Ch 31 Gluconeogenesis Synthesis of glucose from non-carbohydrate precursors.
Ch 31 Gluconeogenesis
Synthesis of glucose from non-carbohydrate precursors.
Note. Dashed line part of gluconeogenesis.
NOTE that you are making GLYCOGEN in fasting while making GLUCOSE in starved.
Glycerol from fats, AA from muscles. Lactate from RBC & anaerobic muscle metabolism.
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Liver Quantitatively, the human organ which uses
gluconeogenesis the most Primary non-carbohydrate precursors
amino acids from muscle tissue lactate from RBC’s + Anaerobic Musc. glycerol from adipose tissue
In fasted state, glycerols from fat cells will be taken up by other tissues also
Most reaction steps in the path utilize enzymes of the glycolytic path Need bypass enzymes to get over the 3 enzymes that
aren’t reversible.
Three irreversible steps in glycolysis
Three steps which cannot be used in reverse Pyruvate kinase – last step Phosphofructokinase-1 (found everyday in
cell.) Glucokinase (lv) (Hexokinase in other cells)
By-passing these steps are unique steps to gluconeogenesis
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KNOW THIS SLIDE
GLYCOLYSIS LFT
GLUCONEO RGHT
FED STATE HERE GOES DOWN
Fasted StATE. START AT THE BOTTOM.
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*. Need 6C structures to feed in.
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Know Pyruvate Carboxylase + PEP Carboxylase. Needs Energy
Endergonic
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Glycerol goes to DHAP
Note OAA, PEP Carboxylase with Pyruvate.
Glu + Asp can get into the tCA cycle
AAs that can enter into Gluconeogenesis = Glucogenic Amino acids
Four additional enzymes involved – Unique to Gluconeogenesis
Pyruvate carboxylase Pyruvate OAA (NEEDS ATP +HCO3-)
(3C)---- (4C)
Phosphoenolpyruvate carboxykinase (PEP CK) OAA + CO2 + GTP --> PEP + GDP
Fructose 1,6 bisphosphate phosphatase (FDPase) Fructose 1,6 bisP + H2O --> Fructose 6 P + PO4
-2 - releases phosphate to circulation
Glucose 6 P Phosphatase
Unique step in Gluconeogensis
Lactate can enter here.
Asp oxaloacetate
Glu alpha KG
They feed in here.
Transaminase can swap out Carboxyl and Amino groups. Need B6 support.-”Push me pull yous” Convert aspartate into OAC, along with AlphaKG into
Pyruvate to OAA
pyruvate gets carboxylated to OAA this occurs in the mitochondria OAA is reduced to malate Malate transported out of mito into the
cytosol Malate DHase in cytosol returns malate to
OAA KNOW THAT THEre is a shutle system
involving Malate, then ENDS us as Oxaloactetate.
Cytosolic OAA (ejected OAA in to cytosol)
converted to PEP by PEP carboxykinase glycolytic enzymes then are reversed up
to PFK. (Phoshofructo kinase) See FDPase notes above Reverse steps on top half of glycolysis
except Glucokinase G6P phosphatase is by-pass for
Glucokinase
Alternative C - Sources
Reduced oxidized
DHAP – intersection of Lipid metab with CHO metab
Lactate
Converted to Pyruvate Thus lactate is a source of the starting
material for gluconeogenesis
Aspartate
Aspartate can be converted to OAA Other amino acids said to be glucogenic
give rise to intermediates in TCA or glycolytic pathways Key.
Second Example Glutamic acid or glutamate can give rise to -ketoglutarate
See hand drawing in notebook KNOW Asp w/OAA, Glutamic Acid w/-KG
Alanine
Converted to pyruvate (both have 3C, just converts the fxnal group
Follows path from pyruvate to OAA Then by-pass reaction with
decarboxylation to PEP Follows rest of gluconeogenic path
Glycerol
Glycerol derived from hydrolysis of triacylglycerol is converted in the liver to glycerol 3 P by glycerolkinase Glycerolkinase is unique, in the LV, breaks down
glycerol into Glucose and sent into Blood. Triacylglyceral from Adipose. Glycerolkinase unique to Liver
Brain + RBC uses Glucose
Glycerol 3P is converted to DHAP by glycerolphosphate dehydrogenase DiHydroxyAceytalPhosphate
Organelles involved
Mitochondria. Pyruvate has to get into the it.
Pyruvate goes through stps to get to OAA
OAA doesn’t do much good in the Mitochondria, get it out by making it into ASP, then
PEP ---- dotted lines are rest of glycolysis.
Blocks- switched off during glycolysis:
1. Pyruvate Dehydrogenase
2. Pyruvate Kinase*
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1. Trading Carboxyl groups with Amino groups = Transaminase *
Regulation
Reciprocal regulation of the opposing paths is achieved as shown on the next slide One is on, the other is off
E.g. Glycolysis vs. Gluconeogenesis
This is Good picture to know
* Only in LV
* inducible
*SER
SKIP THIS PICTURE
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UNIQUE: only Lv can let Gluc back into Hb.
2 ways to get Gluc in to Hb
1. Glycolysis
2. Gluconeogenesis
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Blood glucuse goes up after a meal then drops. dL= 1/10 of a liter
Blip of Insulin
Gluc goes up b/c need sugar
Spike in insulin
Note BIG Spikes of Insulin after meals.
Note on Zone: Sears is Endocrinologist. Concerned about spikes. Wanted spikes to be lower in insulin
High Carb
•Take Glucose and Use ATP to make Gluc-6-P. (1st step in Glycolysis).
•Note how Low the ½ saturation point on Hexokinase.
•Glucokinase – in Lv
•S0.5 = ½ way saturation pt
•Km = has to do with Concentration
•Liver designed to take up Gluc when Higher concentration = FED state
•Not hog Gluc in fasted
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Fed State
A. Insulin High
Glycogen synthesis
VLDL synthesis – Lv makes to ship FA to adipose
Resting Muscle
Transport in Glucose
Synthesis of Glycogen
Adipose cell – Fed State
FA = fatty acid
TG = triacylglycerol – (glycerol w/3 fatty acids
+ = stimulated by Insulin
Chylomicrons – fats from dietary fat
Chylomicrons too into Adip.
SKIPPED
SKIPPED
Tissue Interrelationship
FASTED. START HERE.
GLUCONEOGENESIS: All intermediates into LV
Note all fed into Gluconeogensis
•AA: Asp, Glutamate, Ala
•Lactate
•Glycerol
•FA KB (Ketonebodies) = condensed Acetyl CoA – leads to ketoacedosis
•Urea – must excrete
Fuel Usage vs. Time
Note Glucose drops in Fasting initially but statys constant
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KB goes up, can only use it with Gluc
Fed, Fasted, Starved
Cycles of GlucoseCori Cycle-gluconeogenesis
Ala Cycle (get Ala from Musc)
In Musc + Lv
Unique characteristics
Pyruvate carboxylase requires biotin as a coenzyme Converts Pyruvate to OAA
Pyruvate carboxylase is activated by acetyl coenzyme A – (Acetyl CoA I abundance during fasting) HIGH LEVELS OF ACETYLE CoA WILL
ACCELERTAE PYRUVATE CARBOXYLASE. Glycolysis and Gluconeogenesis are
reciprocally regulated
Additional Info: Syndrome X Precursor to Type 2 diabetes If someone on XS simple sugars – problems. Gluc intolerane Insulin Resistane
Syndrome X Diebetes II S/S
Frequent Urination, frequent thirst, XS hunger Unexplained weight Gain, Hard to concentrate,
drowsy, Feel tired most of timem, particularly after Lu or Din, Decrease endurance during Physical exertion
Fasting (morning) Blood glucose is ~130
Syndrome X
4 components – to Insulin Resistance High Cholestrol Obesity High Triglycerides High BP