glycolysis: the central pathway of glucose degradation nutr 543 advanced nutritional biochemistry...
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Glycolysis:The Central Pathway of Glucose Degradation
NUTR 543
Advanced Nutritional BiochemistryDr. David L. Gee
Central Washington University
![Page 2: Glycolysis: The Central Pathway of Glucose Degradation NUTR 543 Advanced Nutritional Biochemistry Dr. David L. Gee Central Washington University](https://reader036.vdocuments.us/reader036/viewer/2022062409/56649c9e5503460f9495e7fa/html5/thumbnails/2.jpg)
Clinical Case:
15 y.o. female Hemolytic anemia diagnosed at age 3 mo. Recurrent episodes of pallor, jaundice, leg ulcer
Enlarged spleen, low Hb, low RBC count, elevated reticulocyte count
Abnormal RBC shape, short RBC life, elevated total and indirect bilirubin
RBC with elevated 2,3-BPG and low ATP
Following spleenectomy clinical and hematological symptoms improved.
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Glycolysis:Embden-Myerhof
Pathway Oxidation of glucose
Products:2 Pyruvate2 ATP2 NADH
Cytosolic
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Glycolysis: General Functions
Provide ATP energyGenerate intermediates for other pathwaysHexose monophosphate pathwayGlycogen synthesisPyruvate dehydrogenase
Fatty acid synthesisKrebs’ Cycle
Glycerol-phosphate (TG synthesis)
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Glycolysis: Specific tissue functions
RBC’s Rely exclusively for energy
Skeletal muscle Source of energy during exercise, particularly high
intensity exercise
Adipose tissue Source of glycerol-P for TG synthesis Source of acetyl-CoA for FA synthesis
Liver Source of acetyl-CoA for FA synthesis Source of glycerol-P for TG synthesis
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% Substrate Utilzation vs Heart Rate
0%
20%
40%
60%
80%
100%
0 50 100 150 200
Heart Rate
Cal
ori
es p
er h
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Absolute Substrate Utilization vs Heart Rate
050
100150200250300350400450500
0 50 100 150 200
Heart Rate
Ca
lori
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Data from 2007 NUTR 442 Indirect Calorimetry Laboratory
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Regulation of Cellular Glucose Uptake
Brain & 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 concentration
Muscle & Adipose: GLUT-4 is sensitive to insulin
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Glucose Utilization
Phosphorylation of glucoseCommits glucose for use by that cellEnergy consuming
Hexokinase: muscle and other tissues
Glucokinase: liver
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Properties of
Glucokinase and Hexokinase Table 11-1
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Regulation of Cellular Glucose Utilization in the Liver
Feeding Blood glucose concentration high GLUT-2 taking up glucose Glucokinase induced by insulin High cell glucose allows GK to phosphorylate glucose
for use by liver
Post-absorptive state Blood & cell glucose low GLUT-2 not taking up glucose Glucokinase not phophorylating glucose Liver not utilizing glucose during post-absorptive state
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Regulation of Cellular Glucose Utilization in the Liver
StarvationBlood & cell glucose concentration lowGLUT-2 not taking up glucoseGK synthesis repressedGlucose not used by liver during starvation
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Regulation of Cellular Glucose Utilization in the Muscle
Feeding and at rest High blood glucose, high insulin GLUT-4 taking up glucose HK phosphorylating glucose If glycogen stores are filled, high G6P inhibits HK,
decreasing glucose utilization
Starving and at rest Low blood glucose, low insulin GLUT-4 activity low HK constitutive If glycogen stores are filled, high G6P inhibits HK,
decreasing glucose utilization
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Regulation of Cellular Glucose Utilization in the Muscle
Exercising Muscle (fed or starved)Low G6P (being used in glycolysis)No inhibition of HKHigh glycolysis from glycogen or blood
glucose
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Regulation of Glycolysis
Regulation of 3 irreversible steps
PFK-1 is rate limiting enzyme and primary site of regulation.
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Regulation of PFK-1 in Muscle
Relatively constitutiveAllosterically stimulated by AMP High glycolysis during exercise
Allosterically inhibited by ATP
High energy, resting or low exercise Citrate
Build up from Krebs’ cycle May be from high FA beta-oxidation -> hi acetyl-CoA Energy needs low and met by fat oxidation
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Regulation of PFK-1 in LiverInducible enzyme Induced in feeding by insulinRepressed in starvation by glucagon
Allosteric regulationLike muscle w/ AMP, ATP, CitrateActivated by Fructose-2,6-bisphosphate
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Role of F2,6P2 in Regulation of PFK-1
PFK-2 catalyzes F6P + ATP -> F2,6P2 + ADP
PFK-2 allosterically activated by F6P F6P high only during feeding (hi glu, hi GK activity)
PFK-2 activated by dephophorylation Insulin induced protein phosphatase Glucagon/cAMP activates protein kinase to inactivate
Therefore, during feeding Hi glu + hi GK -> hi F6P
Insulin induces prot. P’tase and activates PFK-2 Activates PFK-2 –> hi F2,6P2
Activates PFK-1 -> hi glycolysis for fat synthesis
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Coordinated Regulation of PFK-1 and FBPase-1
Both are inducible, by opposite hormones
Both are affected by F2,6P2, in opposite directions
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Pyruvate Dehydrogenase:The enzyme that links glycolysis with other pathways
Pyruvate + CoA + NAD -> AcetylCoA + CO2 + NADH
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The PDH ComplexMulti-enzyme complex Three enzymes 5 co-enzymes Allows for efficient direct transfer of product from
one enzyme to the next
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The PDH ReactionE1: pyruvate dehydrogenase Oxidative decarboxylation of pyruvate
E2: dihydrolipoyl transacetylase Transfers acetyl group from TPP to lipoic acid
E3: dihydrolipoyl dehydrogenase Transfers acetly group to CoA, transfers electrons from reduced lipoic acid to produce NADH
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Regulation of PDH
MuscleResting (don’t need) Hi energy state Hi NADH & AcCoA
Inactivates PDH Hi ATP & NADH & AcCoA
Inhibits PDH
Exercising (need) Low NADH, ATP, AcCoA
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Regulation of PDH
LiverFed (need to make FA)Hi energy Insulin activates PDH
Starved (don’t need)Hi energyNo insulin
PDH inactive
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Clinical Case:
Pyruvate Kinase Deficiency
15 y.o. female Hemolytic anemia diagnosed at age 3 mo. Recurrent episodes of pallor, jaundice, leg ulcer
Enlarged spleen, low Hb, low RBC count, elevated reticulocyte count
Abnormal RBC shape, short RBC life, elevated total and indirect bilirubin
RBC with elevated 2,3-BPG and low ATP
Following spleenectomy clinical and hematological symptoms improved.
![Page 25: Glycolysis: The Central Pathway of Glucose Degradation NUTR 543 Advanced Nutritional Biochemistry Dr. David L. Gee Central Washington University](https://reader036.vdocuments.us/reader036/viewer/2022062409/56649c9e5503460f9495e7fa/html5/thumbnails/25.jpg)
Clinical Case:
Pyruvate Kinase Deficiency
RBC dependent on glycolysis for energySodium/potassium ion pumps require ATPAbnormal RBC shape a result of
inadequate ion pumpingExcessive RBC destruction in spleen
Hemolysis Jaundice (elevated bilirubin, fecal urobilinogens) Increased reticulocyte count
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Clinical Case:
Pyruvate Kinase Deficiency
<10% activity of PK Results in increase in
glycolytic intermediates (2,3-BPG)
Recessive autosomal disorders of isozyme found only in RBC’s
Heterozygous defect occurs in about 1% of Americans
Second most common genetic cause of hemolytic anemia (G6PDH deficiency #1)
Rare (51/million Caucasian births, may be underdiagnosed)