METABOLISM

METABOLISM.

METABOLISM. Sum of all the chemical processes involved in energy production, energy release and growth.

LAW OF THERMODYNAMICS. Energy can neither be created nor destroyed Input = Output.

Carbohydrate Energy Fat input Protein Equal to Mechanical work Synthetic reactions Membrane transport Energy output Signal generation and conduction Heat production Detoxification and degradation Muscle contraction Movement of cells, organelles, appendages Creation of essential functional molecules Minerals Organic anions/cations Amino acids Electrical Chemical Mechanical Temperature regulation Ineffecient chemical reactions Urea formation Conjugation Oxidation Reduction Fuel Storage Growth.

BASAL METABOLIC RATE. Absolute minimal energy expenditure.

ENERGY GENERATION. ATP Basic chemical currency of energy 2 high energy terminal phosphate bonds 12 kcal/mole potential energy.

p Inorganic phosphate Adenine Phosphate bond o Phosphates Ribose Adenosine triphosphate ATP Adenine o pup) Phosphates Ribose Adenosine diphosphate ADP When you need energy, your body hydrolyzes one of the phosphate bonds, releasing one phosphate and a tremendous amount of energy. With the release of one phosphate from ATP, a new molecule with only two phosphates is formed, adenosine diphosphate, or ADP. A phosphate group is added back to ADP to reform ATP during catabolism. Copyright 0 2010 Pearson Education, Inc..

ENERGY GENERATION. Energy From ATP mechanical work body movement circulation/respiration cellular work membrane transport/nerve conduction signal transduction chemical work DNA and protein synthesis metabolic activities transferred into high energy bonds released to form low energy compounds.

(c) Chemical work: ATP phosphorylates key reactants P Membrane protein Motor protein P i Protein moved (a) Mechanical work: ATP phosphorylates motor proteins ATP (b) Transport work: ATP phosphorylates transport proteins Solute P P i transported Solute Glu Glu NH 3 NH 2 P i P i + + Reactants: Glutamic acid and ammonia Product (glutamine) made ADP + P.

Glucose AT p ADP Glucose-6-phosphate Fructose-6-phosphate AT p AD p Fructose-I ,6-diphosphate Dihydroxyacetone phosphate 2 (Glyceraldehyde-3-phosphate) 2 (1 ,3-Diphosphoglyceric acid) 2ADP +2ATP 2 (3-Phosphoglyceric acid) 2 (2-Phosphoglyceric acid) 2 (Phosphoenolpyruvic acid) 2 (Pyruvic acid) Net reaction per molecule of glucose: Glucose + 2ADP + 2P04E->2 Pyruvic acid + 2ATP + 4B.

ENERGY (ATP) GENERATION  substrate level phosphorylation  chemiosmotic phosphorylation.

Fats Fatty acids Glycerol Glycogen Glucose Pyruvate Acetyl group cycle lectron transport ystem Protein Amino acids Carbon backbone (2) ATP ATP many NH Urea (waste).

RESPIRATORY QUOTIENT. CO2 produced O2 consumed CHO RQ = 6CO2 C6H12O6 + 6O2 + 38 ADP + 38 Pi 6 O2  6CO2 + 6H2O + 38 ATP + heat = 1.0 FAT RQ = 16CO2 C15H31COOH + 23O2 + 129 ADP + 129 Pi 23 O2  16CO2 + 16H2O + 129 ATP + heat = 0.7 CHON RQ = 0.8 – 0.85.

ENERGY EQUIVALENTS. ENERGY YIELD RQ (Kcal/gram of substrate) CHO 4.1 1.0 CHON 4.3 0.80 – 0.85 FAT 9.4 0.7.

ENERGY STORAGE (ANABOLISM). I > O A. CHO stored as glycogen in liver and muscle <1% of total energy reserves needed for CNS metabolism and short bursts of intense muscle work.

Glycogen Phosphorylase (n residues) Glucose Hexokinase (muscle) Glucokinase (liver) Glycogen residues) Glycogen synthase I-JDP Glucose-6-phosphate glucomutase Glucose-I •phosphate 011 Pentose phosphate pathway I.JDP glucose pyrophosphoMase UDP-øucose Ribose-5-phosphate H —C—OH H2C — O uridine H OH OH.

ENERGY STORAGE (ANABOLISM). B. FAT stored as triglycerides in adipose tissue and skeletal muscles 75% of energy reserves efficient storage fuel because of its great energy density (9kcal/g).

CM Remnants KEY LPL = lipoprotein LDL = low-density lipoprotein HDL = high-density Excess cholesterol excreted in bile CM Blood vessels o Chylomicrons (CM) from intestine via lymphatics LPL Fatty acids and lyceride LDL-choIester HDL-cholesterol oo o o Lipoprotein complexes holesterol + Fatty + Lipoproteins acids Liver cells Reassembled into triglycerides Storage Lipolysis Adipose cells for energy Cholesterol used for synthesis Most cells.

lipoprotein-structure. lipoproteins.

ENERGY STORAGE (ANABOLISM). B. FAT LPL (lipoprotein lipase): hydrolyzes chylomicron triglyceride to fatty acid and glycerol for energy storage HDL (High Density Lipoprotein): transfer lipid components between other lipoprotein particles and ultimately between organs LDL (Low Density Lipoprotein): transfer cholesterol to tissues.

10_1038_1805-f1_large_2. Molecular mechanism of plaque formation in the artery. Low density lipoprotein (LDL) cholesterol enters dysfunctional endothelium (which is damaged by smoking or diabetes, for example, and this is reflected by decreased nitric oxide (NO) production) and is oxidized by macrophage and smooth muscle cells. Release of growth factors and cytokines, and upregulation of adhesion molecules, attracts further monocytes. Foam cells (arising from lipid-laden macrophages) accumulate and smooth muscle cells proliferate, which results in the growth of the plaque. Inflammatory cell infiltrate, smooth muscle cell death through apoptosis, and matrix degradation through proteolysis (by matrix metalloproteinases MMPs) generate a vulnerable plaque with a thin fibrous cap and a lipid-rich necrotic core. Plaque rupture can cause thrombosis which might be sufficient to cause vessel occlusion..

ENERGY STORAGE (ANABOLISM). C. CHON stored as proteins in all tissues (structural or functional) 25% of energy reserves important tissue components such that catabolism contributes less.

ENERGY TRANSFER. INTERCONVERSION Excess CHO - triglycerides (lipogenesis) Excess CHON - glucose (gluconeogenesis) glycogen (glycogenesis) triglyceride (lipogenesis) Excess FAT - triglyceride (lipogenesis).

ENERGY EXPENDITURE. During energy storage and transfer after meal ingestion (diet-induced thermogenesis) after interconversion.

ENERGY LIBERATION (CATABOLISM). I < O A. CHO Step 1: glycogen breakdown (glycogenolysis) 75% muscle – local use liver – widespread tissue use gluconeogenesis 25% liver from amino acid, pyruvate, glycerol, kidneys lactate Regulation: 1. hormonal – upregulation of enzymes 2. hepatic – autoregulation dependent on blood glucose level.

Glucose Liver only Glucose 6—phosphate Y c o L s s NH3 2 ATP Anaerobic cone some amino acids Pyruvate Lactate Aerobic con Cytoplasm Mitochondria Pyruvate Electron transpo system 32-34 ATP + H20 -—-—--—Fatty acids Acetyl CoA Ketone bodies (in liver) 02 Citric acid 2 ATP cycle NH3 Some amino acids.

ENERGY LIBERATION (CATABOLISM). I < O A. CHO Step 1: glycogen breakdown (glycogenolysis) 75% muscle – local use liver – widespread tissue use gluconeogenesis 25% liver from amino acid, pyruvate, glycerol, kidneys lactate Regulation: 1. hormonal – upregulation of enzymes 2. hepatic – autoregulation dependent on blood glucose level.

Enzyme 1 Enzyme 2 glucose GLUCOSE Net glucose synthesis GLYCOGEN Net glycogen synthesis glycogen Without regulation of enzymatic activity, the pathway will simply cycle back and forth. Fed state metabolism under the influence of insulin Fasted state metabolism under the influence of glucagon.

A MUSCLE Extracellular Epinephrine Cytosol G protein complex B LIVER c Glucagon — Adenylyl cyclase ATP pp Phosphoprotein phosphatase ADIPOCYTES —Epinephrine AC CAMP Protein kinase A ATP Protein kinase A Phosphorylase kinase Glycogen phosphorylase (inactive) Glycogen phosphorylase (active) cAMP GPb GPa Glucose Glycogen UDP glucose pyrophosphorylase Glycogen synthase GS UDP Glucose Hormone-sensitive lipase (HSL) Triglycerides Fatty acids glycerol Glucose-6-phosphatase (liver and kidney only) glucomutase Glucose Glucose Hexokinase (muscle) Glucokinase (liver) Glycolysis.

Hepatocyte-fed state Insulin O [Glucose] high 0000 GLUT-2 Glucose low ATP Signal cascade ADP G-6-p.

Hepatocyte-fasted state O [Glucose] low Low insulin GLUT-2 Glycogen stores and gluconeogenesis O.

ENERGY LIBERATION (CATABOLISM). A. CHO Step 2: glycolysis can support high energy demand for only a few minutes Step 3: glucose oxidation (Kreb’s cycle and oxidative phosphorylation) End-product  ATP, CO2, H2O, heat Regulation: 1. substrate availability 2. product accumulation 3. feedback inhibition of key enzymes.

1 Glucose GLYCOLYSIS 2 Pyruvic acid FORMATION OF ACETYL COENZYME A 2 Acetyl coenzyme A O 2 2 NADH +2 H+ 2 NADH +2 KREBS CYCLE 2 4 6 2 o ADH + 6 H + F ADH Electrons O ELECTRON TRANSPORT CHAIN 6 32 or 34 o 6 25.02.

lycolysi ATP Krebs eyele Intermembrane space Inner mitochondrial membrane Mitochondrial matrix Electron transport chain and oxidative phosphoryla ATP NADH + (carrying from food) H20 Core ATP NAD+ Electron Transport Chain ATP Synthase.

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ENERGY LIBERATION (CATABOLISM). B. FAT (TRIGLYCERIDE) Step 1: Lipolysis hormone-sensitive lipase (HSL): hydrolyze intracellular triglyceride Step 2:  - Oxidation end-product: acetyl coA Step 3: Citric acid cycle and oxidative phosphorylation.

Extracellular space Fatty acids Glycerol HS—COA cytosol 00 Fatty acids ATP COA Mitochondrion intermembrane space Acyl COA Malonyl CoA Mitochondrion matrix HS-COA AMP CH20H Glycerol Phosphorylation Oxidation Isomera lion Glyceraldehyde- 3-phosphate Pyruvate Acyl carnitine carnitine Carnitine acyl transferase I (CAT 1) Acyl carnitine Carnitine Acyl CoA synthase HS-CoA ACYI CoA Carniti carrier protein Camitine acyl transferase 11 (CAT 11) CH. (CHA—CH C —S Acyl CoA FAD Oxida lion FADH2—- Enoyl CoA Hydration L-HydoxyacyI CoA NAD Oxidation —E 2.5 Ketoacyl CoA Thiolysis Acyl CoA is shortened by two carbon atoms, and reenters the cycle. Acyl COA Acetyl CoA 10 L.

ENERGY LIBERATION (CATABOLISM). C. CHON Step 1 : proteolysis breakdown into amino acids Step 2: gluconeogenesis / citric acid cycle and oxidative phosphorylation amino acids converted to intermediates in citric acid cycle Step 3: ketogenesis and ureagenesis ketogenic AA produce acetoacetate AA degradation release ammonia ; detoxified in liver by incorporation into urea.

Amino acids C02 + AT P + Ammonia Carbamyl phosphate Citrulline Aspartic acid Ornithine U rea Urine Arginine Fumaric acid Arginosuccinic acid.

NITROGEN BALANCE. an indicator of the change in whole-body protein stores urinary nitrogen (urea excretion): both dietary and endogenous protein breakdown POSITIVE: infants and children; Postsurgical/previously sick patients NEGATIVE: burn/trauma patients.

Liver Liver glycogen stores GlycogenolysiS Fatty acids b-oxidation Ketone bodies Ene produ ton Brain lucose Glucose 000 Ketone bodies p5uåYon Adipose riglyceride stores Fatty acids Muscle nergy productio Glycogen Proteins Pyruvate Lactate Amino acids.

FASTING. Glycogenolysis Gluconeogenesis Ketogenesis Long-term Starvation Dec. BMR Ketoacids: energy source of CNS Dec. Gluconeogenesis; Dec. Proteolysis.

Plasma glucose a cells of pancreas t Glucago Lactate, pyruvate, amino acids Liver..••• . Fatty acids Prolonged hypoglycemia Glycogenolysis Negative Téédbåök• luconeogenesis plasma glucose Ketones cells of pancreas unsulin Muscle and adipose tissue Brain and ripheral tissue.

FASTING. Glycogenolysis Gluconeogenesis Ketogenesis Long-term Starvation Dec. BMR Ketoacids: energy source of CNS Dec. Gluconeogenesis; Dec. Proteolysis.

STARVATION. Carbohydrate 1.5 days Fat 2 months Protein 10 days.

EXERCISE. stored CP/ATP muscle glycogenolysis and glycolysis muscle/liver glycogenolysis, gluconeogenesis lipolysis and B - oxidation.

o c ATP + creatine phosphate Anaerobic glycolysis muscle glycogen 0123456 Minutes Aerobic oxidation Plasma FFA Adipose tissue triglycerides Aerobic oxidation Muscle glycogen Plasma glucose Liver glycogen 2 Hours Time 3 4.

REGULATION OF ENERGY STORES. Adipocytes secrete peptide-signaling molecules that affect metabolism 1. tumor necrosis factor  and resistin - reduce insulin responsiveness 2. adiponectin - decreases hepatic glucose production 3. plaminogen activator inhibitor-1 - inhibits thrombolysis 4. PPAR  - stimulate preadipocyte differentiation 5. leptin - dec. food intake/inc. energy expenditure.