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-bisphosphate-Fru 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 acceptor-oxygen

• 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 macromoleculesynthesized

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 source-

triglycerides – 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 needed- converted 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 succinyl-CoAKrebs 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• breakdown produces ammonia as byproduct

– toxic• needed for structural & functional uses in cells• loss of too much would endanger homeostasis

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 down-glycogenolysis

• 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)glycogen breakdown

• sympathetic nervous systemincreases outputadrenal medullaepinephrine & norepinephrinelipolysis

Metabolism Overview