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 +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*

*

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. (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

*

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

.

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