Introduction to Metabolism

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• Introduction to Metabolism

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Metabolism

• The sum of the chemical changes that convert
  nutrients into energy and the chemically complex
  products of cells
• Hundreds of enzyme reactions organized into
  discrete pathways
• Substrates are transformed to products via many
  specific intermediates
• Metabolic maps portray the reactions
• Intermediary metabolism

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A Common Set of Pathways

• Organisms show a marked similarity in their major
  metabolic pathways
• Evidence that all life descended from a common
  ancestral form
• There is also significant diversity

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The Sun is Energy for Life

• Phototrophs use light to drive synthesis of
  organic molecules
• Heterotrophs use these as building blocks
• CO2, O2, and H2O are recycled

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Metabolism

• Metabolism consists of catabolism and anabolism
• Catabolism degradative pathways
• Usually energy-yielding!
• Anabolism biosynthetic pathways
• energy-requiring!

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Catabolism and Anabolism

• Catabolic pathways converge to a few end products
• Anabolic pathways diverge to synthesize many
  biomolecules
• Some pathways serve both in catabolism and
  anabolism
• Such pathways are amphibolic

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Organization in Pathways

• Pathways consist of sequential steps
• The enzymes may be separate
• Or may form a multienzyme complex
• Or may be a membrane-bound system
• New research indicates that multienzyme complexes
  are more common than once thought

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Mutienzyme complex
Separate enzymes
Membrane Bound System
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Organization of Pathways
Closed Loop (intermediates recycled)
Linear (product of rxns are substrates for
subsequent rxns)
Spiral (same set of enzymes used repeatedly)
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Metabolism Proceeds in Discrete Steps

• Enzyme specificity defines biosynthetic route
• Controls energy input and output
• Allow for the establishment of control points.
• Allows for interaction between pathways

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Regulation of Metabolic Pathways

• Pathways are regulated to allow the organism to
  respond to changing conditions.
• Most regulatory response occur in millisecond
  time frames.
• Most metabolic pathways are irreversible under
  physiological conditions.
• Regulation ensures unidirectional nature of
  pathways.
• Flow of material thru a pathway is referred to as
  flux.
• Flux is regulated by supply of substrates,
  removal of products, and activity of enzymes

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Enzyme Regulation of Flux

• Common mechanisms
• feedback inhibition product of pathway down
  regulates activity of early step in pathway
• Feedforward activation metabolite produced
  early in pathway activates down stream enzyme

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Metabolic Control Theory

• Pathway flux is regulated by multiple enzymes in
  a pathway.
• Control coefficient determined for each enzyme.
  D activity / D enzyme concentration.
• Enzymes with large control coefficients impt to
  overall regulation.
• Recent finding suggest that the control of most
  pathways is shared by multiple pathwayt enzymes

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Regulating Related Catabolic and Anabolic Pathways

• Anabolic catabolic pathways involving the same
  compounds are not the same
• Some steps may be common to both
• Others must be different - to ensure that each
  pathway is spontaneous
• This also allows regulation mechanisms to turn
  one pathway and the other off

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Metabolic Pathways are not at Equilibrium

• Metabolic pathways are not at equilibrium
• A lt-gt B
• Instead pathways are at steady state.
• A -gt B -gt C
• The rate of formation of B rate of utilization
  of B.
• Maintains concentration of B at constant level.
• All pathway intermediates are in steady state.
• Concentration of intermediates remains constant
  even as flux changes.

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Thermodynamics and Metabolism

• Standard free energy A B lt-gt C D
• DGo -RT lnCD/AB
• DGo -RT ln Keq
• DGo lt 0 (Keqgt1.0) Spontaneous forward rxn
• DGo 0 (Keq1.0) Equilibrium
• DGo gt 0 (Keq lt1.0) Rxn requires input of energy

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DG (not DGo) is impt in vivo

• DG DGo RT ln Q
• Q (mass action ratio) CD/AB
• Actual reactants and products used to
  determine Q.
• Because reactions are at steady state not
  equilibrium, Q does not equal Keq
• When Q is close in value to Keq
  near-equilibrium rxn (reversible)
• If Q is far from Keq metabolically
  irreversible rxn.

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ATP

• ATP is the energy currency of cells
• In phototrophs, light energy is transformed into
  the light energy of ATP
• In heterotrophs, catabolism produces ATP, which
  drives activities of cells
• ATP cycle carries energy from photosynthesis or
  catabolism to the energy-requiring processes of
  cells

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Phosphoric Acid Anhydrides

• ADP and ATP are examples of phosphoric acid
  anhydrides
• Large negative free energy change on hydrolysis
  is due to
• electrostatic repulsion
• stabilization of products by ionization and
  resonance
• entropy factors

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Phosphoryl-group Transfer

• Energy produced from a rxn can be coupled to
  another rxn that requires energy to proceed.
• Transfer of a phosphate group from high energy
  phosphorylated compounds can activate a substrate
  or intermediate of an energy requiring rxn.
• A-P ADP -gt A ATP, ATP C-gt ADP C-P
• The ability of a phosphorylated compound to
  transfer a phosphoryl group is termed its
  phosphoryl-group-transfer-potential.

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Phosphoryl-group Transfer