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METABOLISM Energy • needed for all physical & metabolic activities • food principle source of energy • digested & absorbed • supplies energy • serves as building blocks for synthesis of complex molecules • stored for future use Metabolism • all chemical reactions occurring in an organism • involves • Catabolism – breakdown of organic molecules – releases energy • Anabolism – synthesis of new organic molecules – formation of new chemical bonds • • Nutrients metabolism requires nutrients – ingested chemicals needed for growth, repair or maintenance of body obtained through ingestion & digestion – • • • • • • • • absorbed from interstitial fluids all organic building blocks available are placed into nutrient pool can be turned into metabolic fuels Macronutrients must be consumed in large quantities – Carbohydrates – Lipids – Proteins Micronutrients only needed in small amounts – Vitamins – Minerals – Water many can be manufactured by body others cannot be made – essential nutrients ATP • universal energy currency – adenosine tri-phosphate • PO4 bonds between phosphate groups-high energy bonds • PO4 groups are transferred from molecule to molecule provide energy to power cellular functions • ATPADP + energy AMP + energy ATP • body has limited capacity to store ATP • maximum work levels ATP depleted in seconds • to sustain activity need to continually replenish ATP • most cells make ATP by breaking down carbohydrates especially glucose • Glucose oxidized ATP + energy Carbohydrates • • • • • composed of monosaccharides – simple sugars Glucose-C6H12O6 – building block for complex carbohydrates Disaccharides – formed by 2 monosaccharides – glucose + fructose sucrose Polysaccharides – composed of repeating monosaccharides subunits – important in energy storage Starch – carbohydrate store in plants – compact & insoluble • Glycogen – polysaccharide energy storage form in animals – kind of animal starch Carbohydrate Processing • digestion – complex carbohydrate converted to simpler, soluble form – can be transported across intestinal wall & delivered to tissues • anabolic or biosynthetic reactions – small precursor moleculesmacromolecules synthesized – lipids, proteins & glycogen • catabolic reactions-oxidization – complete breakdown of glucose • C6H12O6 + 6O2 6CO2 + 6H2O + ATP + heat Glucose Oxidation Steps • Glycolysis – occurs in cytosol – does not require oxygen – also called anaerobic • Formation of Acetyl COA – connects glycolysis with Kreb’s cycle • Kreb’s Cycle – occurs in mitochondria – require O2 – aerobic • Electron Transport Chain – occurs in mitochondria – require O2 – aerobic Complete Oxidation of Glucose • C6H12O6 + 6O2 6CO2 + 6H2O • for one thing to be oxidized-another must be reduced • oxidation & reduction reactions typically occur together • redox reactions Oxidation/Reduction Reactions • Oxidation – occurs when H+ atoms are removed from compounds • Oxidized things lose electrons • electron lostoxidized-loses energy • Reduction – occurs when H+ atoms are added to compounds • gain electronreduced-gains energy • food fuels are oxidized-lose energy transferred to other moleculesATP • enzymes cannot accept H atoms • coenzymes act as hydrogen or electron acceptors – reduced each time substrate is oxidized Hydrogen Atom Transfers • coenzymes found in glucose oxidation reactions • NAD+-nicotinamide adenine dinucleotide • FAD-flavinadenine dinucleotide Glycolysis • first step in complete oxidation of glucose • takes place in cytosol • begins when enzyme phosphorylates – adds PO4 group to glucose Glu6PO4 • traps glucose – most cells do not have enzyme to reverse reaction & lack transport system for phosphorylated sugars – ensures glucose is trapped • Glu6PO4isomerizedFru6P+ ATP fructose-1,6-bisphosphateFru 1,6diP • reactions use 2 ATPs • Energy investment phase ATP Glycolysis • glyceraldehyde-3-P dehydrogenase catalyzes NAD+ dependent oxidation of glyceraldehyde 3P2 pyruvates • H+ that is removed is picked up by NAD+NADH + H+ • glucose + 2NAD + 2ADP + pi2 pyruvic acids + 2NADH + 2 ATP Glycolysis Pyruvate • fate depends on oxygen availability • not enough oxygen – NAD+ is regenerated by converting pyruvatelactic acid • anaerobic fermentation • limited by buildup of lactic acid – produces acid base problems – degrades athletic performances – impairs muscle cell contractions & produces physical discomfort • O2 available • pyruvic acid enters aerobic pathways of Krebs cycle & electron transport chain (ETC) • aerobic respiration Aerobic Respiration • pyruvic acid enters mitochondria – aerobic pathways of Krebs cycle & electron transport chain (ETC) • specific mechanisms transport pyruvate molecule into mitochondria • once inside pyruvate dehydrogenase converts pyruvateacetyl CoA • hydrogen atoms of pyruvate are removed by coenzymes • pyruvate is decarboxylated (carbons removed) released as CO2diffuses out of cells into bloodexpelled by lungs • pyruvic acid + NAD + + coenzyme A CO2 + NADH + Acetyl CoA Acetyl CoA • major branch point in metabolism • 2 carbons can be converted into fatty acids, amino acids or energy Krebs Cycle • named for discoverer, Hans Krebs – also tricarboxylic acid cycle or Citric Acid Cycle • during cycle hydrogen atoms are removed from organic moleculestransferred to coenzymes • begins & ends with oxaloacetate (OAA) • acetyl CoA condenses with oxaloacetate- 4 carbon compoundcitrate-6 carbon compound • cycle continues around through 8 successive step • during steps atoms of citric acid are rearranged producing different intermediates called keto acids • eventually turns into OAA Krebs Cycle • complete revolution per acetyl CoA includes 2 decarboxylations & 4 oxidations • Yields – 2 CO2 – reducing equivalents-3 NADH & 1 FADH2 • further oxidized in electron transport chain – 1 GTP-ATP equivalent Since two pyruvates are obtained from oxidation of glucose amounts need to be doubled for complete oxidation results Electron Transport • transfers pairs of electrons from entering substrate to final electron acceptoroxygen • reactions takes place on inner mitochondrial membrane • mitochondria have dual, inner membranes that are only permeable to water, oxygen & CO2 Oxidative Phosphorylation/Electron Transport Chain System • • • • • • responsible for 90% of ATP used by cells basis-2H + O22 H20 releases great deal of energy all at once cells cannot handle so much energy at one time reactions occur in series of steps Oxidation reactions – remove H+ atoms & lose energy (H+) • • • • • Oxidized things lose electrons compounds that gain electrons reduced-gain energy enzymes cannot accept H atoms Coenzymes needed to accept hydrogens when coenzyme accepts hydrogen atoms coenzyme reduced & gains energy Electron Transport Chain • during oxidative phosphorylation electrons are led through series of oxidation-reduction reactions before combining with O2 atoms • • • • • • • Chemiosmosis ETC creates conditions needed for ATP production by creating steep concentration gradient across inner mitochondrial membrane as energy is released as electrons are transferred drives H ion pumps that move H across membrane into space between 2 membranes pumps create large concentration gradients for H H ions cannot diffuse into matrix-not lipid soluble channels allow H ions to enter matrix Chemiosmosis – energy released during oxidation of fuels=chemi – pumping H ions across membranes of mitochondria into inter membrane space =osmo – creates steep diffusion gradient for Hs across membrane when hydrogens flow across membrane, through membrane channel proteinATP synthase attaches PO4 to ADP ATP ATP synthase Oxidative Phosphorylation • captures free energy released during electron transport & couples it to phosphorylation of ADPATP • for each pair of electrons removed by NAD from substrate in TCA cycle6 hydrogen ions are pumped across inner membrane of mitrochondria makes 3 ATP • FAD4 hydrogens pumped across2 ATP Energy Yield • aerobic metabolism generates more ATP per mole of glucose oxidized than anaerobic metabolism • of 686 kcal of energy available in 1 mole of glucose262 kcal are captured as ATP • 38% of energy • Glycolysis – net 2 ATPs • Krebs Cycle – 2 ATP – 8 NADH + H+ X 3=24 ATP – 2 FADH2 X 2=4 ATP • 2 moles pyruvate2 NADH + H+-glycolysis 2 X 2 = 4 ATP • Total 36 ATP Carbohydrate Biosynthetic Reactions • anabolic reactions –small precursor molecules macromolecule synthesized Glycogenesis • consuming large quantity of glucose, does not form great deal of ATP • ATP cannot be stored • excess glucose stored as glycogen or fat • once glycolysis stopsglucose molecules combineglycogen – animal carbohydrate storage product • glycogenesis – glucose enters cells phosphorylated glu-6-P isomerized glu1PO4 glycogen synthase cleaves terminal PO4-attaches glucose to growing glycogen chain • reaction takes place mostly in liver & skeletal muscle cells • blood glucose levels low glycogen breaks downglycogenolysis Gluconeogenesis • liver can only store enough glucose as glycogen to last about 12 hours • synthesis of new glucose from non carbohydrate sources- gluconeogenesis • carried out in liver • protects body especially nervous system from effects of hypoglycemia • glucose can be synthesized from amino acids, Krebs cycle intermediates, pyruvate or glycerol Lipids • most concentrated source of energy • highly efficient & important energy store • capable of storing more energy for weight than carbohydrates • provide large amount of ATP • form compact fat droplets which exclude water • insoluble & take up minimal space • most abundant dietary sourcetriglycerides – mainly stored in adipocytes • triglycerides contain 3 long chain fatty acids & glycerol • • • • • • • • • • • • • • • • • • • • Lipid Transport lipids are not water soluble most circulate as lipoproteins – lipid-protein complexes – spherical-protein, phospholipids & cholesterol surrounding inner core of triglycerides – proteins in other shell are apoproteins 4 groups by size & proportion of lipid to protein chylomicrons 95% triglycerides made by epithelial cells of small intestine carry dietary lipids enter lactealsabsorbed into lympthblood stream Travel to adipocytes where the fat is stored VLDL -very low density lipoproteins made by liver carry endogenous lipids transport to adipocytes for storage LDL-low density lipoproteins deliver cholesterol to tissues carry 75% of body’s cholesterol excess-desposited around arteries HDL-high density lipoproteins- good cholesterol contain equal amounts of lipid & protein transport excess cholesterol to liver for storage Lipolysis • breakdown of lipids • triglyceride2 F.A.s + glycerol • reaction is hydrolysis • catalyzed by lipases • epinephrine & norepinephrine stimulate breakdown • insulin inhibits it • glycerol & fatty acids are catabolized in different pathways Glycerol Oxidation • converted to glyceraldehydes 3-PO4 (a product formed during glycolysis) • ATP-not neededconverted to glucose • ATP-needed-enters TCA cycle after being converted to pyruvic acid • • • • • • • • Fatty Acid Oxidation-Beta Oxidation fatty acidsmitochondria matrix refers to oxidation at -carbon or 3rd position removal occurs in repeating sequential removal of 2-carbon units attaches them to coenzyme A which enters Krebs cycle for every 2 C fragments removed 12 ATPs made from processing acetyl coA in Krebs cycle fatty acids with odd number of carbons-broken to propionyl-CoA – 3 carbon compound cannot enter another round of oxidation Propionyl-CoA succinylCoAKrebs cycle Ketogenesis • process by which excess acetyl groups can be metabolized by liver • 2acetyl groups condense acetoacetic acid • some is converted to beta hydroxybutyric acid & acetone • ketone bodies • able to cross plasma membranes • enter the blood stream • some cells use these by attaching them to 2 coenzyme A molecules2 acetyl coA molecules which can enter Kreb’s cycle Lipogenesis • glucose & amino acid levels highstored in adipose tissue • Lipogenesis • body cannot make all fatty acids • ones that cannot be made are essential fatty acids • linoleic acid or linolenic • must be obtained in diet Lipid Metabolism Proteins • polymers of amino acids joined by peptide bondspeptide protein • basic building blocks of cells • comprise • cell structure • skin • keratin-hair, nails • connective tissue-tendons, cartilage, muscles • membranes • serve as enzymes – facilitate chemical reactions • part of hemoglobin • hormones Amino Acids • 20 amino acids • 10 essential – cannot be made by body • body can’t make 8 • isoleucine, leucine, lysine, phenylalaine, valine, methionine, tryptophane & threonine • do not make inadequate amounts of arginine & histidine • • • • • • • • • Proteins ingested in animal products – complete proteins Ingested via other sources • incomplete proteins • low in one or more essential amino acids excess proteins are not stored liver continually breaks proteins down & absorbs amino acids from blood amino acids can be used to make new proteins or in TCA cycleATP not enough carbohydrates or fats ingested to make ATPdietary & tissue proteins can be broken down to provide energy average ATP yield-similar to yield from carbohydrates impractical energy sources more difficult to break down than carbohydrates or lipids Protein Metabolism • digestion breaks down into amino acids • before can be oxidized or catabolizedmust be deaminated – occurs in liver • involves removal of amino group & H atomNH3-ammonia or NH4+ • Ammonia is toxic – body cannot allow high concentrations to accumulate • removed by converting it to urea in urea cycle • once amino acids are ready-can be converted into glucose (gluconeogenesis), into fatty acids (lipogenesis) or into ketone bodies (ketogenesis) Protein Metabolism • new proteins can be made by forming peptide bonds between amino acids • carried out on ribosomes • directed by DNA and RNA • non-essential amino acids can be made by transamination • transfer of amino group from amino acid to pyruvate or to an acid (ketoacid) in Krebs cycle • original amino acid becomes keto acid-intermediate in Krebs Cycle – can be broken down in that cycle • most amino acids transfer amine group to -ketoglutarate • amino acid + ketoacidketoacid + amino acid-glutamic acid Absorptive & Post Absorptive States • over 24 hours body two patterns of metabolic activity • Absorptive – fed state • Post absorptive – fasting stage • metabolic controls equalize blood concentration of nutrients between these 2 states Absorptive State • time during & shortly after eating • lasts about 4 hrs • energy sources are absorbed & stored • overall biosynthesis of stored reserves such as glycogen, protein & fat • Anabolic processes> catabolic processes Absorptive State • primary hormone-insulin • directs nearly all events of absorptive state • Hypoglycemic – takes glucose out of blood • glucose increases>100mg glucose/100ml blood humoral stimulus cells pancreatic isletsinsulin • release enhanced by GI tract hormones especially gastrin, CCK & secretin & by elevated amino acid levels • binds to membrane receptors on target cellsactivates carrier mediated facilitated diffusion of glucose into cellsincreases glucose into cells 15-20X within seconds Absorptive Processes • lipids, proteins & carbohydrates are ingested & absorbed by intestinal mucosa • 50% of glucose is oxidized to ATP • Glucoseglycogen (glycogenesis) • fatty acidspackaged in chylomircons enter lactealsstored as fat • excess glucose transported to adipocytes & stored as triglycerides • amino acids enter hepatocytes where they are deaminated to ketoacids & either enter the Krebs cycleATP or used in fatty acid synthesis Post Absorptive State • GI tract empty • no nutrient absorption • body relieves on internal energy resources supplied by breakdown of body reserves • occurs during late morning, afternoon & all night • about 12 hours • metabolic activity focuses on mobilization of energy reserves & maintenance of normal glucose levels • coordinated by hormones & neural mechanisms Post Absorptive State • glucose below 80 mg/dl glycogen reserves broken downglycogenolysis • epinephrine, growth hormone & glucocoricoids fat mobilization-adipocytes lipolysis fatty acids + glycerolglucose • as glucose reserves continue to decreasegluconeogenesis using amino acids & lactic acid begins • fat undergoes beta oxidation acetyl CoATCA cycle ATP used in gluconeogenesis or converted to ketone bodies which can be used by peripheral tissues for energy Post Absorptive State Regulation • hormones & sympathetic division of ANS • blood glucose levels decreasepancreatic alpha cellsglucagon liver (primary target increases glucose in blood from gluconeogenesis & glucogenolysis Post Absorptive State Regulation • low blood glucose stimulates sympathetic nervous systemincreases output epinephrine (neurotransmitter)glycog en breakdown • sympathetic nervous systemincreases outputadrenal medullaepinephrine & norepinephrinelipolysis Metabolism Overview