Principles of Metabolic Regulation

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Principles of Metabolic Regulation

• S 2006 BIOC 3406
• 02-23-06

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Cells maintain a dynamic steady state

• As conditions change, fluxes change, but levels
  of intermediates stay close to the same
• Internal. Changes in amounts of fuel regulate
  the speed of processing
• External. Remote changes sensed via hormones and
  other messengers, change the levels of processing

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Important Ratios

• ATP/ADP, ATP/AMP
• NADH/NAD
• NADPH/NADP

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Selective pressures over evolutionary time scales

• Maximization of efficiency of fuel utilization
• Minimization of futile cycling
• Partitioning of metabolites between alternative
  pathways
• Choice of best fuel for needs
• Blocking of pathways when metabolites accumulate

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Glycolysis and Gluconeogenesis Coordination

• Gluconeogenesis occurs (mostly, and in mammals)
  in liver
• Glycolysis occurs in liver and muscle
• 3 exergonic reactions from glucose to pyruvate
• 3 exergonic reactions from pyruvate to glucose

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Hexokinase Isozymes

• I, II, III muscle enzymes allow steady
  consumption of glucose for energy
• II predominant, KM 0.1 mM. Saturated under
  normal conditions
• I, II inhibited by G-6-P
• IV liver enzyme maintains blood glucose
• KM10 mM (blood glucose 5 mM)
• Senses glucose through GLUT2 and quickly responds
• Regulatory protein in nucleus activated by F-6-P
  and dissociated by glucose
• IV NOT inhibited by G-6-P

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PFK-1

• Inhibited by ATP
• Effect of ATP increased by citrate
• Activated by ADP, AMP
• Activated by fructose 2,6-bisphosphate

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Pyruvate Kinase

• 3 isozymes
• ATP, AcSCoA, long chain fatty acids inhibit all
  isozymes
• L inhibited by phosphorylation by glucagon
  activated cAMP-dependent protein kinase (low
  blood sugar ? cAMP)
• M activated by cAMP in response to epinephrine
  (G-protein system)

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The fate of pyruvate in mitochondria

• ?AcSCoA (via pyruvate dehydrogenase) ? citric
  acid cycle
• AcSCoA inhibits PDH
• ?oxaloacetate (via pyruvate carboxylase) ?
  gluconeogenesis
• AcSCoA activates pyruvate carboxylase

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FBPase-1 and PFK-1

• FBPase-1 inhibited by AMP
• PFK-1 stimulated by AMP, ADP, inhibited by
  citrate, ATP

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Fructose 2,6-bisphosphate

• PFK-1 is virtually inactive without Fructose
  2,6-bisphoshate
• Fructose 2,6-bisphoshate activate PFK-1 and
  allows glycolysis to occur.
• When blood sugar is low, glucagon ? ß-adrenergic
  system ? adenylyl cyclase ? cAMP ? protein kinase
  ? FBPase-2 ? gluconeogenesis
• When blood sugar is high, insulin ?
  phosphoprotein phosphatase ? PFK-2 ? glycolysis

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