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Bioenergetics and Regulation of Metabolism
Biochemistry/Lab (CHEM 3650)
Nova Southeastern University
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Bioenergetics and Regulation of Metabolism NOTES (can be used for mcat review as well)
Thermodynamics and Bioenergetics
Biological Systems
Considered open systems since they can exchange both heat and matter with their environment o Energy is exchanged in the form of mechanical work or as heat energy o Material is exchanged through food consumption and elimination, as well as respiration The cellular and subcellular level of an organism is considered to be closed: no exchange of matter with the environment o Internal energy (sum of all different interactions between and within the atoms in a system) can only be changed through work or heat Work is the change in pressure and volume, however this is usually constant in living system, so only contributing factor to internal energy is heat.
Enthalpy, Entropy and Free Energy
Bioenergetics: used to describe energy states in biological systems Free energy (G): provides information about chemical reactions and can predict whether a chemical reaction is favorable and will occur Enthalpy and entropy changes is what determines whether a chemical reaction o Enthalpy: measures the overall change in heat of a system during a reaction Equal to the heat exchange when pressure and volume are held constant o Entropy: measures the degree of disorder or energy dispersion in a system Gibb’s Equation relates these three quantities:
Above equation can determine whether or not a spontaneous reaction will occur. o Spontaneous reaction proceeds in the forward direction, exhibits a net loss of energy and has a negative free energy o Non-spontaneous are opposite of spontaneous and would be considered spontaneous in the reverse direction o Free energy approaches zero as a reaction reaches equilibrium
Physiological conditions
Standard free energy (G) is the energy changing occurring at standard conditions of 1 M, pressure of 1 atm and temperature of 25C
Modified Standard State: takes into account that a 1 M concentration of protons would result in a highly acidic solution, so the standard proton concentration for these conditions is assumed to be: [H+] = 10-7 M (pH of 7) o This condition is specified by G’
There is a general trend that reactions with more products than reactants have a more negative free energy, vice versa is also true.
The Role of ATP
Fats are more energy-rich than carbohydrates, proteins or ketones o Combustion of a fat results in 9 kcal/g while only 4 kcal/g for the others o This is the reason that fat is preferred for long term storage End goal of all energy sources is to have as much readily available energy as possible (ATP is this readily available form)
ATP as an Energy Carrier
A mid-level energy carrier that is formed from substrate-level phosphorylation and from oxidative phosphorylation ATP is a mid-level carrier to minimize any wasted energy. o If the ATP energy release is greater than required, the added energy is not regained Most ATP is produced by mitochondrial ATP synthase, but some is also produced in glycolysis and from the citric acid cycle (indirectly through GTP) Consists of an adenosine molecule attached to three phosphate groups o Generated from ADP and Pi along with energy input ATP is consumed through hydrolysis or through the transfer of a phosphate group to another molecule o ATP, ADP & AMP are continuously recycled more than 1000 times per day High energy phosphate bonds are what makes ATP such an adept energy carrier o Negative charges on each group makes the molecule experience repulsive forces o ADP is more stable due to resonance of losing a phosphate group o ATP and ADP have similar G values since they both still experience repulsion, however, AMP has a much smaller free energy value (-30 kJ/mol vs -9 kJ/mol)
Hydrolysis and Coupling
ATP hydrolysis will usually occur within a coupled reaction o These reaction use ATP as an energy source o E. – Movement of sodium and potassium against their gradients ATP cleavage: transfer of high-energy phosphate groups from ATP to another molecule o Generally, activates or inactivates the target molecule o Also known as phosphoryl group transfers. Overall free energy of the reaction will be determined by taking the sum of the free energies of the individual reactions
Phosphoryl Group Transfers
ATP is able to provide a phosphate group as a reactant o E. – during glycolysis, ATP donates a phosphate group to glucose to form glucose 6-phosphate
E. – storing sodium at a high concentration on one side of the cell allows for the storage of potential energy
Postprandial (Absorptive or Well-Fed) State
Occurs shortly after eating and is characterized by greater anabolism/fuel storage than catabolism o Anabolism is the synthesis of biomolecules o Catabolism is the breakdown of biomolecules for energy Nutrients make their way through the digestive system, where they are absorbed by the hepatic portal vein and into the liver o In the liver, the nutrients can be stored or distributed to other tissues This state generally lasts 3-5 hours after eating Blood glucose levels rise after eating and stimulate the release of insulin o Promotes glycogen synthesis in the liver and muscle o Once the glycogen stores are filled, the liver converts excess glucose to fatty acids and triacylglycerols Promotes triglyceride synthesis in adipose tissue and protein synthesis in muscle Also promotes glucose entry into both of these tissues o Energy needs of the liver are met by the oxidation of excess amino acids o Nervous tissue and red blood cells are not affected by insulin Nervous tissue needs a continuous supply of glucose regardless, all energy is derived from oxidizing glucose to CO 2 and water Unless in prolonged fasting state RBC’s only use glucose anaerobically for all of their energy needs
Postabsorptive (Fasting) State
Counterregulatory Hormones: hormones that oppose the actions of insulin o Glucagon, cortisol, epinephrine, norepinephrine and growth hormone o Stimulate glycogen degradation in the liver and stimulates the release of glucose into the blood
o Glucagon also stimulates Hepatic Glycogenolysis This is a much slower response to the almost instantaneous Glycogenolysis process. Epinephrine increase and insulin decrease stimulates the release of amino acids from the skeletal muscle and fatty acids o These provide the necessary carbon skeletons and energy required for gluconeogenesis
Prolonged Fasting (Starvation)
Glucagon and epinephrine levels are highly elevated Increased level of glucagon as compared to insulin results in the rapid degradation of glycogen stores in the liver As glycogen stores are depleted, gluconeogenic activity is consistently occurring. o After 24 hours, this is the predominant source of glucose for the body Fats begin breaking down (Lipolysis) relatively quickly o Results in excess Acetyl-CoA, which can be used in the synthesis of ketone bodies Once levels of fatty acids and ketones is high enough in the blood, muscle tissue will utilize fatty tissue as its main source of energy. The brain will also adapt to using ketones for energy (after a long period of time). o Brain derivers approximately 2/3 of energy from ketones and 1/3 from glucose after several weeks of fasting o Shift from glucose to ketones allows gluconeogenesis to be slowed This reduced the quantity of amino acids that must be degraded to support gluconeogenesis This spares proteins which are vital for living function Cells that do not have mitochondria (e. – RBCs) continue to be dependent on glucose
Hormonal Regulation of Metabolism
Metabolism is regulated across the entire organism, which is best organized by hormones
Increased calcium concentration is what stimulates the exocytosis of preformed insulin through vesicles Glucagon Peptide hormone that is secreted by the alpha cells of the pancreatic islets of Langerhans Primary target for glucagon action is the hepatocyte (liver cell) Glucagon acts through second messengers to cause the following effects: o Liver Glycogenolysis is increased: Glucagon activates glycogen phosphorylase and inactivates glycogen synthase o Increased Liver Gluconeogenesis: promotes the conversion of pyruvate to phosphoenolpyruvate by the enzymes pyruvate carboxylase and phosphoenolpyruvate carboxykinase (PEPCK) Does this by increasing the conversion of fructose 1,6-biphosphate to fructose 6-phosphate by using fructose 1,6-biophosphatase o Increased liver ketogenesis and decreased lipogenesis o Increased lipolysis in the liver: Activates hormone-sensitive lipase in the liver. Glucagon is not a major fat-mobilizing hormone since it acts on the liver and not an adipocyte Glucagon is secreted in response to low plasma glucose (hypoglycemia) and is inhibited by hyperglycemia. o Also promoted by amino acids (especially the basic amino acids: arginine, lysine, histidine) I. – glucagon is secreted in when protein is ingested Functional Relationship of Insulin & Glucagon Two hormones are antagonistic: insulin is associated with a well-fed state, while glucagon is associated with a Postabsorptive metabolic state Enzymes that are phosphorylated by glucagon are usually dephosphorylated by insulin, and vice versa
Glucocorticoids
Formed in the adrenal cortex and are responsible for the stress response In the “fight or flight” response, glucose must be rapidly mobilized from the liver in order to actively fuel contracting muscle cells o Fatty acids are also released from adipocytes.
Secreted in response to many forms of stress (especially cortisol) o Stress like exercise, cold and emotional stress Cortisol is a steroid hormone that promotes the mobilization of energy stores through the degradation and increased delivery of amino acids and increased lipolysis o Also increases blood glucose levels to increase the glucose uptake ability for nervous tissue Cortisol inhibits glucose uptake in most tissues Increases hepatic output of glucose via gluconeogenesis o Cortisol also has a permissive function that enhances the activity of glucagon, epinephrine, and other Catecholamines Long term exposure to Glucocorticoids causes persistent hyperglycemia which stimulates insulin o Promotes fat storage rather than lipolysis
Catecholamines
Secreted by the adrenal medulla E. – Epinephrine, norepinephrine or adrenaline and noradrenaline Increase the activity of liver and muscle glycogen phosphorylase o This promotes Glycogenolysis which increases glucose output by the liver In muscles, the glucose is simply used by the muscle since it cannot be released into the bloodstream since muscle cannot produce glucose-6- phosphate Act on adipose tissue by increasing lipolysis through stimulating the activity of lipase o Glycerol from triacylglycerol breakdown is used in gluconeogenesis Epinephrine also acts directly on target organs o E. – Increases the basal metabolic rate of the heart. “adrenaline rush”
Thyroid Hormones
These hormones activity are largely permissive, which means that thyroid hormones are kept at a relatively constant level. These increase the basal metabolic rate o Increased O 2 consumption and heat production when thyroid hormones are secreted Thyroxine (T 4 ): Increases the metabolic rate more slowly, but effects can last for several days Triiodothyronine (T 3 ): more rapid metabolic increase but has shorter term effects.
Between meals and during prolonged fast, the liver begins releasing glucose into the blood. o Caused by an increase in glucagon which induces both glycogen degradation and gluconeogenesis Lactate from anaerobic metabolism, glycerol from triglycerides, and amino acids provide the carbon skeletons for glucose synthesis.
Adipose Tissue
Elevated insulin levels stimulate glucose uptake by adipose tissue, after a meal. o Also triggers fatty acids to release from VLDL and chylomicrons (carry triglycerides that are absorbed from the digestive tract) o Also stimulates lipoprotein lipase Fatty acids that are released from lipoproteins are taken up by adipose tissue o Are then re-esterified to triacylglycerols for storage Glycerol phosphate that is required for this is provided by glucose metabolism in adipocytes Insulin also suppresses the release of fatty acids from adipose tissue In fasting state: decreased insulin levels and increased epinephrine activate hormone- sensitive lipase in fat cells o This allows fatty acids to be released into circulation.
Skeletal Muscle
Resting Muscle Major fuels are glucose and fatty acids and skeletal muscle is the major consumer of fuel Insulin promotes glucose uptake in skeletal muscle o This replenishes glycogen stores and amino acids that are used in protein synthesis These excess amino acids and glucose molecules can also be oxidized for energy In fasting state, resting muscle uses fatty acids that are derived from free fatty acids that are circulating in the blood stream o Ketone bodies are also used in states of prolonged fasting
Active Muscle Primary fuel source in muscle depends on the magnitude and duration of exercise, and the major fibers that are involved. Creatine Phosphate: short-lived (2-7 seconds) source of energy o Transfers a phosphate group to ADP to form ATP Also use stores of glycogen and triacylglycerols o Can also use glucose or free fatty acids Short bursts of high intensity exercise can be supported by anaerobic glycolysis that draw on the stored glycogen. Moderately high intensity (continuous exercise), oxidation of glucose and fatty acids are needed o Stored of glycogen become depleted after 1-3 hours.
Intensity of exercise declines to a rate that can be supported by oxidation of fatty acids. Cardiac Muscle Cardiac myocytes prefer fatty acid as their major source of fuel Use ketones in prolonged states of fasting Cardiac myocytes act like skeletal muscle that is used during extended periods of exercise Patients with cardiac hypertrophy (thickening of heart muscle): glucose oxidation increases and beta-oxidation decreases (reverses the process) Brain 2% of body weight, but receives 15% of cardiac output, uses 20% of O 2 , and consumes 25% of the total glucose Glucose is the brains primary food o This is why blood glucose levels are so tightly regulated, so that a sufficient glucose supply to the brain can be maintained Normal function depends on continuous glucose supply from the blood stream o If brain becomes hypoglycemic (<70 mg/dL), then the hypothalamic center of the brain releases glucagon and epinephrine to combat the reduced glucose level Fatty acids cannot cross the blood-brain barrier, so they are not used at all in the brain. Between meals, the brain relies on blood glucose that is to be supplied through hepatic Glycogenolysis and gluconeogenesis Brain adapts to use ketone bodies after prolonged states of starvation (only uses a maximum of up to two-thirds)
Integrative Metabolism
Analysis of Metabolism
Levels of glucose, thyroid hormones, and thyroid-stimulating hormone, insulin, glucagon, oxygen, and carbon dioxide can all be measured in the blood o These substrates have a predictable effect on metabolism, so they can be used as indicators Respirometry allows for accurate measurement of the respiratory quotients o This quotient depends on the fuels used by the organism:
Complete combustion of the fuel source is different for each nutrient: o Carbohydrates need an RQ of 1. o Lipids need a RQ of 0. RQ is generally around 0 in resting state, but can change under conditions of high stress, starvation, and exercise Calorimeters Measures the basal metabolic rate (BMR) o Based on heat exchange with the environment Requires the use of large insulated chambers that have specialized heat sinks
Bioenergetics and Regulation of Metabolism
Course: Biochemistry/Lab (CHEM 3650)
University: Nova Southeastern University
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