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metabolism_lecture_5

metabolism_lecture_5 - Regulation glycolysis v...

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Regulation glycolysis v. gluconeogenesis Regulation at the  irreversible and bypass steps hexokinase  controls glycolytic  flux  phosphofructokinase-1 mediates metabolic homeostasis (in vitro glycolysis experiment with  liver   e xtrac t)
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= committed step in glycolysis! ATP acts as a negative effector: at high concentrations, it binds to an  allosteric site  and lowers  PFK-1 activity (affinity for Fruc. 6-P)    “Do not spend glucose in glycolysis if there is already plenty of ATP  present!” Substrate binding site Allosteric site ATP Regulation of Phosphofructokinase-1
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 ADP, AMP  stimulate  PFK-1  AMP strongly  inhibits FBPase-1    in the corresponding step of    gluconeogenesis Regulation of Phosphofructokinase-1 and Fructose 1,6-bisphosphatase-1 Another important allosteric regulator: Fructose 2,6-bisphosphate (F26BP) stimulates PFK-1 inhibits FBPase-1
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Effect on PFK-1 Effect on FBPase-1 F26BP with opposite effects on PFK-1 and FBPase-1 Prevents glycolysis and gluconeogenesis from  occurring simultaneously. K K M Also: increase in sensitivity to inhibition by AMP
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Tandem-enzyme: Phosphofructokinase-2 and Fructose 2,6 bisphosphatase-2 in one polypeptide The activity of PFK-2/FBPase-2 in the liver is regulated by phosphorylation / dephosphorylation in response to insulin or glucagon Where does Fructose 2,6-bisphosphate (F26BP) come from? Low blood sugar level High blood sugar level from Stryer, 5 th  ed.
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Xylulose 5-phosphate 2A pho s pho pro te in pho s phatas e  2A (PP2A) Regulation of Fructose 2,6-bisphosphate by Xylulose 5-phosphate in the liver Xylulose -5P is a product of the PPP   [Xylulose-5P] when   [Glucose]  -> Xylulose-5P stimulates PP2A -> PFK-2 dephosphorylated = active -> increase in F26BP      stimulates glycolysis     inhibits gluconeogenesis -> increase in  [acetyl-CoA]    with  NADPH  from PPP used for      fatty acid synthesis Specificity for target prot determined by different regulatory subunits.
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Regulation of the last step in glycolysis: Pyruvate-Kinase allosteric effectors Glucagon-induced phosphorylation of the L (liver) isozyme Different isoenzymes are regulated differently:    L-type (liver)  M-type (muscle) R-type (erythrocytes)
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Controlling the fate of pyruvate: Gluconeogenesis and storage as glycogen vs. Citric acid cycle and energy production allosteric control by acetyl-CoA : -> stimulation  of Pyruvate carboxylase (first bypass step of gluconeogenesis)   -> inhibition  of Pyruvate dehydrogenase  complex    [acetyl-CoA] from fatty acid  β -oxidation or  when Citric acid cycle is inhibited by   [ATP]  glycogen
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Glycolysis, fatty acid synthesis Transcriptional regulation of metabolic enzymes IRS1 PDX1 PDX1 PDX1 P P P enzymes for glycolysis, PPP, fatty acid synthesis P P P Gluconeogenesis, Glucose release into blood IRS1 P P  Change in enzyme levels through changes in the 
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