabolism
• Different reactions occur because of nutritional status or level of physical activity Role of Glucose 6-Phosphate
• Glucose is converted to glucose 6-phosphate just after entering the cell
• Possible fates of glucose 6-phosphate – used to synthesize glycogen when glucose is abundant – if glucose 6-phosphatase is present, glucose can be re-released from the cell
– precursor of a five-carbon sugar used to make RNA & DNA
– converted to pyruvic acid during glycolysis in most cells of the body Role of Pyruvic Acid
• 3-carbon molecule formed when glucose undergoes glycolysis
• If oxygen is available, cellular respiration proceeds • If oxygen is not available, only anaerobic reactions can occur – pyruvic acid is changed to lactic acid
• Conversions – amino acid alanine produced from pyruvic acid
– to oxaloacetic acid of Krebs cycle Role of Acetyl coenzyme A
• Can be used to synthesize fatty acids, ketone bodies, or cholesterol • Can not be converted to pyruvic acid so can not be used to reform glucose Metabolic Adaptations
• Absorptive state – nutrients entering the bloodstream
– glucose readily available for ATP production – 4 hours for absorption of each meal so absorptive state lasts for 12 hours/day
• Postabsorptive state – absorption of nutrients from GI tract is complete
– body must meet its needs without outside nutrients • late morning, late afternoon & most of the evening • assuming no snacks, lasts about 12 hours/day • more cells use ketone bodies for ATP production
– maintaining a steady blood glucose level is critical
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Metabolism during Absorptive State
• Body cells use glucose for ATP production – about 50% of absorbed glucose
• Storage of excess fuels occur in hepatocytes, adipocytes & skeletal muscle
– most glucose entering liver cells is converted to glycogen (10%) or triglycerides (40%)
– dietary lipids are stored in adipose tissue – amino acids are deaminated to enter Krebs cycle or are converted to glucose or fatty acids
– amino acids not taken up by hepatocytes used by other cells for synthesis of proteins
Regulation of Metabolism during Absorptive State
• Beta cells of pancreas release insulin • Insulin’s functions – increases anabolism & synthesis of storage molecules
– decreases catabolic or breakdown reactions – promotes entry of glucose & amino acids into cells
– stimulates phosphorylation of glucose
– enhances synthesis of triglycerides – stimulates protein synthesis along with thyroid & growth hormone
Metabolism During Postabsorptive State
• Maintaining normal blood glucose level (70 to 110 mg/100 ml of blood) is major challenge
– glucose enters blood from 3 major sources • glycogen breakdown in liver produces glucose • glycerol from adipose converted by liver into glucose • gluconeogenesis using amino acids produces glucose
– alternative fuel sources are • fatty acids from fat tissue fed into Krebs as acetyl CoA • lactic acid produced anaerobically during exercise • oxidation of ketone bodies by heart & kidney
• Most body tissue switch to utilizing fatty acids, except brain still need glucose. Regulation of Metabolism During Postabsorptive State
• As blood glucose level declines, pancreatic alpha cells release glucagon – glucagon stimulates gluconeogenesis & glycogenolysis within the liver
• Hypothalamus detects low blood sugar
– sympathetic neurons release norepinephrine and adrenal medulla releases norepinephrine & epinephrine • stimulates glycogen breakdown & lipolysis • raises glucose & free fatty acid blood levels
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Metabolism During Fasting & Starvation
• Fasting means going without food for hours/days
• Starvation means weeks or months
– can survive 2 months or more if drink enough water
– amount of adipose tissue is determining factor
• Nutritional needs – nervous tissue & RBC need glucose so amino acids will be broken down for gluconeogenesis • blood glucose stabilizes at 65 mg/100 mL • lipolysis releases glycerol used in gluconeogenesis
– increase in formation of ketone bodies by liver cells due to catabolism of fatty acids • by 40 days, ketones supply 2/3’s of brains fuel for ATP
Absorption of Alcohol
• Absorption begins in the stomach but is absorbed more quickly in the small intestine
– fat rich foods keep the alcohol from leaving the stomach and prevent a rapid rise in blood alcohol
– a gastric mucosa enzyme breaks down some of the alcohol to acetaldehyde
• Females develop higher blood alcohols
– have a smaller blood volume
– have less gastric alcohol dehydrogenase activity Metabolic Rate
• Rate at which metabolic reactions use energy – energy used to produce heat or ATP
• Basal Metabolic Rate (BMR) – measurements made under specific conditions
• quiet, resting and fasting condition
• Basal Temperature maintained at 98.6 degrees – shell temperature is usually 1 to 6 degrees lower
Heat Production
• Factors that affect metabolic rate and thus the production of body heat
– exercise increases metabolic rate as much as 15 times
– hormones regulate basal metabolic rate • thyroid, insulin, growth hormone & testosterone increase BMR
– sympathetic nervous system’s release of epinephrine & norepinephrine increases BMR
– higher body temperature raises BMR
– ingestion of food raises BMR 10-20%
– children’s BMR is double that of an elderly person
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Mechanisms of Heat Transfer
• Temperature homeostasis requires mechanisms of transferring heat from the body to the environment
– conduction is heat exchange requiring direct contact with an object – convection is heat transfer by movement of gas or liquid over body
– radiation is transfer of heat in form of infrared rays from body
– evaporation is heat loss due to conversion of liquid to a vapor (insensible water loss)
Hypothalamic Thermostat
• Preoptic area in anterior hypothalamus
– receives impulses from thermoreceptors
– generates impulses at a higher frequency when blood temperature increases
– impulses propagate to other parts of hypothalamus • heat-losing center • heat-promoting center
• Set in motion responses that either lower or raise body temperature Thermoregulation
• Declining body temperature – thermoreceptors signal hypothalamus to produce TRH – TRH causes anterior pituitary to produce TSH resulting in
• vasoconstriction in skin • adrenal medulla stimulates cell metabolic rate • shivering • release of more thyroid hormone raises BMR
• Increases in body temperature – sweating & vasodilation
Hypothermia
• Lowering of core body temperature to 35°C (95°F)
• Causes – immersion in icy water (cold stress)
– metabolic diseases (hypoglycemia, adrenal insufficiency or hypothyroidism)
– drugs (alcohol, antidepressants, or sedatives) – burns and malnutrition
• Symptoms that occur as body temperature drops
– shivering, confusion, vasoconstriction, muscle rigidity, bradycardia, acidosis, hypoventilation, coma & death
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Regulation of Food Intake
• Hypothalamus regulates food intake
– feeding (hunger) center – satiety center
• Stimuli that decrease appetite
– glucagon, cholecystokinin, epinephrine, glucose & leptin – stretching of the stomach and duodenum
• Signals that increase appetite – growth releasing hormone, opioids, glucocorticoids, insulin, progesterone & somatostatin
Guidelines for Healthy Eating
• Nutrients include water, carbohydrates, lipids, proteins, vitamins and minerals
• Caloric intake – women 1600 Calories/day is needed
– active women and most men 2200 Calories
– teenage boys and active men 2800 calories
• Food guide pyramid developed by U.S. Department of Agriculture
– indicates number of servings of each food group to eat each day Minerals
• Inorganic substances = 4% body weight
• Functions – calcium & phosphorus form part of the matrix of bone
– help regulate enzymatic reactions • calcium, iron, magnesium & manganese
– magnesium is catalyst for conversion of ADP to ATP
– form buffer systems
– regulate osmosis of water
– generation of nerve impulses Vitamins
• Organic nutrients needed in very small amounts
– serve as coenzymes
• Most cannot be synthesized by the body
• Fat-soluble vitamins
– absorbed with dietary fats by the small intestine
– stored in liver and include vitamins A, D, E, and K
• Water-soluble vitamins are absorbed along with water in the Gl tract
– body does not store---excess excreted in urine – includes the B vitamins and vitamin C
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Antioxidant Vitamins
• C, E and beta-carotene (a provitamin)
• Inactivate oxygen free radicals – highly reactive particles that carry an unpaired electron • damage cell membranes, DNA, and contribute to atherosclerotic plaques • arise naturally or from environmental hazards such as tobacco or radiation
• Protect against cancer, aging, cataract formation, and atherosclerotic plaque Vitamin and Mineral Supplements
• Eat a balanced diet rather than taking supplements
• Exceptions – iron for women with heavy menstrual bleeding
– iron & calcium for pregnant or nursing women
– folic acid if trying to become pregnant • reduce risk of fetal neural tube defects
– calcium for all adults
– B12 for strict vegetarians – antioxidants C and E recommended by some
Fever
• Abnormally high body temperature
– toxins from bacterial or viral infection = pyrogens
– heart attacks or tumors
– tissue destruction by x-rays, surgery, or trauma
– reactions to vaccines
• Beneficial in fighting infection & increasing rate of tissue repair during the course of a disease
• Complications--dehydration, acidosis, & brain damage. Obesity
• Body weight more than 20% above desirable standard
• Risk factor in many diseases
– cardiovascular disease, hypertension, pulmonary disease,
– non-insulin dependent diabetes mellitus
– arthritis, certain cancers (breast, uterus, and colon), – varicose veins, and gallbladder disease.