CHAPTER 15 Principles of Metabolic Regulation

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CHAPTER 15 Principles of Metabolic Regulation
Key topics

• Principles of regulation in biological systems
• Glycolysis vs. gluconeogenesis?

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Metabolic Pathways

• The biochemical reactions in the living cell
  the metabolism is organized into metabolic
  pathways
• The pathways have dedicated purposes
• Some are dedicated to extraction of energy
• Some are dedicated to storage of fuels
• Some are dedicated for synthesis of important
  building blocks
• Some are dedicated to elimination of waste
  materials
• The pathways can be represented as a map
• Follow the fate of metabolites and building
  blocks
• Identify enzymes that act on these metabolites
• Identify points and agents of regulation
• Identify sources of metabolic diseases

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Map of Metabolic Pathways
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Homeostasis

• Organisms maintain homeostasis by keeping the
  concentrations of most metabolites at steady
  state
• In steady state, the rate of synthesis of a
  metabolite equals the rate of breakdown of this
  metabolite

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Principles of Regulation

• The flow of metabolites through the pathways is
  regulated to maintain homeostasis
• Sometimes, the levels of required metabolites
  must be altered very rapidly
• Need to increase the capacity of glycolysis
  during the action
• Need to reduce the capacity of glycolysis after
  the action
• Need to increases the capacity of gluconeogenesis
  after successful action

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Feedback Inhibition

• In many cases, ultimate products of metabolic
  pathways directly or indirectly inhibit their own
  biosynthetic pathways
• ATP inhibits the commitment step of glycolysis

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Reactions Far From Equilibrium are Common Points
of Regulation

• Living systems thrive by keeping some metabolic
  reactions far from equilibrium while the levels
  of metabolites are in steady state

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Rates of a Biochemical Reactions

• Rates of a biochemical reactions depend on many
  factors
• Concentration of reactants
• Activity of the catalyst
• Concentration of the enzyme
• Intrinsic activity of the enzyme
• Concentrations of effectors
• Allosteric regulators
• Competing substrates
• pH, ionic environment
• Temperature

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Factors that Determine the Activity of Enzymes
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Active Protein Molecules have a Finite Lifespan

• Different proteins in the same tissue have very
  different half-lives
• less than an hour to about a week for liver
  enzymes
• The stability correlates with the sequence at
  N-terminus
• Some proteins are as old as you are
• Crystallins in the eye lens

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Phosphorylation of Enzymes Affects their Activity

• Protein phosphorylation is catalyzed by protein
  kinases
• Dephosphorylation is spontaneous, or catalyzed by
  protein phosphatases
• Typically, hydroxyl groups of Ser, Thr, or Tyr
  are phosphorylated

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Some Enzymes in the Pathway Limit the Flux of
Metabolites More than Others

• Hexokinase and phosphofructokinase are
  appropriate targets for regulation of glycolytic
  flux
• Increased hexokinase activity enables activation
  of glucose
• Increased phosphofructokinase-1 activity enables
  catabolism of activated glucose via glycolysis

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Control of Glycogen Synthesis

• Insulin signaling pathway
• increases glucose import into muscle
• stimulates the activity of muscle hexokinase
• activates glycogen synthase
• Increased hexokinase activity enables activation
  of glucose
• Glycogen synthase makes glycogen for energy
  storage

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Regulation of Hexokinase IV by Sequestration
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Rate of Reaction Depends on the Concentration of
Substrates

• The rate is more sensitive to concentration at
  low concentrations
• Frequency of substrate meeting the enzyme matters
• The rate becomes insensitive at high substrate
  concentrations
• The enzyme is nearly saturated with substrate

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Isozymes may Show Different Kinetic Properties

• Isozymes are different enzymes that catalyze the
  same reaction
• They typically share similar sequences
• Their regulation is often different

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Glycolysis vs. Gluconeogenesis
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Regulation of Phosphofructokinase-1

• The conversion of fructose-6-phosphate to
  fructose 1,6-bisphosphate is the commitment step
  in glycolysis
• ATP is a negative effector
• Do not spend glucose in glycolysis if there is
  plenty of ATP

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Phosphofructokinase-1 (PFK-1)
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Regulation of Phosphofructokinase 1 and Fructose
1,6-Bisphosphatase

• Go glycolysis if AMP is high and ATP is low
• Go gluconeogenesis if AMP is low

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Regulation by Fructose 2,6-Bisphosphate

• F26BP activates phosphofructokinase (glycolytic
  enzyme)
• F26BP inhibits fructose 1,6-bisphosphatase
  (gluconeogenetic enzyme)

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Regulation by Fructose 2,6-Bisphosphate

• Go glycolysis if F26BP is high
• Go gluconeogenesis if F26BP is low

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Regulation of 2,6-Bisphosphate Levels
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Molecular Origin of Enzyme Regulation

• Regulation of catalysis typically involves
• Binding of inhibitors, often to the active site
• Binding of regulatory protein subunits

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Regulation of Pyruvate Kinase

• Signs of abundant energy supply allosterically
  inhibit all pyruvate kinase isoforms
• Signs of glucose depletion (glucagon) inactivate
  liver pyruvate kinase via phosphorylation
• Glucose from liver is exported to brain and other
  vital organs

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Two Alternative Fates for Pyruvate

• Pyruvate can be a source of new glucose
• Store energy as glycogen
• Generate NADPH via pentose phosphate pathway
• Pyruvate can be a source of acetyl-CoA
• Store energy as body fat
• Make ATP via citric acid cycle
• Acetyl-CoA stimulates glucose synthesis by
  activating pyruvate carboxylase

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Epinephrine and Glucagon Stimulate Breakdown of
Glycogen
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