Metabolism

• Definition: Sum of all chemical reactions in the body

• Anabolic versus Catabolic Reactions– Anabolic Rxns = use chemical energy to

synthesize products– Catabolic Rxns = break down substances to

generate chemical energy

Chemical Energy Production

Energy (sunlight)

CO2 + H2O Carbohydrates + O2

Photosynthesis (plants)

Carbohydrates + O2 CO2 + H20 + ATP

Respiration (animals and plants)

Food Consumption

Food ingested is digested to elementary

units by catabolic reactions that convert:

a. Lipids to glycerol and fatty acids

b. Proteins to amino acids

c. Complex carbohydrates to simple sugars

Food Utilization

Elementary units (glycerol, f.a., a.a., simple sugars) produced by digestion and ab- sorption are:a. used for energy productionb. storedc. converted to other cellular productsd. used for production of other cell components

Carbohydrate Metabolism

• Carbohydrates can be used to generate ATP

• Can be stored as glycogen– mostly in liver and skeletal muscle tissue

• Can be converted to fat and stored

Fat Metabolism• Triglycerides are used to generate energy (ATP)– F.A. generate acetyl Coenzyme A which enters Kreb’s

cycle and generates ATP– At rest, @ half of energy used by muscle, liver and

kidneys comes from f.a. catabolism

• Glycerol can be converted to glucose– Anaerobic and/or aerobic metabolism of glucose can

generate ATP– Glucose can be converted to fat and stored

• Can be stored as fat– Accounts for majority of energy stored in body– Most cells can store some fat

• Adipocytes = specialized cells designed for storing fat

• Body will preferentially convert reserves to fat for storage because gram per gram, fat generates more energy than does protein or carbohydrate

Fat Metabolism (continued)

H O

H - N - C - C - OH

H R

Protein Metabolism• Proteins broken down to amino acids

• Amino acids can be used to generate ATP– the amino group cannot be used to generate

ATP– the remainder of most amino acids can

generate intermediates that can enter the glycolytic pathway or the Kreb’s cycle

Protein Anabolism

• Nonessential amino acids are those that can be synthesized by the body– glucose and fats can be used to generate some

amino acids• Essential amino acids (8) cannot be synthesized in

body– must be obtained from dietary intake

Energy Considerations

• Catabolic reactions release energy– Majority released as heat energy

• Homeostasis strives to maintain constant internal environment, including constant internal temperature

• Pathways combine multiple reactions, each of which generates small amounts of energy, to minimize heat generation

• Definition: A sequence of enzyme-mediated reactions leading to the formation of a particular product

• Mechanism for controlling thermal energy release associated with chemical reactions

Metabolic Pathway

Anaerobic versus Aerobic Energy Production

• Anaerobic Metabolism– DOES NOT Require oxygen

– Occurs in cytoplasm

– Converts glucose to pyruvate by glycolysis• Generates ATP

• Generates much lower levels of ATP than aerobic metabolism of glucose

• Aerobic Metabolism– DOES require oxygen

– Occurs in mitochondria

– Converts pyruvate to Acetyl CoA• Generates ATP via the

Kreb’s cycle and electron transport chain

• Generates much more ATP than anaerobic metabolism

Chemical Oxidation & Reduction

• GER = GAIN OF ELECTRONS– gain of an electron equivalent to gain of H

atom– when a molecule gains electrons it becomes

REDUCED

• LEO = LOSS OF ELECTRONS– loss of electron equivalent to loss of H atom– when molecule loses electrons it becomes

OXIDIZED

NAD and FAD• NAD = nicotinamide adenine dinucleotide– derived from vitamin B3

• FAD = flavin adenine dinucleotide– derived from vitamin B2

• Participate in oxidation/reduction reactions– NAD and FAD are coenzymes for several reactions in the

Kreb’s cycle– Become ‘reduced’ when they accept H atoms – Become ‘oxidized’ when they donate their H atoms

• Shuttle hydrogen atoms between molecules by vacillating back and forth between oxidized and reduced forms

NAD and ATP Production

• Oxidized form = NAD+

• Reduced form = NADH + H+

• Each molecule of reduced NAD (NADH + H+) formed produces 3 ATP by oxidative phosphorylation in the mitochondria

FAD and ATP Production

• Oxidized form = FAD• Reduced form = FADH2

• Each reduced FAD (FADH2) formed produces 2 ATP by oxidative phosphorylation in the mitochondria

• 2 FADH2 produced in Kreb’s cycle (one per molecule of pyruvate)– produces 4 molecules of ATP by oxidative

phosphorylation

Phosphorylation• Definition: Addition of phosphate group to an organic molecule• Two types of phosphorylation– Substrate level

• The process of transferring a phosphate group between two organic molecules– i.e. make ATP by transferring a phosphate group from some organic molecule to

ADP to form ATP

– Oxidative• The process of adding an inorganic phosphate to an organic molecule

– i.e. make ATP by adding a free phosphate group (unattached to any organic molecule) to ADP

Oxidative Phosphorylation • Formation of ATP by adding inorganic

phosphate to ADP• Occurs in mitochondria• Energy used to drive the production of ATP

comes from the production of water (H2O) by the combining of H atoms and oxygen

• H + O2 H2O• ADP + Pi ATP

• Reduced NAD and FAD provide the H atoms that combine with oxygen to form water

Glycolysis• Conversion of glucose pyruvate– one 6-carbon sugar two 3-carbon molecules

• Occurs in the cytoplasm • USES 2 ATP molecules – transfers 2 phosphates from ATP to ‘trap’ glucose and

later intermediates inside the cell

• Gross ATP production = 10 ATP• Net ATP production = 6 ATP per molecule of

glucose utilized (8 ATP in heart and liver)

Gross ATP Production by Glycolysis

• 4 ATP by substrate-level phosphorylation (SLP)• 6 ATP by oxidative phosphorylation (OP)– 2 molecules of reduced NAD (NADH + H+)– 3 ATP per molecule of reduced NAD

• Gross ATP = ATP by SLP + ATP by OP– Gross ATP = 4 + 6 = 10 ATP

• 2 ATP molecules used for each molecule of glucose converted to pyruvate– One to trap glucose inside cell

– One to energize intermediate

• 2 ATP molecules used to supply energy to transport reduced NAD to mitochondria– Exception: liver and heart, which move reduced

NAD to mitochondria by non-ATP dependent process

Glycolysis and ATP Consumption

Net ATP Production by Glycolysis

• Net ATP = Gross ATP produced – ATP used

• In Most Tissues = 10 – 4 = 6 ATP• In liver and heart = 10 – 2 = 8 ATP

Fate of Pyruvate Generated in Glycolysis

• If oxygen is present pyruvate is converted to Acetyl CoA– 1 molecule glucose yields 2 molecules

pyruvate in glycolysis and so can produce 2 molecules of Acetyl CoA

– Acetyl CoA enters mitochondria and is shuttled into the Kreb’s cycle

• If oxygen is absent pyruvate is converted to lactate and handled by Cori cycle

Kreb’s Cycle• Occurs in mitochondria• Acetyl CoA feeds into cycle that

1. Generates 3 reduced NAD and 1 reduced FAD per revolution

-reduced NAD yields 9 ATP per revolution -reduced FAD yields 2 ATP per revolution

2. Generates one ATP by substrate-level phosphorylation per revolution• Two revolutions occur per molecule glucose metabolized

ATP Production via Kreb’s Cycle

• Per revolution = 12 ATP– 11 ATP by oxidative phosphorylation– 1 ATP by substrate level phosphorylation

• Two revolutions per glucose moleculeyields 24 (I.e. 12 X 2 = 24) ATP total per

molecule of glucose metabolized via Kreb’s

cycle

ATP per glucose molecule

• By glycolysis– 4 by SLP– 6 by OP

• Gross = 10 ATP• Net = 6 (or 8 in liver and

heart) ATP– 2 used to trap and

energize– 2 used to transport

reduced NAD to mitochondria (except in liver and heart)

Anaerobic Metabolism• 6 (8 in liver and heart)

by glycolysis

• 6 by OP in conversion of pyruvates to Acetyl CoA

• 24 by Kreb’s cycle

– 22 by OP

– 2 by SLP

Anaerobic Metabolism

Cori Cycle

• In the absence of oxygen, pyruvate is converted to lactate (lactic acid)

• Cori cycle = cycle by which lactate is handled in the body

• Lactate moves from muscle to blood; pyruvate cannot leave muscle

• Lactate moves from blood to liver– in liver, lactate is converted back to pyruvate– pyruvate is converted back to glucose– glucose can enter bloodstream and return to

muscle for energy production or be stored in liver as glycogen

Cori Cycle

MUSCLE BLOOD LIVER

Glycogen Glycogen

Glucose Glucose

Pyruvate Pyruvate

Lactate LactateLactate

Glucose

Cori Cycle

Metabolic States• Absorptive state– period when ingested nutrients are entering

the bloodstream from the G.I. Tract– takes around 4 hours to completely absorb

average meal

• Post-absorptive state– period when G.I. tract is empty of nutrients

and energy must be supplied by body’s stored reserves

Absorptive State

• Glucose = major energy source• Blood glucose levels high• Insulin secreted from beta cells of pancreas– insulin = protein hormone– stimulates transport of glucose from bloodstream

into cells• all cells except brain and liver require insulin action to

move glucose into cells

• Net synthesis of glycogen, fat, and protein occurs

Insulin Actions in Liver

• Glucose can enter liver cells without insulin• Promotes conversion of glucose to glycogen

(storage form of carbohydrates)• Promotes conversion of fatty acids and amino

acids to fat

Insulin Action in Muscle

• Essential for transport of glucose into cells– skeletal muscle = majority of body mass and

major consumer of metabolic fuel, even at rest

• Promotes conversion of glucose to glycogen

Insulin Action in Fat

• Promotes uptake of glucose from bloodstream

• Promotes conversion of glucose and fatty acids to fat (triacylglycerols)

Insulin Action in Most Cells

• Promotes uptake of glucose from bloodstream and use for energy (ATP) production

• Promotes uptake of fatty acids and their use for energy (ATP) production

• Promotes uptake of amino acids and their conversion to protein

Glucose and the Brain

• Glucose can enter brain without insulin action– Brain cannot synthesize or store enough

glucose to provide energy from ATP for more than a few minutes

• Body strictly regulates blood glucose to meet brain’s needs

• Several hours after a meal

• Blood glucose levels are low

• Body must obtain glucose from reserves

• Glucagon = main hormone in circulation, produced by alpha cells of pancreas

Post-absorptive State

Post-absorptive State (continued)Catabolic reactions occur to: 1. Provide blood glucose

a. Glycogen converted to glucose b. Gluconeogenesis = production of glucose from non-carbohydrate sources (i.e. Cori cycle lactate to glucose) 2. Promote glucose sparing (preferential use of fat over glucose in most tissues)

Actions of Glucagon in Liver

• Stimulates glycogenolysis (glycogen to glucose)

• Stimulates fats to fatty acids

• Stimulates proteins to amino acids

Glucagon Action in Fat

Stimulates fat conversion to fatty acids

Glucagon Action in Most Cells

Stimulates protein conversion to amino acids

Sources of Glucose• Intestinal absorption• Glycogen breakdown (glycogenolysis)• Biosynthesis from non-carbohydrate

sources (gluconeogenesis)• Most cells can synthesize glycogen from

and hydrolyze glycogen to glucose• Only LIVER and KIDNEY can release

glucose into bloodstream

Enzymes and Glucose Metabolism

• Insulin and Glucagon

• Glycogen Synthetase– needed to synthesize glycogen from glucose– found in most cells

• Phosphorylase– needed to hydrolyze glycogen to glucose– found in most cells

• Pyruvate carboxylase, phosphoenolpyruvate, and fructose 1,6 diphosphatase– enzymes needed for gluconeogenesis– found only in liver and kidney

• Glucose-6-phosphatase– needed to release glucose into circulation– found only in liver and kidney

Enzymes and Glucose Metabolism

Liver and Glucose Production

• Liver can produce glucose by gluconeogenesis • Liver can release synthesized glucose for use by

other cells• When liver is producing and releasing glucose

for use by other tissues it uses ketone bodies as source of energy– metabolic products produced by acetyl CoA

– acetoacetate, b-hydroxybutyrate, and acetone

Caloric Content of Major Food Groups and Ethanol

Group cal/gm

carbohydrate 4

protein 4

fat 9*

ethanol 7

*fat provides most energy per unit weight of all foods; is best storage form of food

Exercise and Metabolism

• At rest– skeletal muscle uses fatty acid metabolism to

provide energy– blood glucose is reserved primarily for brain

• Exercise increases glucose utilization by muscle

• Endogenous glucose production increased to meet demands of low intensity exercise

• Exhaustive high demand exercise– first depletes glycogen stores– then depletes liver-derived glucose – eventually results in utilization of fatty acids

Exercise and Metabolism(continued)

Regulation of Food Intake• Hypothalamus– site of feeding center (on switch for food intake)

– site of satiety center (off switch for food intake)

• Leptin– protein hormone produced by fat cells

– acts at level of hypothalamus to decrease food intake

– may be part of negative feedback loop that monitors body fat levels (lipostat)

Set-Point Theory • ‘Predetermined’ weight optimum – body strives to maintain setpoint and will defend

attempts to alter it (i.e. diets)

• Rhythm method of ‘girth’ control– repeated cycles of alternating weight gain followed

by weight loss

– when body has reason to anticipate episodes of starvation it adjusts metabolic processes to more efficiently absorb and store food when it is available