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Principles of Metabolic Regulation

Principles of Metabolic Regulation. S 2006 BIOC 3406 02-23-06. 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

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Principles of Metabolic Regulation

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  1. Principles of Metabolic Regulation S 2006 BIOC 3406 02-23-06

  2. 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

  3. Important Ratios • ATP/ADP, ATP/AMP • NADH/NAD+ • NADPH/NADP+

  4. 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

  5. Slide 29

  6. 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 Slide eight

  7. -5.0 -27 -23 ? -23 -17

  8. 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 • KM~10 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 Slide 32

  9. PFK-1 • Inhibited by ATP • Effect of ATP increased by citrate • Activated by ADP, AMP • Activated by fructose 2,6-bisphosphate

  10. 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)

  11. 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

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

  13. 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  β-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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