Glycolysis: The Central Pathway of Glucose Degradation

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Glycolysis: The Central Pathway of Glucose Degradation. NUTR 543 Advanced Nutritional Biochemistry Dr. David L. Gee Central Washington University. Clinical Case:. 15 y.o. female Hemolytic anemia diagnosed at age 3 mo. Recurrent episodes of pallor, jaundice, leg ulcer - PowerPoint PPT Presentation

Text of Glycolysis: The Central Pathway of Glucose Degradation

  • Glycolysis:The Central Pathway of Glucose DegradationNUTR 543Advanced Nutritional BiochemistryDr. David L. GeeCentral Washington University

  • Clinical Case:15 y.o. femaleHemolytic anemia diagnosed at age 3 mo.Recurrent episodes of pallor, jaundice, leg ulcerEnlarged spleen, low Hb, low RBC count, elevated reticulocyte countAbnormal RBC shape, short RBC life, elevated total and indirect bilirubinRBC with elevated 2,3-BPG and low ATPFollowing spleenectomy clinical and hematological symptoms improved.

  • Glycolysis:Embden-Myerhof Pathway Oxidation of glucoseProducts:2 Pyruvate2 ATP2 NADHCytosolic

  • Glycolysis: General FunctionsProvide ATP energyGenerate intermediates for other pathwaysHexose monophosphate pathwayGlycogen synthesisPyruvate dehydrogenaseFatty acid synthesisKrebs CycleGlycerol-phosphate (TG synthesis)

  • Glycolysis: Specific tissue functionsRBCsRely exclusively for energySkeletal muscleSource of energy during exercise, particularly high intensity exerciseAdipose tissueSource of glycerol-P for TG synthesisSource of acetyl-CoA for FA synthesisLiverSource of acetyl-CoA for FA synthesisSource of glycerol-P for TG synthesis

  • Data from 2007 NUTR 442 Indirect Calorimetry Laboratory

    Chart1

    0.6660.334

    0.5280.472

    0.2920.708

    0.06370.9363

    %fat

    %CHO

    Heart Rate

    Calories per hour

    % Substrate Utilzation vs Heart Rate

    Sheet1

    Ex.LevelHRV(e)FeCO2FeO2VCO2VO2RQCal/lO2Cal/hr%fatCalFat/hrCalCHO/hrHR%fat%CHO

    0786.2650.03150.17030.1954680.2443350.84.80170.38314010.45932.305861305938.07727879417867%33%

    5012318.920.04170.15980.7832880.936540.83636363644.85272.533140.425115.8265845156.706555512353%47%

    8014326.440.04220.16321.1078361.2188840.90889370934.936360.984685440.22681.5825389094279.402146530614329%71%

    11017037.020.04240.16641.5585421.5881580.98135198145.022478.543768560.031815.2176918402463.32607671981706%94%

    Joe Tibay

    Sheet1

    Cal/hr

    Heart Rate

    Calories per hour

    Energy Expenditure vs Heart Rate

    Sheet2

    CalFat/hr

    CalCHO/hr

    Heart Rate

    Calories per hour

    Absolute Substrate Utilization vs Heart Rate

    Sheet3

    %fat

    %CHO

    Heart Rate

    Calories per hour

    % Substrate Utilzation vs Heart Rate

    Chart2

    32.305861305938.0772787941

    115.8265845156.7065555

    81.5825389094279.4021465306

    15.2176918402463.3260767198

    CalFat/hr

    CalCHO/hr

    Heart Rate

    Calories per hour

    Absolute Substrate Utilization vs Heart Rate

    Sheet1

    Ex.LevelHRV(e)FeCO2FeO2VCO2VO2RQCal/lO2Cal/hr%fatCalFat/hrCalCHO/hrHR%fat%CHO

    0786.2650.03150.17030.1954680.2443350.84.80170.38314010.45932.305861305938.07727879417867%33%

    5012318.920.04170.15980.7832880.936540.83636363644.85272.533140.425115.8265845156.706555512353%47%

    8014326.440.04220.16321.1078361.2188840.90889370934.936360.984685440.22681.5825389094279.402146530614329%71%

    11017037.020.04240.16641.5585421.5881580.98135198145.022478.543768560.031815.2176918402463.32607671981706%94%

    Joe Tibay

    Sheet1

    Cal/hr

    Heart Rate

    Calories per hour

    Energy Expenditure vs Heart Rate

    Sheet2

    CalFat/hr

    CalCHO/hr

    Heart Rate

    Calories per hour

    Absolute Substrate Utilization vs Heart Rate

    Sheet3

    %fat

    %CHO

    Heart Rate

    Calories per hour

    % Substrate Utilzation vs Heart Rate

  • Regulation of Cellular Glucose UptakeBrain & RBC: GLUT-1 has high affinity (low Km)for glucose and are always saturated. Insures that brain and RBC always have glucose.Liver:GLUT-2 has low affinity (hi Km) and high capacity.Uses glucose when fed at rate proportional to glucose concentrationMuscle & Adipose:GLUT-4 is sensitive to insulin

  • Glucose UtilizationPhosphorylation of glucoseCommits glucose for use by that cellEnergy consumingHexokinase: muscle and other tissuesGlucokinase: liver

  • Properties of Glucokinase and Hexokinase Table 11-1

  • Regulation of Cellular Glucose Utilization in the LiverFeedingBlood glucose concentration highGLUT-2 taking up glucoseGlucokinase induced by insulinHigh cell glucose allows GK to phosphorylate glucose for use by liverPost-absorptive stateBlood & cell glucose lowGLUT-2 not taking up glucoseGlucokinase not phophorylating glucoseLiver not utilizing glucose during post-absorptive state

  • Regulation of Cellular Glucose Utilization in the LiverStarvationBlood & cell glucose concentration lowGLUT-2 not taking up glucoseGK synthesis repressedGlucose not used by liver during starvation

  • Regulation of Cellular Glucose Utilization in the MuscleFeeding and at restHigh blood glucose, high insulinGLUT-4 taking up glucoseHK phosphorylating glucoseIf glycogen stores are filled, high G6P inhibits HK, decreasing glucose utilizationStarving and at restLow blood glucose, low insulinGLUT-4 activity lowHK constitutiveIf glycogen stores are filled, high G6P inhibits HK, decreasing glucose utilization

  • Regulation of Cellular Glucose Utilization in the MuscleExercising Muscle (fed or starved)Low G6P (being used in glycolysis)No inhibition of HKHigh glycolysis from glycogen or blood glucose

  • Regulation of GlycolysisRegulation of 3 irreversible stepsPFK-1 is rate limiting enzyme and primary site of regulation.

  • Regulation of PFK-1 in MuscleRelatively constitutiveAllosterically stimulated by AMPHigh glycolysis during exerciseAllosterically inhibited by ATPHigh energy, resting or low exerciseCitrateBuild up from Krebs cycleMay be from high FA beta-oxidation -> hi acetyl-CoAEnergy needs low and met by fat oxidation

  • Regulation of PFK-1 in LiverInducible enzymeInduced in feeding by insulinRepressed in starvation by glucagonAllosteric regulationLike muscle w/ AMP, ATP, CitrateActivated by Fructose-2,6-bisphosphate

  • Role of F2,6P2 in Regulation of PFK-1PFK-2 catalyzesF6P + ATP -> F2,6P2 + ADPPFK-2 allosterically activated by F6PF6P high only during feeding (hi glu, hi GK activity)PFK-2 activated by dephophorylation Insulin induced protein phosphataseGlucagon/cAMP activates protein kinase to inactivateTherefore, during feedingHi glu + hi GK -> hi F6PInsulin induces prot. Ptase and activates PFK-2Activates PFK-2 > hi F2,6P2Activates PFK-1 -> hi glycolysis for fat synthesis

  • Coordinated Regulation of PFK-1 and FBPase-1Both are inducible, by opposite hormonesBoth are affected by F2,6P2, in opposite directions

  • Pyruvate Dehydrogenase:The enzyme that links glycolysis with other pathwaysPyruvate + CoA + NAD -> AcetylCoA + CO2 + NADH

  • The PDH ComplexMulti-enzyme complexThree enzymes5 co-enzymesAllows for efficient direct transfer of product from one enzyme to the next

  • The PDH ReactionE1: pyruvate dehydrogenaseOxidative decarboxylation of pyruvateE2: dihydrolipoyl transacetylaseTransfers acetyl group from TPP to lipoic acidE3: dihydrolipoyl dehydrogenaseTransfers acetly group to CoA, transfers electrons from reduced lipoic acid to produce NADH

  • Regulation of PDHMuscleResting (dont need)Hi energy stateHi NADH & AcCoAInactivates PDHHi ATP & NADH & AcCoAInhibits PDHExercising (need)Low NADH, ATP, AcCoA

  • Regulation of PDHLiverFed (need to make FA)Hi energyInsulin activates PDHStarved (dont need)Hi energyNo insulinPDH inactive

  • Clinical Case:Pyruvate Kinase Deficiency15 y.o. femaleHemolytic anemia diagnosed at age 3 mo.Recurrent episodes of pallor, jaundice, leg ulcerEnlarged spleen, low Hb, low RBC count, elevated reticulocyte countAbnormal RBC shape, short RBC life, elevated total and indirect bilirubinRBC with elevated 2,3-BPG and low ATPFollowing spleenectomy clinical and hematological symptoms improved.

  • Clinical Case:Pyruvate Kinase DeficiencyRBC dependent on glycolysis for energySodium/potassium ion pumps require ATPAbnormal RBC shape a result of inadequate ion pumpingExcessive RBC destruction in spleenHemolysisJaundice (elevated bilirubin, fecal urobilinogens)Increased reticulocyte count

  • Clinical Case:Pyruvate Kinase Deficiency

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