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. * *

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 *

KNOW THIS SLIDE GLYCOLYSIS LFT GLUCONEO RGHT FED STATE HERE GOES DOWN Fasted StATE. START AT THE BOTTOM. * *. Need 6C structures to feed in. * * * * ** * * Know Pyruvate Carboxylase + PEP Carboxylase. Needs Energy Endergonic * 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 +HCO 3 - ) (3C)----  (4C) Phosphoenolpyruvate carboxykinase (PEP CK)  OAA + CO 2 + GTP --> PEP + GDP Fructose 1,6 bisphosphate phosphatase (FDPase)  Fructose 1,6 bisP + H 2 O --> Fructose 6 P + PO 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 Reducedoxidized 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 * *

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

* UNIQUE: only Lv can let Gluc back into Hb. 2 ways to get Gluc in to Hb 1.Glycolysis 2.Gluconeogenesis * *

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. (1 st step in Glycolysis). Note how Low the ½ saturation point on Hexokinase. Glucokinase – in Lv S 0.5 = ½ way saturation pt K m = has to do with Concentration Liver designed to take up Gluc when Higher concentration = FED state Not hog Gluc in fasted *

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

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. KB goes up, can only use it with Gluc

Fed, Fasted, Starved

Cycles of Glucose Cori 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