Integration Of Metabolic Processes In The Human Body PDF

1 INTEGRATION OF METABOLIC PROCESSES IN THE HUMAN BODY 2 Metabolism can be divided into two main categories: Catabolism - processes in which complex substances are broken down into simpler molecules. Anabolism - processes primarily associated with the synthesis of compl...

1 INTEGRATION OF METABOLIC PROCESSES IN THE HUMAN BODY 2 Metabolism can be divided into two main categories: Catabolism - processes in which complex substances are broken down into simpler molecules. Anabolism - processes primarily associated with the synthesis of complex organic molecules. Catabolism is generally accompanied by a net release of chemical energy. Anabolism requires a net input of chemical energy. These two sets of reactions are linked together by ATP. 3 Both catabolic and anabolic pathways occur in three stages of complexity: Stage 1: interconversion of polymers and complex lipids to monomeric intermediates Stage 2: interconversion of monomeric sugars, amino acids and lipids to even simpler organic compounds Stage 3: final decomposition to (or synthesis from) inorganic compounds, including CO2, H2O and NH3. 4 Integration of metabolic processes -Why integrate processes? -What processes are subject to integration? -How can these processes be controlled?  Why integrate processes? 5 A common goal  Why integrate processes? 6 A common goal  What processes are subject to integration? 7 All metabolic (and non-metabolic) processes are integrated (or at least interact with each other) in the body -Glycolysis -Gluconeogenesis -Krebs cycle -Pentosephosphate pathway -Glycogen synthesis and degradation -Fatty acid synthesis and degradation -Metabolism of amino acids -Oxidative phosphorylation The integration of metabolic processes should be considered at two levels: -Cellular -Tissue/whole organism  How can these processes be controlled? 8 Allosteric regulation Covalent modifications Enzyme regulation Compartmentalization Metabolic specialization of organs Integration of metabolic processes should be considered at two levels: Cellular Tissue / Whole organism  Major metabolic pathways and their key metabolites in integration 9 Glycolysis  Major metabolic pathways and their key metabolites in integration 10 Glycolysis Glucose-6-phosphate: Widespread in almost all cell types Due to its ubiquity, it has many possible “fates” Thus becomes a critical point Primary purpose: Glycolysis (in a state of energy demand) Pentose-phosphate pathway (in a state of NADPH deficiency, needed, for example, for fatty acid synthesis, product: ribose-5-phosphate) Possible substrate for glycogen biosynthesis Most of the glucose entering the cell will be converted to G6P  Major metabolic pathways and their key metabolites in integration 11 Glycolysis Pyruvate: Product of glycolysis Turning point of metabolism depending on the oxidative state of the cell When oxygen is available, converted to Acetyl-CoA  Major metabolic pathways and their key metabolites in integration 12 Glycolysis Pyruvate: Product of glycolysis Turning point of metabolism depending on the oxidative state of the cell In the absence of oxygen, it is converted to lactate  Major metabolic pathways and their key metabolites in integration 13 Glycolysis Pyruvate: Product of glycolysis Turning point of metabolism depending on the oxidative state of the cell In the absence of oxygen, it is converted to lactate muscle soreness  Major metabolic pathways and their key metabolites in integration 14 Glycolysis Pyruvate: Product of glycolysis Turning point of metabolism depending on the oxidative state of the cell Transamination with the formation of alanine is possible  Major metabolic pathways and their key metabolites in integration 15 Glycolysis Pyruvate: Product of glycolysis Turning point of metabolism depending on the oxidative state of the cell Carboxylation with formation of oxaloacetate is possible  Major metabolic pathways and their key metabolites in integration 16 Gluconeogenesis Gluconeogenesis as a reversal of glycolysis Most of the reactions of glycolysis function in equilibrium However, three reactions are so strongly exoergic that they should be considered irreversible Glucose -> glucose 6 phosphate Fructose 6 phosphate -> fructose 1,6 bis phosphate Phosphoenolpyruvate -> pyruvate  Major metabolic pathways and their key metabolites in integration 17 Gluconeogenesis Gluconeogenesis as a reversal of glycolysis Thus, in order to carry out gluconeogenesis, these three reactions must be bypassed  Major metabolic pathways and their key metabolites in integration 18 Gluconeogenesis Coordinated simultaneous regulation of glycolysis and gluconeogenesis Factors/conditions that promote glycolysis simultaneously inhibit gluconeogenolysis. And vice versa!  Major metabolic pathways and their key metabolites in integration 19 Krebs cycle The substrate is Acetyl-CoA Acetyl-CoA is oxidized to two molecules of CO2 Oxaloacetate molecule is regenerated in the cycle Reduction of 3x NAD and 1x FAD 1 molecule of ATP / GTP is formed  Major metabolic pathways and their key metabolites in integration 20 Krebs cycle Acetyl-CoA is the central compound of all metabolism Extramitochondrial production: At high glucose concentration and intensive glycolysis there is accumulation of citrate which is later converted to Acetyl-CoA and oxaloacetate At low glucose concentration mainly catabolism of ketogenic amino acids Mitochondrial production: At high glucose concentration directly from pyruvate At low glucose concentration from beta-oxidation Utilization: In cellular respiration In the Krebs Cycle In fatty acid metabolism In the synthesis of steroids, acetylcholine and melatonin In acetylation (e.g., of histones) As an allosteric regulator (e.g., of the pyruvate dehydrogenase complex)  Major metabolic pathways and their key metabolites in integration 21 Krebs cycle Acetyl-CoA is the central compound of all metabolism  Major metabolic pathways and their key metabolites in integration 22 Krebs cycle Anaplerotic pathways will rebuild Krebs Cycle intermediates  Major metabolic pathways and their key metabolites in integration 23 The pentose-phosphate pathway Ribulose-5-phosphate for nucleotide synthesis NADPH serves as a reductant in many biosynthetic reactions in the cytosol NADPH to reduce glutathione and protect the cell in oxidative stress  Major metabolic pathways and their key metabolites in integration 24 Glycogen synthesis and degradation Glycogen is located in the liver and muscles It is a “medium-term” form of energy storage  Major metabolic pathways and their key metabolites in integration 25 Antagonistic effect of insulin and glucagon Fed state: Insulin secretion Fasting state: Increased glucagon secretion Starvation:...  Major metabolic pathways and their key metabolites in integration 26 Antagonistic effect of insulin and glucagon  Major metabolic pathways and their key metabolites in integration 27 Antagonistic effect of insulin and glucagon Insulin's effect on sugars: Facilitates the transport of glucose into cells Facilitates the conversion of glucose to glycogen in liver and muscle by increasing glycogen synthase activity Reduces glycogen degradation and glucose release by decreasing glycogen phosphorylase activity  Major metabolic pathways and their key metabolites in integration 28 Antagonistic effect of insulin and glucagon Insulin's effect on proteins: Stimulates protein synthesis Inhibits protein degradation Decreases gluconeogenesis by Decreasing the activity of pyruvate carboxylase Decreasing the activity of phosphoenolpyruvate carboxykinase Decreasing the activity of fructose-1,6-bisphosphatase  Major metabolic pathways and their key metabolites in integration 29 Antagonistic effect of insulin and glucagon Insulin's effects on fat: Inhibition of free fatty acids mobilization from adipose tissue through suppression of lipolysis Inhibition of cellular uptake and beta oxidation of FFA Inhibition of VLDL synthesis in the liver Stimulation of fatty acid biosynthesis  Major metabolic pathways and their key metabolites in integration 30 Antagonistic effect of insulin and glucagon The impact of insulin in time perspective: Increase in glucose uptake - seconds Change in enzyme activity (e.g., by [de]phosphorylation) - minutes/hours Change in the amount of enzymes (glucokinase, phosphofructokinase) - hours/days  Major metabolic pathways and their key metabolites in integration 31 Antagonistic effect of insulin and glucagon  Major metabolic pathways and their key metabolites in integration 32 Antagonistic effect of insulin and glucagon Glucagon effects: Degradation of hepatic glycogen by increasing glycogen phosphorylase activity Increasing gluconeogenesis in the liver Increase in pyruvate carboxylase activity Increase in phosphoenolpyruvate carboxykinase activity Increase in fructose-1,6-bisphosphatase activity Stimulation of hormone-sensitive lipase (HSL) Promotion of lipolysis  Major metabolic pathways and their key metabolites in integration 33 Adaptation of metabolism to reduced energy supply Normal state Opposing effects of insulin and glucagon dependent on glucose levels and instantaneous energy requirements Early stage of reduced energy supply (fasting, >2 days) Glycogenolysis and gluconeogenesis as main sources of glucose Alternative sources of energy (beta oxidation of FA) Intermediate stage of reduced energy supply (prolonged fasting, up to about 3 weeks) Glycogen virtually depleted Main sources of energy are FA and KB supplied to heart, kidney, muscle  Major metabolic pathways and their key metabolites in integration 34 Adaptation of metabolism to reduced energy supply Long-term reduced energy supply (starvation, more than 3 weeks) Decreased delivery of KB to heart, kidneys, muscles, priority - brain Heart, kidney and muscle - FA Protein protection - transport of lactate and alanine from muscle to liver for glucose synthesis  Major metabolic pathways and their key metabolites in integration 35 Adaptation of metabolism to reduced energy supply  Major metabolic pathways and their key metabolites in integration 36 Adaptation of metabolism to reduced energy supply  Major metabolic pathways and their key metabolites in integration 37 Źródła energii podczas wysiłku  Major metabolic pathways and their key metabolites in integration 38 Energy sources during exercise  Major metabolic pathways and their key metabolites in integration 39 Synthesis and degradation of fatty acids  Major metabolic pathways and their key metabolites in integration 40 Amino acid metabolism  Major metabolic pathways and their key metabolites in integration 41 Oxidative phosphorylation  Major metabolic pathways and their key metabolites in integration 42  Major metabolic pathways and their key metabolites in integration 43 Glucose-6-phosphate Pyruvate Acetyl-CoA  Major metabolic pathways and their key metabolites in integration 44  Metabolic specialization of organs 45 Pancreas Brain Secretion of insulin and glucagon Integration of peripheral signals and external in response to changes in blood stimulation, control of other organs glucose levels Lymphatic system Transport of lipids from the Liver gut to the liver Processing of ingested sugars, proteins and fats. Synthesis and distribution of lipids, ketone bodies and glucose Adipose tissue Lipid synthesis, storage and mobilization Portal vein Transmission of nutrients from the intestine to the liver Skeletal muscles Small intestine ATP utilization, glycogen Absorption of nutrients storage and their transfer to the bloodstream  Metabolic specialization of organs Brain 46 Two of the most important facts about the brain from a metabolic perspective: Very high levels of cellular respiration - 20% of the oxygen consumed by the body is consumed by the brain (even though it accounts for ~2% of body weight) Very high level of glucose consumption - despite the lack of any storage substances, the brain consumes about 120g of glucose/24h, relying entirely on the supply of the circulatory system to meet the demand Consumption of both oxygen and glucose is (fairly) constant and independent of the state of the brain (sleep, state of stimulation, state of rest...)  Metabolic specialization of organs Brain 47 Why is the energy demand so high? The brain needs ATP to maintain the membrane potential necessary for signal transduction (sodium-potassium pump - Na+/K+ ATPase)  Metabolic specialization of organs Brain 48  Metabolic specialization of organs Brain 49 In a situation of reduced glucose supply, its role can be partially taken over by ketone bodies, which are able to supply the brain with energy Ketone bodies are formed in the liver: Starvation acetone (~2%) Ketone Bodies acetylacetic acid (~20-25%) β-hydroxybutyric acid (~75-80%) Normal condition β-hydroxybutyrate is converted to Acetyl- Glucose CoA for inclusion in the Krebs Cycle and further energy production Na+/K+ ATPaze  Metabolic specialization of organs Brain 50 β-hydroxybutyrate Acetylacetic acid Acetoacetylo-CoA 2x Acetylo-CoA  Metabolic specialization of organs Muscles 51 At rest, muscles consume 20-30% of absorbed oxygen In a state of intense exertion, this value can rise to 90% Unlike the brain, the demand is variable ATP is used during relaxation (to break the bond between the myosin heads and the actin filament). Muscles at rest prefer fatty acids as an energy source Rapidly contracting muscles prefer glucose Muscles show a high tolerance in terms of the energy source used - they are able to use glucose, fatty acids and ketone bodies Phosphocreatine - a compound with higher energy potential than ATP  Metabolic specialization of organs Muscles 52 Intense exercise: Muscle glycolysis is very efficient, glucose 6 phosphate concentrations can rise more than 2000x in the first seconds of exercise Glycolysis very quickly lowers the pH by producing lactate leading to muscle fatigue Transamination of pyruvate leads to the production of large amounts of alanine, which will be exported to the liver  Metabolic specialization of organs Cardiac muscle 53 Cardiac muscle has 3 basic differences from skeletal muscle: Its activity is constant, uninterrupted and fairly uniform Its activity Is based entirely on oxidative metabolism (it is very rich in mitochondria) It has no stored substances (glycogen, fatty acids) - it is very quickly damaged in the absence of an energy source (inhibition of circulation) Preferred source of energy is fatty acids  Metabolic specialization of organs Cardiac muscle 54 Rest state Substrates: Fatty acids ~40-70% Glucose ~20-30% Lactate ~5-15% Others