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Introduction to Metabolism[1]

Introduction to Metabolism[1] - Chapter 16 Introduction to...

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Unformatted text preview: Chapter 16 Introduction to Metabolism Metabolism The overall process through which living systems acquire and use free energy to carry out their various functions • Catabolism (or degradation) – Nutrients and cell constituents are broken down to salvage their components and/or to generate energy • Anabolism (or biosynthesis) – Biomolecules are synthesized from simpler components How do living things acquire energy? • Autotrophs – synthesizing all their cellular constituents from simple molecules – Chemolithotrophs: energy from the oxidation of inorganic compounds such as NH3, H2S or Fe2+ – Photoautotrophs: energy from photosynthesis • Heterotrophs – obtaining free energy through the oxidation of organic compounds (carbohydrates, lipids, and proteins) ultimately obtained from autotrophs major metabolic pathways Roles of ATP and NADPH in metabolism Overview of catabolism Enzymes catalyze the reactions of metabolic pathways Thermodynamics of metabolism • Metabolic pathways are irreversible – At least one highly exergonic reaction (ΔG <<0) is strategically located in a metabolic pathway, making the entire pathway irreversible • Every metabolic pathway has a first committed step (irreversible step) • Catabolic and anabolic pathways differ – independent control of two pathways Control of metabolic flux • Short-term control mechanism (seconds or minutes) – Allosteric control – Covalent modification – Substrate cycle • Long-term control mechanism (hours or days) – Genetic control Allosteric control Control by covalent modification Control by substrate cycle Metabolic pathways occur in specific cellular locations Oxidation states of carbon Number of valence electrons on the free atom (4 for carbon) – (the number of its lone pair + the number of its assigned electrons) 4-(0+0)=4 4-(0+1)=3 4-(0+8)=-4 Modes of C-H bond breaking Biological nucleophiles Biological electrophiles Types of biological reactions • • • • • • • Group-transfer reactions Oxidations and reductions Eliminations Isomerizations Rearrangements C-C bond formations C-C bond cleavages Types of metabolic group transfer reactions Acyl group transfer Phosphoryl group transfer Glycosyl group transfer Inversion of stereochemistry Oxidations and reductions Oxidation states of FAD Elimination reactions Trans and cis configuration Isomerization C-C bond formation C-C bond formation C-C bond formation Stabilization of carbanions How to study metabolism • Metabolic blocks: accumulation of metabolic intermediates – Metabolic inhibitors – Genetic defects – Genetic manipulation • Stable and radioactive isotopes: tracing the interconversion of metabolic intermediates • Isolation of organs, cells and subcellular organells: identifying the location of specific metabolic pathway Intermediate accumulation by genetic defects Intermediate accumulation by genetic manipulation Isotopes in biochemistry Study of metabolism in whole animal by NMR Detection of creatine phosphate in transgenic mouse liver by in vivo 31P NMR Study of metabolism in whole animal by NMR Monitoring conversion of [1-13C]glucose to glycogen by in vivo 13C NMR Tracing precursor by isotopic labeling Detection of radioactive isotopes • Proportional counting (Geiger counting) – Detecting ionization in a gas caused by the passage of radiation (not useful for low energy β-emitters like 3H, 14C) • Liquid scintillation counting – Detecting light emitted from scintillation cocktail when struck by radiation • Autoradiography – Blackening of photographic film by radiation Establishment of precursor-product relationships by radioactive tracers Starting material* → A* → B* → later products* d [B*] = k[A*] − k[B*] = k ([A*] − [B*]) dt d [B*] 1. While the radioactivity of a product is rising ( > 0), it should be less than that of its precursor ([A*] > [B*]) dt d [B*] 2.When the radioactivity of a product is at its peak ( = 0), it should be equal to that of its precursor ([A*] = [B*]) dt d [B*] 3. After the radioactivity of a product has peaked ( < 0), it should be greater that of its precursor ([A*] < [B*]) dt “High energy” compounds • • • • • • ATP Acyl phosphates Enol phosphates Phosphoguanidines Nucleotide triphosphates Thioesters ATP ATP + H2O ATP + H2O ADP +Pi AMP + PPi ΔG= -30.5 kJ/mol ΔG= -32.2 kJ/mol Acyl phosphate Phosphoguanidines (Phosphagens) Phosphocreatine or phosphoarginine provides a “high-energy” reservoir for ATP formation ATP + Creatine Phosphocreatine + ADP ΔG ≈ 0 Sources of “high energy” Competition in resonance Electrostatic repulsion Resonance stabilization Energy release from phosphate hydrolysis Coupled Reactions (1) A + B (2) D + E (1+2) A + B + E C+D F+G ΔG1 ΔG2 ΔG3 C+ F + G When ΔG3=ΔG1+ΔG2 < 0 : Spontaneous Examples of the coupled spontaneous reactions ATP is the free energy currency The role of ATP: the universal energy currency • Consumption of ATP – – – – Early stage of nutrient breakdown Interconversion of nucleoside triphosphates Driving force of otherwise endergonic physiological processes PPi cleavage also drives the reactions • Formation of ATP – Substrate-level phosphorylation: direct transfer of the phosphate from a substrate to ADP – Oxidative phosphorylation and photophosphorylation: coupled with proton (H+) concentration gradient across a membrane – Adenylate kinase reaction (AMP + ATP ↔ 2ADP) PPi hydrolysis can drive the reaction ΔGo' = -33.5 kJ/mol Rate of ATP turnover • ATP is a free energy transmitter rather than a energy reservoir • ATP is continuously hydrolyzed and regenerated • Half-life of ATP is from seconds to minutes • Phosphocreatine (or phosphoarginine) provides a “high-energy” reservoir for ATP formation ATP + Creatine Phosphocreatine + ADP ΔG ≈ 0 Oxidation-Reduction reactions (redox or oxidoreduction reactions) • Processes involving the transfer of electrons – Electron donor (reductant or reducing agent) – Electron acceptor (oxidant or oxidizing agent) • Sources of most free energy for living things Electrochemical cells Reduction Half-reaction Half-cell Oxidation Half-reaction Half-cell Nernst Equation n+ n+ A ox + Bred ↔ A red + Box ΔG = − nFΔE n+ RT [A red ][Box ] ΔE = ΔE − ) ln( n + nF [A ox ][Bred ] o ΔE0 : the standard redox potential F: the Faraday constant n: the moles of electrons transferred in a half-reaction Measure of redox potentials n+ n+ A ox + Bred ↔ A red + Box For its two half reactions : n+ A ox + ne − ↔ A red n+ Box + ne − ↔ Bred The reduction potentials : RT [A red ] ln( n + ) EA = E − [A ox ] nF o A RT [B red ] EB = E − ln( n + ) nF [Box ] o B ΔE o = E(oe − acceptor) − E(oe − donor) o o ΔE o = E A − EB Standard reduction potential for biochemical reactions For the standard hydrogen half - reaction 2H + + 2e - ↔ H 2 (g) Standard reduction potential E o = 0 V at [H + ] = 1 (pH = 0), 25o C and 1 atm At biochemical standard state (pH = 7), the standard reduction potential E o ' = - 0.421 V O2 is a strong electron acceptor (oxidizing agent) Redox potential can be modulated by the protein component Spontaneity of biochemical redox reactions ΔG = -nFΔE When ΔE > 0, ΔG < 0 (Spontaneous) Concentration gradient generates the free energy n+ n+ A ox (half-cell 1) + A red (half-cell 2) ↔ A ox (half-cell 2) + A red (half-cell 1) n+ RT [A ox (half-cell 2)] [A red (half-cell 1)] ΔE = ln( n + ) nF [A ox (half-cell 1)] [A red (half-cell 2)] e.g. • Proton concentration gradient across mitochondrial inner membrane drives ATP synthesis • Nerve impulses are transmitted through the discharge of [Na+] and [K+] gradients across the nerve cell membranes ...
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