Metabolism: Catabolism and Anabolism

• Metabolism includes all chemical reactions occurring in the body and consists of catabolism and anabolism.

Catabolism

• Catabolism involves breaking down complex molecules into simpler ones.
• Catabolic reactions are exergonic reactions that release energy stored in molecules.
• Catabolism is required to convert substrates to a 2-carbon molecule for ATP production by mitochondria.

Anabolism

• Anabolism involves combining simple molecules into complex ones.
• Anabolic reactions are endergonic reactions that require energy.
• Anabolism is required for replacing membranes, organelles, enzymes, and structural proteins.

Cellular Catabolism/Respiration

• Cellular catabolism, also known as aerobic metabolism or cellular respiration, requires oxygen and occurs in the mitochondria.
• 40% of the energy from cellular catabolism is captured and used to convert ADP to ATP.
• 60% of the energy from cellular catabolism escapes as heat, warming the cell and surrounding tissue.

ATP

• ATP is the "energy currency" of the body, with energy stored in the bonds between phosphate groups.
• ATP is created in exergonic reactions and used in endergonic reactions.
• ADP + P + energy ↔ ATP
• Catabolic reactions like glycolysis create ATP, while anabolic reactions like glycogenesis require energy.

Utilization of Nutrients

• Nutrients come from the diet and from reserves.
• Reserves are mobilized when absorption across the digestive tract is insufficient.
• Liver cells break down triglycerides and glycogen into fatty acids and glucose.
• Adipocytes break down triglycerides into fatty acids
• Skeletal muscle cells break down contractile proteins into amino acids.
• All these reserves can be used to create ATP.

Restoration of Nutrient Reserves

• Reserves are stocked when absorption by the digestive tract exceeds immediate needs.
• Liver cells store triglycerides and glycogen.
• Adipocytes convert excess fatty acids to triglycerides.
• Skeletal muscles build glycogen reserves and use amino acids to increase myofibril numbers.

Utilization of Resources

• Cells in most tissues continuously absorb and catabolize glucose.
• Nervous tissue requires a continuous supply of glucose; other tissues can shift to fatty acid or amino acid catabolism during starvation, also can use ketones conserving glucose for nervous tissue

Oxidation-Reduction (Redox) Reactions

• Oxidation involves the removal of electrons from a molecule (OIL - Oxidation is Loss), decreasing potential energy.
• Reduction involves the addition of electrons to a molecule (RIG - Reduction is Gain), increasing potential energy.
• Redox reactions always occur together in pairs.

Coenzymes

• Coenzymes are molecules that accept hydrogen atoms (electrons) during oxidation.
• NAD+ is reduced to NADH + H+.
• FAD is reduced to FADH2.
• These coenzymes are used to create more ATP and are not proteins.

Glucose Metabolism

• Glucose (C6H12O6) is split into 2 pyruvate molecules (C3H4O3) during glycolysis, resulting in the loss of 4 hydrogen atoms.
• These hydrogen atoms are accepted by NAD+, which becomes NADH/H+.

ATP Generation Mechanisms

• Substrate-level phosphorylation: Transfers a high-energy phosphate group from an intermediate directly to ADP (e.g., glycolysis, citric acid cycle, phosphocreatine).
• Oxidative phosphorylation: Removes electrons and passes them through the electron transport chain to oxygen.

Carbohydrate Metabolism

• Glucose is the breakdown product of carbohydrates absorbed in the small intestine.
• Glucose is the preferred energy source, and most other saccharides are converted to glucose.
• Glucose is small, soluble, easily distributed, provides ATP anaerobically, and can be stored as glycogen.
• Glycogenolysis, the breakdown of glycogen, occurs quickly, making glucose easily mobilized.

GluT Transporters

• GluT transporters bring glucose into the cell via facilitated diffusion.
• Insulin increases the expression of GluT transporters, increasing glucose entry into cells.
• Glucose becomes trapped inside cells after being phosphorylated.

Fate of Glucose

• ATP production: If energy is needed immediately.
• Glycogen synthesis: Glucose molecules combine to form glycogen (stored form of glucose).
• Synthesis of amino acids: Used to form proteins.
• Triglyceride synthesis: When other body stores are full, excess glucose is converted to fats.

Cellular Respiration

• Cellular respiration has four steps in the complete utilization of a glucose molecule: glycolysis, formation of acetyl coenzyme A, citric acid cycle, and electron transport chain reactions:
• Glycolysis: Anaerobic, uses substrate-level phosphorylation
• Formation of acetyl coenzyme A: Aerobic
• Citric Acid Cycle (Kreb's Cycle): Aerobic, uses substrate-level phosphorylation
• Electron Transport Chain reactions: Aerobic, uses "oxidative phosphorylation"

Glycolysis

• Glycolysis is the first step in cellular respiration.
• One 6-carbon glucose molecule is split into two 3-carbon molecules of pyruvic acid in cytosol.
• 10 reactions consume 2 ATP but generate 4, resulting in a net gain of 2 ATP and 2 NADH.
• The first 5 steps use ATP and increase the potential energy in molecules.
• Steps 6-10 generate 4 ATP.

Phosphofructokinase

• Phosphofructokinase is a rate-limiting enzyme, meaning it determines that determines how fast the whole pathway can be carried out.

Glycolysis End Products

• Two pyruvate molecules are created from one glucose molecule.
• There is a net gain of 2 ATP molecules (4 ATP produced, 2 ATP consumed).
• 2 NADH are produced, which will go to the ETC to create more ATP if oxygen is available.

Fate of Pyruvate

• If oxygen is scarce (anaerobic), pyruvic acid is reduced to lactic acid.
• If oxygen is plentiful (aerobic), pyruvic acid is converted to acetyl coenzyme A and enters the Citric Acid Cycle.

Formation of Acetyl Coenzyme A

• Acetyl Coenzyme A formation is the second step in cellular respiration and is aerobic.
• It is a transitional step between glycolysis and the Krebs cycle.
• Each pyruvic acid is converted to a 2-carbon acetyl group by removing one molecule of CO2 as waste.
• The process occurs in the mitochondrial matrix.
• Each pyruvic acid loses 2 hydrogen atoms: NAD+ reduced to NADH/H+.
• By-products per glucose molecule: 2 CO2 (waste product), 2 NADH (go to ETC).

The Cori Cycle

• In scarce oxygen (anaerobic) conditions pyruvic acid is reduced to lactic acid.
• 2 pyruvic acid + 2NADH + 2H+ → 2 Lactic acid and 2 NAD+
• Once lactic acid is produced, it diffuses out of the cell and enters the blood.
• Hepatocytes can convert lactic acid to glucose and other oxygenated tissue can reduce the lactic acid back into pyruvate.
• The Cori Cycle occurs in anaerobic conditions can replenish glucose to be used for substrate level phosphorylation, however, is not sustainable due to a net loss.

The Citric Acid Cycle

• The Citric Acid Cycle is also known as Kreb's Cycle or TCA Cycle, it is the third step of cellular respiration.
• It requires oxygen (aerobic respiration) and occurs in the matrix of mitochondria.
• It involves a series of redox reactions that transfer energy to coenzymes by removing hydrogen atoms from organic molecules.

Citric Acid Cycle End Products

• 2 CO2 (4 CO2 per glucose molecule) - waste product.
• 3 NADH (6 NADH per glucose molecule) - will go to ETC.
• 1 FADH2 (2 FADH2 per glucose molecule) - will go to ETC.
• 1 ATP (2 ATP per glucose molecule).

Electron Transport Chain (ETC)

• The Electron Transport Chain consists of a series of electron carriers called cytochromes in the inner mitochondrial membrane.
• Cytochromes receive electrons from NADH and FADH2 and are reduced or oxidized as they pass along electrons down the chain.
• O2 is the final electron acceptor.
• Each NADH yields 2.5 ATP.
• Each FADH2 yields 1.5 ATP.

ETC Overview

• Each electron carrier has an increased infinity for electrons as we move down the chain, which releases energy.
• Energy is used to pump H+ ions into the intermembrane space.
• Energy stored in the electrochemical gradient is used to create ATP.
• Water is formed when the final electron acceptor is O2.
• The ETC produces more than 90% of ATP used in the body.
• The ETC stops if there is a lack of oxygen or if cytochromes are blocked (e.g., by poisons such as cyanide).
• Cells die from lack of ATP without a functioning ETC.
• Proton-motive force refers to there the gradient.
• Chemiosmosis refers to the movement of hydrogen back into the matrix.
• ATP synthase is an enzyme that uses the movement of energy to generate ATP and is bound to the inner mitochondrial membrane.

ATP Tally

• ATP Production per Molecule of Glucose:

  • Glycolysis: 2 NADH, 2 ATP
  • Formation of Acetyl CoA: 2 NADH, N/A ATP
  • Citric Acid Cycle: 6 NADH, 2 FADH2, 2 ATP
  • The total yields 10 NADH, 2 FADH2, 4 ATP

• Total is 32 ATP per glucose molecule in most cells.

• In skeletal muscle and neurons it is 30 ATP because it costs energy.

Glycogenesis (Glucose Storage)

• Glycogenesis is the creation of glycogen.
• Glycogen is the only stored carbohydrate in humans.
• Insulin stimulates hepatocytes and skeletal muscle cells to synthesize glycogen (storage hormone).
• The body can store about 500g of glycogen, 75% of which is in skeletal muscle.

Glycogenolysis (Glucose Release)

• Glycogenolysis: Glycogen stored in hepatocytes is broken into glucose and released into blood.
• Glycogen stored in muscle will be converted to glucose-6-phosphate and then will enter glycolysis because skeletal muscle lacks the enzyme to cleave the final phosphate
• Stimulated by glucagon and epinephrine.
• The reverse of glycogenesis.

Gluconeogenesis

• Gluconeogenesis: Glucose formed from noncarbohydrate sources.
• Substances that can be used: glycerol, lactic acid, most amino acids.
• Occurs in the liver and is stimulated by cortisol and glucagon.

Lipid Metabolism: Lipid Transport

• Lipids, being nonpolar and hydrophobic, are transported by lipoproteins.
• Lipoproteins are made more water-soluble by combining them with proteins.
• Lipoproteins are spherical with an outer shell of proteins, phospholipids, and cholesterol surrounding fats.
• Proteins in the outer shell are called apoproteins, each with specific functions.

Lipoproteins Classification

• Chylomicrons: Transport dietary fats.
• VLDLs (Very Low-Density Lipoproteins): Transport triglycerides to adipocytes.
• LDLs (Low-Density Lipoproteins): Transport cholesterol to body cells.
• HDLs (High-Density Lipoproteins): Remove excess cholesterol from body cells and blood.

Chylomicrons

• Formed in small intestine mucosal epithelial cells.
• Transport dietary lipids to skeletal muscle, cardiac muscle, adipose tissue and the liver for usage or storage.

VLDLs

• Formed in hepatocytes (liver) and transport triglycerides to adipocytes.
• Become LDLs once triglycerides are removed, for endogenous fats.

LDLs

• Known as "bad cholesterol" and carries 75% of total cholesterol in blood.
• Deliver to body cells for repair of cell membranes and synthesis of steroid hormones.
• Excess LDL leads to cholesterol deposits in smooth muscle of arteries, increasing the risk of coronary artery disease.
• Transports cholesterol (cholesterol carriers).

HDLs

• Known as "good cholesterol" and act to remove excess cholesterol from body cells and blood (cholesterol scavenger).
• Deliver cholesterol to the liver for elimination as bile salts.
• High HDL levels are associated with a decreased risk of coronary artery disease.

Cholesterol Sources

• Two sources of cholesterol in the body:
  • Present in foods: Trans fats and saturated fats have the biggest impact on circulating cholesterol
  • Endogenous cholesterol: Made in the liver.

Lipid Catabolism: Lipolysis

• Lipolysis: Breakdown of lipids into pieces that can be converted to pyruvate or channeled directly into the citric acid cycle.
• Triglycerides consist of glycerol and 3 fatty acids, both of which can generate ATP.
• Enhanced by epinephrine, norepinephrine, cortisol, and thyroid hormones.
• Insulin acts to inhibit lipolysis.

Glycerol

• Converted to glyceraldehyde 3-phosphate (glycolysis intermediate) and eventually pyruvate (yields 2 ATP).

Fatty Acids

• Catabolized to acetyl-CoA through beta-oxidation (chopping 2 carbons off at a time) in the mitochondrial matrix.
• An enzymatic reaction breaks off the first two carbons as acetyl-CoA
• For each step in beta-oxidation, the cell gains 13 ATP.
• Can be repeated until the entire fatty acid has been broken down.

Ketone Formation

• Excessive beta oxidation, with a lack of glucose, results in the formation of ketones in the liver.
• Heart, brain, and RBCs can use ketone bodies to generate ATP.
• Excessive ketones can lead to ketosis and/or ketoacidosis, of which the latter damages tissue.
• Lipid catabolism is useful because beta-oxidation is very efficient and excess lipids can be easily stored as triglycerides.
• Lipid catabolism because it cannot provide large amounts of ATP quickly and is difficult for water-soluble enzymes to access the insoluble droplets but is well-suited for chronic energy demands during stress or starvation.

Lipid Anabolism: Lipogenesis

• Lipogenesis: Liver cells and adipose cells synthesize lipids.
• Begins with acetyl-CoA, which can be derived from lipids, amino acids, and carbohydrates.
• Occurs when more calories are consumed than needed for ATP production.
• Excess dietary carbs, proteins, and fats are converted to triglycerides.
• Essential fatty acids cannot be synthesized and must be obtained from the diet (e.g., omega-3 and omega-6 fatty acids).

Protein Metabolism

• Amino acids are either oxidized to produce ATP or used to synthesize new proteins.
• Excess dietary amino acids are converted into glucose or triglycerides.

Protein Catabolism

• Protein from worn out cells are recycled, can be converted to other amino acids and reformed to make new proteins or enter the CAC
• Protein from worn out cells are recycled and can be converted to other amino acids and reformed to proteins or enter CAC.
• Before entering CAC, amine group must be removed (deamination), which occurs in hepatocytes.
• Produces ammonia, which the liver converts to urea for excretion in urine.
• Various points at which amino acids enter the Krebs cycle for oxidation.

Protein Anabolism

• Protein synthesis is carried out using ribosomes (translation) using free amino acids
• Amino acids are either essential or nonessential.
• Essential amino acids: Cannot be synthesized; must be obtained from diet (e.g., omega 3s and 6s).
• Nonessential amino acids: Can be synthesized by body cells using amination and transamination.
• Transamination is the transfer of an amine group from one amino acid to a ketoacid to form a new amino acid.
• There are 9 essential amino acids and 11 nonessential amino acids in humans.

Absorptive State

• The absorptive state is the time following a meal when nutrient absorption is occurring
• It typically continues for about 4 hours and is regulated by insulin.
• Insulin stimulates glucose uptake and glycogenesis, amino acid uptake and protein synthesis, and triglyceride synthesis.
• Glycolysis and aerobic metabolism provide the ATP needed to power cellular activities and synthesize lipids and proteins.
• There is storage of excess fuel molecules in hepatocytes, adipocytes, and skeletal muscle cells

Postabsorptive State

• Postabsorptive State occurs about 4 hours after the last meal, and absorption in the small intestine is nearly complete.
• In the postabsorptive state, blood glucose levels start to fallmain purpose is to maintain blood sugar and metabolic activity is focused on mobilizing energy reserves and blood glucose.
• Coordinated by several hormones (glucagon, epinephrine, glucocorticoids):
  • Glucocorticoids: Stimulate the mobilization of lipid and protein reserves, enhanced by growth hormone.
  • Glucagon: Stimulates glycogenolysis and gluconeogenesis, primarily in the liver.
  • Epinephrine: Important in stimulating glycogenolysis in skeletal and cardiac muscle, and lipolysis in adipocytes.
• Blood levels are conserved by oxidation of fatty acids, lactic acid, amino acids, ketone bodies and blood levels are conserved by oxidation of fatty acids, lactic acid, amino acids, ketone bodies and breakdown of muscle glycogen.
• Release of fatty acids by adipocytes is responsible for a decrease blood lipid level.
• Amino acid release by skeletal muscles and other tissues, is responsible for a decrease blood amino acid level.
• Glucose release by liver, is responsible for a decrease blood glucose level.
• Catabolism of lipids and amino acids in the liver produces acetyl-CoA, which leads to the formation of ketone bodies

Fasting and Starvation

• Fasting: Going without food for many hours or a few days.
• Starvation: Implies weeks or months of food deprivation or inadequate food intake.
• The nervous tissue and RBCs continue to use glucose to produce ATP during times of fasting or starvation.
• During periods of fasting or starvation, the most dramatic metabolic change that occurs is the increase in formation of ketone bodies by hepatocytes from excess fatty acid metabolism - can be used as an alternative fuel source.

Energetics

• Energetics: Study of energy flow and energy conversion.
• Metabolic rate: Overall rate at which metabolic reactions use energy.
• Basal metabolic rate (BMR): Minimum resting energy expenditure of awake, alert person (70 calories per hour or 1680 calories per day).
• Various factors can affect BMR (size, weight, level of physical activity).
• Food intake must be adequate to support activities.

Thermoregulation

• Thermoregulation: Body's metabolic activities generate heat that can be measured as temperature.
• Calorie (cal): Amount of energy required to raise 1 gram of water 1 degree Celsius.
• Kilocalorie (kcal) or Calorie (Cal): 1000 calories.
• Core temperature (~37 degrees C or 98 degrees F) vs shell temperature (1-6 degrees C lower).

Heat Transfer Mechanisms:

• Radiation: Heat energy transfer as infrared radiation ("light").
• Convection: Heat loss due to air movement.
• Evaporation: Water changing from liquid to vapor absorbs 0.58 Cal per gram of water (insensible and sensible perspiration).
• Conduction: Direct transfer of energy through physical contact

Temperature Regulation

• If core temperature is too low:
• blood vessels of dermis constrict
• contraction of arrector pili
• release of thyroid hormones, epinephrine generates heat and norepinephrine increases cellular metabolism
• shivering
• If core temperature is too high:
• the dilation of skin blood vessels and heat loss through radiation and convection occur.
• stimulate sweat glands, and generate heat

Appetite Regulation

• The hypothalamus: Involves feeding centre and satiety centre with opposite effects.
• Short-term regulation
• Long-term regulation

Short-Term Regulation of Appetite

• Stimulation of the satiety centre occurs via:
• elevation blood glucose levels,
• hormones of the digestive tract (e.g., CCK),
• stretching of digestive tract wall
• Stimulation of the feeding centreoccurs via:
• neurotransmitters Neuropeptide Y(NPY)
• Ghrelin

Long-Term Regulation of Appetite

• Stimulation of the satiety centre occurs via:
• Leptin

Metabolic Syndrome

• A grouping of conditions that increases, risk of cardiovascular disease, stroke, and of type II diabetes.
• Central obesity and two of the following: hypertension, increased triglycerides, reduced HDL cholesterol, and raised fasting blood glucose.
• Epidemiology: Estimate of 25% of adult population worldwide.
• Risk Factors: Sedentary lifestyle, poor diet, high BMI, genetics, smoking, socioeconomic status, and education.