Metabolism Physiology

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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.

2 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

3 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

4 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

5 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

6 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

7 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.

8 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

9 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 weightbearing 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

10 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

11 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

12 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

13 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

14 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

15 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.