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
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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.

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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
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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
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 to a molecule

25-5

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.
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Phosphorylation in Animal Cells

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

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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 (glycogen synthesis)
hundreds of glucose molecules combined to form glycogen for storage in liver & skeletal muscles

Lipogenesis (triglyceride synthesis)

converted to glycerol & fatty acids within liver &
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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 25-10 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)
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 Breakdown of six-carbon glucose molecule into 2 threecarbon 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

Glycolysis of Glucose & Fate of Pyruvic Acid

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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10 Steps of Glycolysis

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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).
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Krebs Cycle (Citric Acid Cycle)

Series of oxidationreduction & 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 25-15

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

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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
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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 25-19

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) 25-20

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
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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

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

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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 cant release glucose enzyme activated by glucagon (pancreas) & epinephrine (adrenal)
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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 25-25

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 25-26

 Chylomicrons (2 % protein)

Classes of Lipoproteins

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
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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
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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.
25-29

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
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Lipid Catabolism: Lipolysis & Glycerol

Triglycerides are split into fatty acids & glycerol by lipase

glycerol
if cell ATP levels are high, converted into glucose 25-31 if cell ATP levels are low, converted into pyruvic acid which enters

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 25-32

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

25-33

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
25-34

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
25-35

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

25-36

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
25-37

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

25-39

Role of Glucose 6-Phosphate

Glucose is converted to glucose 6phosphate 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
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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
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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

25-42

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
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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
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Absorptive State

Points where insulin stimulation occurs.

25-45

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
25-46

 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

Metabolism During Postabsorptive State

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. 25-47

Postabsorptive State

25-48

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 2/3s of brains fuel for ATP
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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
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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

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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
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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)
25-54

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

25-55

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
25-56

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

25-57

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

GHRH, opioids, glucocorticoids, insulin, progesterone & somatostatin
25-58

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

25-59

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
25-60

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 25-61 includes the B vitamins and vitamin C

Antioxidant Vitamins
C, E and beta-carotene (a provitamin) Inactivate 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

25-62

Vitamin and Mineral Supplements

Eat a balanced diet Consider supplementation
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

25-63

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, &
25-64

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.
25-65