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Chapter 27 Essential Question Metabolic Integration and Organ Specialization • What principles underlie the integration of catabolism and energy production with anabolism and energy consumption? • How is metabolism integrated in complex organisms with multiple organ systems? Biochemistry by Reginald Garrett and Charles Grisham Outline 1. Can Systems Analysis Simplify the Complexity of Metabolism? 2. What Underlying Principle Relates ATP Coupling to the Thermodynamics of Metabolism? 3. Can Cellular Energy Status Be Quantified? 4. How Is Metabolism Integrated in a Multicellular Organism? 27.1 – Can Systems Analysis Simplify the Complexity of Metabolism? • The metabolism can be portrayed by a schematic diagram consisting of just three interconnected functional block: 1. Catabolism 2. Anabolism 3. Macromolecular synthesis and growth • Catabolic and anabolic pathways, occurring simultaneously, must act as a regulated, orderly, responsive whole Figure 27.1 Block diagram of intermediary metabolism. • Catabolism: – – – – Foods are oxidized to CO2 and H2O The formation of ATP Reduce NADP+ to NADPH The intermediates serve as substrates for anabolism Glycolysis The citric acid cycle Electron transport and oxidative phosphorylation Pentose phosphate pathway Fatty acid oxidation • Anabolism: – The biosynthetic reactions – The chemistry of anabolism is more complex – Metabolic intermediates in catabolism are the precursor for anabolism – NADPH supplies reducing power – ATP is the coupling energy • Macromolecular synthesis and growth – Creating macromolecules – Macromolecules are the agents of biological function and information – Growth can be represented as cellular accumulation of macromolecules • Just a few intermediates connect major systems – Sugar-phosphates (triose-P, tetraose-P, pentose-P, and hexose-P) − α-keto acids (pyruvate, oxaloacetate, and αketoglutarate) – CoA derivs (acetyl-CoA and suucinyl-CoA) – PEP • ATP & NADPH couple catabolism & anabolism • Phototrophs also have photosynthesis and CO2 fixation systems 27.2 – What Underlying Principle Relates ATP Coupling to the Thermodynamics of Metabolism? Three types of stoichiometry in biological systems 1. Reaction stoichiometry - the number of each kind of atom in a reaction 2. Obligate coupling stoichiometry - the required coupling of electron carriers 3. Evolved coupling stoichiometry - the number of ATP molecules that pathways have evolved to consume or produce - a number that is a compromise, as we shall see 1. Reaction stoichiometry The number of each kind of atom in any chemical reaction remains the same, and thus equal numbers must be present on both sides of the equation C6H12O6 + 6 O2 → 6 CO2 + 6 H2O 2. Obligate coupling stoichiometry 3. Evolved coupling stoichiometry Cellular respiration is an oxidation-reduction process, and the oxidation of glucose is coupled to the reduction of NAD+ and FAD (a) C6H12O6 + 10 NAD+ + 2 FAD + 6 H2O → 6 CO2 + 10 NADH + 10 H+ + 2 FADH2 (b) 10 NADH + 10 H+ + 2 FADH2 + 6 O2 → 12 H2O + 10 NAD+ + 2 FAD • The coupled formation of ATP by oxidative phosphorylation C6H12O6 + 6 O2 + 38 ADP + 38 Pi → 6 CO2 + 38 ATP + 44 H2O • • Prokaryotes: 38 ATP Eukaryotes: 32 or 30 ATP ATP coupling stoichiometry determines the keq for metabolic sequence ATP has two metabolic roles 1. ATP is the energy currency of the cells • The energy release accompanying ATP hydrolysis is transmitted to the unfavorable reaction so that the overall free energy for the coupled process is negative (favorable) • The cell maintains a very high [ATP]/([ADP][Pi]) ratio so that ATP hydrolysis can serve as the driving force for virtually all biochemical events 27.3 – Can Cellular Energy Status Be Quantified? ‘Energy Charge’ • Adenylates provide phosphoryl groups to drive thermodynamically unfavorable reactions • Adenylate kinase interconverts ATP, ADP, and AMP ATP + AMP ↔ 2 ADP • Adenylate pool – – To establish large equilibrium constant To render metabolic sequence thermodynamically favorable 2. An important allosteric effector in the kinetic regulation of metabolism • Energy charge is an index of how fully charged adenylates are with phosphoric anhydrides Energy charge = [ATP] + ½ [ADP] [ATP] + [ADP] + [AMP] • If [ATP] is high, E.C.→1.0 • If [ATP] is low, E.C.→ 0 • Key enzymes are regulated by Energy charge • Regulatory enzymes in energy-producing catabolic pathways show greater activity at low energy charge – PFK and pyruvate kinase • Regulatory enzymes of anabolic pathways are not very active at low energy charge – Acetyl-CoA carboxylase Figure 27.2 Relative concentrations of AMP, ADP, and ATP as a function of energy charge. (This graph was constructed assuming that the adenylate kinase reaction is at equilibrium and that ΔG°' for the reaction is -473 J/mol; Keq = 1.2.) 0.85 - 0.88 Figure 27.3 Responses of regulatory enzymes to variation in energy charge. Enzymes in catabolic pathways have as their ultimate metabolic purpose the regeneration of ATP from ADP. Such enzymes show an R pattern of response to energy charge. Enzymes in biosynthetic pathways utilize ATP to drive anabolic reactions; these enzymes follow the U curve in response to energy charge. Figure 27.4 The oscillation of energy charge (E.C.) about a steady-state value as a consequence of the offsetting influences of R and U processes on the production and consumption of ATP. As E.C. increases, the rates of R reactions decline, but U reactions go faster. ATP is consumed, and E.C. drops. Below the point of intersection, R processes are more active and U processes are slower, so E.C. recovers. Energycharge oscillates about a steady-state value determined by the intersection point of the R and U curves. 27.4 – How Is Metabolism Integrated in a Multicellular Organism? Figure 27.5 Metabolic relationships among the major human organs: brain, muscle, heart, adipose tissue, and liver. Fueling the Brain • The major fuel depots: – – – • Triacylglycerol Glycogen Protein Brain has two remarkable metabolic features 1. very high respiratory metabolism 20 % of oxygen consumed is used by the brain 2. but no fuel reserves Uses only glucose as a fuel and is dependent on the blood for a continuous incoming supply (120g per day) Brain • In fasting conditions, brain can use βhydroxybutyrate (from fatty acids), converting it to acetyl-CoA for the energy production via TCA cycle • Generate ATP to maintain the membrane potentials essential for transmission of nerve impulses Figure 27.6 The structure of β-hydroxybutyrate and its conversion to acetyl-CoA for combustion in the citric acid cycle. Muscle • Skeletal muscles is responsible for about 30% of the O2 consumed by the human body at rest • Muscle can utilize a variety of fuels -glucose, fatty acids, and ketone bodies • Muscle contraction occurs when a motor never impulse causes Ca+2 release from endomembrane compartments Creatine Kinase in Muscle • About 4 second exertion, phosphocreatine and glycogen provide enough ATP for contraction • During strenuous exertion, once phosphocreatine is depleted, muscle relies solely on its glycogen reserves • Glycolysis is capable of explosive bursts of activity • Glycolysis rapidly lowers pH (lactate accumulation), causing muscle fatigue Figure 27.7 Phosphocreatine serves as a reservoir of ATP-synthesizing potential. When ADP accumulates as a consequence of ATP hydrolysis, creatine kinase catalyzes the formation of ATP at the expense of phosphocreatine. During periods of rest, when ATP levels are restored by oxidative phosphorylation, creatine kinase acts in reverse to restore the phosphocreatine supply. Muscle Protein Degradation • During fasting or high activity, amino acids are degraded to pyruvate, which can be transaminated to alanine • Alanine circulates to liver, where it is converted back to pyruvate – a substrate for gluconeogenesis • This is a fuel of last resort for the fasting or exhausted organism Figure 27.8 The transamination of pyruvate to alanine by glutamate:alanine aminotransferase. Heart • The activity of heart muscle is constant and rhythmic • The heart functions as a completely aerobic organ and is very rich in mitochondria • Prefers fatty acid as fuel • Continually nourished with oxygen and free fatty acid, glucose, or ketone bodies as fuel Adipose tissue • Amorphous tissue widely distributed about the body • Consist of adipocytes • ~65% of the weight of adipose tissue is triacylglycerol • continuous synthesis and breakdown of triacylglycerols, with breakdown controlled largely via the activation of hormonesensitive lipase • Lack glycerol kinase; cannot recycle the glycerol of TAG Liver Brown fat • In newborn and hibernating animals • Rich in mitochondria • Thermogenin, uncoupling protein-1, permitting the H+ ions to reenter the mitochondria matrix without generating ATP • Is specialized to oxidize fatty acids for heat production rather than ATP synthesis Figure 27.9 Metabolic conversions of glucose-6-phosphate in the liver. • The major metabolic processing center in vertebrates • Glucose-6-phosphate – From dietary carbohydrate, degradation of glycogen, or muscle lactate – Converted to glycogen, NADPH…. • • • • Buffering the blood glucose – glucokinase Fatty acid turnover Cholesterol synthesis Detoxification organ Are you hungry • • • The hormones control eating behavior Produced in the stomach, liver….; move to brain and act on neurons The hormones are divided into 1. Short-term regulator: determine individual meal 2. Long-term regulator: act as stabilize the levels of body fat deposit • Two subset neurons 1. NPY/ AgRP producing neurons -- stimulating 2. Melanocortin producing neurons-- inhibiting