Chapter 25 Metabolism

1
Chapter 25Metabolism

• 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

2
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.

3
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

4
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.

5
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

6
Mechanisms of ATP Generation
ADP P ATP

• 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.

7
Phosphorylation in Animal Cells

• In cytoplasm (1)
• In mitochondria (2, 3 4)

8
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

9
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

10
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

11
Glucose Catabolism

• Cellular respiration
• 4 steps are involved
• glucose O2 producesH2O 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)

12
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

13
10 Steps of Glycolysis
14
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).

15
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

16
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 CoAmolecule that enters
  the Krebscycle 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 glucoseproduced 2 acetyl CoA
  molecules

17
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

18
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

19
Electron Carriers

• Flavin mononucleotide (FMN) is derived from
  riboflavin (vitamin B2)
• Cytochromes are proteins with heme group (iron)
  existing either in reduced form (Fe2) or
  oxidized form (Fe3)
• 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

20
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)

21
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

22
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

23
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

24
Glycogenesis Glycogenolysis

• Glycogenesis
• glucose storage as glycogen
• 4 steps to glycogenformation in liver
  orskeletal muscle
• stimulated by insulin
• Glycogenolysis
• glucose release not a simplereversal of steps
• enzyme phosphorylase splits off a glucose
  molecule by phosphorylation to form glucose
  1-phosphate
• enzyme only in hepatocytes so muscle cant
  release glucose
• enzyme activated by glucagon (pancreas)
  epinephrine (adrenal)

25
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

26
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 byfunction density
• 4 major classes of lipoproteins
• chylomicrons, very low-density, low-density
  high-density lipoproteins

27
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

28
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

29
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.

30
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

31
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

32
Lipolysis Fatty acids
Liver cells

• 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

33
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

34
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

35
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

36
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

37
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

38
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

39
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

40
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

41
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

42
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

43
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

44
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

45
Absorptive State
Points where insulin stimulation occurs.
46
Regulation of Metabolism during Absorptive State

• Beta cells of pancreas release insulin
• Insulins 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

47
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.

48


Postabsorptive State
49
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

50
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 2/3s of brains fuel
  for ATP

51
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

52
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

53
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 systems release of
  epinephrine norepinephrine increases BMR
• higher body temperature raises BMR
• ingestion of food raises BMR 10-20
• childrens BMR is double that of an elderly person

54
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)

55
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

56
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

57
Hypothermia

• Lowering of core body temperature to 35C (95F)
• 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

58
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

59
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

60
Food Guide Pyramid
61
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

62
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

63
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

64
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

65
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.

66
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.