5-1 Metabolism

Metabolism

• The balance of all anabolic (synthesis) and catabolic (decomposition) reactions in the body.
• 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)

Metabolic Reactions

Metabolism results from the balance of anabolic and catabolic reactions.

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ATP (adenosine triphosphate) is the energy molecule that couples the two types of reactions.

ATP =

Of energy

Metabolic reactions

• 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

Energy Transfer

• Energy is stored in bonds between atoms
• Oxidation is a decrease in the energy content (electrons) of a molecule

Energy transfer

• Reduction is the increase in the energy content (electrons) of a molecule

Energy transfer

• When a substance is oxidized, the liberated hydrogen atoms are transferred by 2 coenzymes to another compound.
• NAD (nicotinamide adenine dinucleotide)
• FAD (Flavin adenine dinucleotide)

Energy transfer

• Oxidation-reduction reactions are always coupled within the body
• whenever a substance is oxidized, another is almost simultaneously reduced.

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Mechanisms of ATP Generation

• Phosphorylation is ADP + Pi 🡪 ATP
• bond attaching 2nd and 3rd phosphate group contain stored energy
• Mechanisms of phosphorylation
• within animals
• substrate-level phosphorylation in cytosol
• oxidative phosphorylation in mitochondria
• in chlorophyll-containing plants or bacteria
• photophosphorylation.

Macromolecules of life

Proteins

• Long 3 dimensional chains of amino acids

Carbohydrates

• Polysaccharides = chains of monosaccharides

Lipids

• Chains of triglycerides

Nucleic acids

• DNA / RNA

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5-2 Carbohydrate Metabolism

Phosphorylation in Animal Cells

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

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Carbohydrate Metabolism

Carbohydrate metabolism is, in reality, mostly glucose metabolism. The body’s use of glucose depends on the needs of cells. These needs include:

• ATP production
• Amino acid synthesis
• Glycogen synthesis
• Triglyceride synthesis

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

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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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10 Steps of Glycolysis

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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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Formation of acetyl coenzyme A

• What happens to the pyruvic acid depends on the availability of oxygen.
• If oxygen is scarce (anaerobic conditions), pyruvic acid is reduced by the addition of 2 hydrogen atoms to form lactic acid.
• If oxygen is plentiful (aerobic conditions), most cells convert pyruvic acid to acetyl coenzyme A.

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Krebs Cycle

• Each Acetyl CoA molecule that enters the Krebs cycle produces:
• 2 molecules of C02
• 3 molecules of NADH + H+
• 1 molecule of GTP (= 1 ATP)
• 1 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

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• Each electron carrier is reduced as it picks up electrons and is oxidized as it gives up electrons

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• 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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Summary of Cellular Respiration

• C₆H₁₂O₆ + 6O₂ 🡪 6H₂O + 6 CO₂ + ATP
• Glycolysis
• IN: 1 Glucose; 2 ATP; 2 NAD+
• OUT: 2 NADH+H; 2 Pyruvic Acid; 2 ATP (net)
• Formation of Acetyl CoA
• IN: 2 Pyruvic Acid; 2NAD+
• OUT: 2 CO₂; 2 NADH+H; 2 Acetyl CoA
• Kreb’s Cycle
• IN: 2 Acetyl CoA; 6 NAD+; 2 FADH+
• OUT: 4 CO₂; 6 NADH+H; 2FADH₂; 2 ATP (GTP converted to ATP)
• Electron Transport Chain
• IN: 10 NADH+H; 2 FADH₂; 6 O₂
• OUT: 6 H₂O; 32-34 ATP

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• 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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5-3 Macromolecule Metabolism

Glycogenesis & Glycogenolysis

• Glycogenesis
• glucose storage as glycogen
• stimulated by insulin
• Glycogenolysis
• Breakdown of glycogen to make glucose/ATP
• Enzyme necessary only in hepatocytes so muscle can’t release glucose
• enzyme activated by glucagon (pancreas) & epinephrine (adrenal)

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 thyroid hormone, cortisol, & glucagon
• cortisol stimulates breakdown of proteins freeing amino acids
• thyroid mobilizes triglycerides from adipose tissue

Transport of Lipids by Lipoproteins

• Most lipids are nonpolar 🡪 must be combined with protein to be transported in blood
• Lipoproteins
• outer shell polar proteins�(apoproteins) & phospholipids
• inner core of triglyceride & �cholesterol esters
• Lipoprotein categorized by�function & density

Classes of Lipoproteins

• Chylomicrons (2 % protein)
• Transport dietary lipids to liver and adipose tissue
• VLDLs (10% protein)
• transport triglycerides formed by hepatocytes to adipocytes
• triglycerides are removed, they become LDLs containing mostly cholesterol
• LDLs (25% protein) --- “bad cholesterol”
• carry 75% of blood cholesterol to body cells
• HDLs (40% protein) --- “good cholesterol”
• liver produces an empty, collapsed protein shell
• travels through the blood picking up cholesterol
• when it returns to the liver, the cholesterol is removed and eliminated in the bile as cholesterol or bile acids

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Blood Cholesterol

• Sources of cholesterol in the body
• food (eggs, dairy, organ meats, meat)
• most 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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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

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

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Key Molecules at Metabolic Crossroads

5-4 Metabolic Regulation

Metabolic Adaptations

• Absorptive state
• nutrients entering the bloodstream
• glucose readily available
• 4 hours for absorption of each meal so absorptive state lasts for 12 hours/day
• Post-absorptive state
• absorption of nutrients from GI tract is complete
• body must meet its needs without outside nutrients
• maintaining a steady blood glucose level is critical

Regulation of Metabolism during Absorptive State

• Beta cells of pancreas release insulin
• Insulin’s 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

Absorptive State

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 tissues switch to utilizing fatty acids, except the brain still needs glucose.

Postabsorptive State

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

Heat and Energy Balance

• Factors that affect metabolic rate include:
• Exercise
• Hormones
• Nervous system
• Body temperature
• Ingestion of food (Specific Dynamic Effect)
• Age
• Gender, climate, sleeping, malnutrition

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Hypothermia

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

Heat and Energy Balance (homeostasis)

• Energy intake is directly dependent on the amount of food consumed.
• Total energy expenditure is based on:
• Basal metabolic rate (60%)
• Physical activity (30–35%)
• Food-induced thermogenesis (5–10%)

Energy intake > energy expenditure = Weight Gain

Energy intake < energy expenditure = Weight Loss

5-5 Appetite and Nutrition

Appetite

• Controlled by hypothalamus
• feeding center (if damaged → loss of appetite)
• orexin hormone stimulates intense hunger
• neuropeptide Y stimulates hunger
• satiety center (if damaged → voracious appetite)
• glucostat neurons absorb blood glucose & signal fullness
• inhibit feeding center
• leptin - secretion proportional to amount of body fat
• inhibits neuropeptide Y
• inhibits fat formation
• inhibits endocannabinoids

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Nutrition

• Minerals
• inorganic elements that play important roles in maintaining a healthy body.

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• Vitamins
• nutrients required in small amounts to maintain growth and normal metabolism.
• Most cannot be synthesized by the body.

Functions of Minerals

• Calcium & phosphorus make up the bones & teeth
• Phosphorus is part of many structural compounds
• bones, teeth, phospholipids, ATP, phosphate buffers,
• Calcium, iron, magnesium & manganese function as cofactors for enzymes
• Magnesium is catalyst for conversion of ADP to ATP
• Iron is essential for hemoglobin & myoglobin
• Chloride is component of stomach acid (HCl)
• Mineral salts function as electrolytes & govern the function of nerve & muscle cells, regulating the distribution of water in the body

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Minerals in the Diet

• Best sources are vegetables, legumes, milk, eggs, fish and shellfish
• Animal tissues contain large amounts of salt
• carnivores rarely lack salt in their diets
• herbivores often must supplement by ingesting soils
• Recommended sodium intake is 1.1 g/day, but typical American diet contains about 4.5 g/day
• salts in processed foods -- MSG, baking soda & powder

Vitamins

• Vitamins are either Water soluble or Fat soluble
• Fat soluble
• A (formed in GI and in food)
• Visual pigments, important for epithelium
• Antioxidant
• D (formed in skin then kidney)
• Promote calcium absorption and bone mineralization, deficiency leads to rickets
• E (dietary)
• Important for membranes, RNA/DNA synthesis, nervous function, wound healing
• K (made in GI)
• Important precursor for clotting factors

Vitamins

• Water-soluble vitamins are absorbed with water from the small intestine & often not stored (C and B)
• B1/B2/B6
• Important coenzymes in various metabolic pathways
• B12
• Important for RBC production, not found in vegetables, need IF for absorption
• Niacin
• Key part of NADH and NADP
• Pantothenic acid (produced in GI)
• Key part of CoA
• Folic acid (produced in gut)
• Needed for normal RBC and WBC formation
• C
• Important for protein synthesis, especially collagen, antioxidant, deficiency leads to scurvy

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

Vitamin and Mineral Supplements

• Eat a balanced diet rather than taking supplements
• Key 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