Dr.S.Chakravarty MD. Gluconeogenesis is the process of synthesizing glucose or glycogen from...
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Transcript of Dr.S.Chakravarty MD. Gluconeogenesis is the process of synthesizing glucose or glycogen from...
GluconeogenesisDr.S.Chakravarty MD
Maintenance of blood glucose during various states
Gluconeogenesis is the process of synthesizing glucose or glycogen from non-carbohydrate precursors.
Biomedical Importance• Gluconeogenesis meets the needs of the body for glucose when insufficient carbohydrate is
available from the diet or glycogen reserves.
• A supply of glucose is necessary especially for the nervous system and erythrocytes.
• Glucose is also important in maintaining the level of intermediates of the citric acid cycle even when fatty acids are the main source of acetyl-CoA in the tissues.
• Gluconeogenesis clears lactate produced by muscle and erythrocytes and glycerol produced by adipose tissue.
• In ruminants, propionate is a product of rumen metabolism of carbohydrates, and is a major substrate for gluconeogenesis.
• Failure of gluconeogenesis is usually fatal. Hypoglycemia causes brain dysfunction, which can lead to coma and death.
• Tissues :- Liver and Kidney are the major gluconeogenic tissues, but the small intestine may also be a source of glucose in the fasting state.
• Subcellular site :- Partly mitochondrial and partly cytosolic.
Substrates for Gluconeogenesis
LactateGlucogenic amino acids
GlycerolPropionate
Glucogenic amino acids
α-ketoglutarate Glutamate
Alanine Pyruvate
α-ketoglutarate Glutamate
Aspartate Oxaloacetate
Alanine transaminase (ALT)
Aspartate transaminase (ALT)
Entry points of Glucogenic amino acids
Lactate
NAD+ NADH + H+
Lactate Pyruvate Lactate Dehydrogenase (LDH)
USMLE!
Remember :-Conversion of Lactate to pyruvate requires NAD and not NADH
Glycerol
ATP ADP
Glycerol Glycerol 3 –P
This enzyme is absent in adipose tissue .
Glycerol kinase
Conversion of Glycerol to Glucose:Triglycerides
Glycerol Fatty acids Beta oxidation
Acetyl Co-A
Liver
Glycerol 3- PO4
Dihydroxyacetone phosphate
Glycerol kinase
Glycerol-3-po4 dehydrogenase
NAD+
NADH
FASTING OR LOW GLUCOSE
Propionate – From oxidation of odd chain fatty acids
The pathway
• Thermodynamic Barriers Prevent a Simple Reversal of Glycolysis.
• Three nonequilibrium reactions in glycolysis catalyzed by hexokinase, phosphofructokinase and pyruvate kinase, prevent simple reversal of glycolysis for glucose synthesis.
Pyruvate
Oxaloacetate
Phosphoenol pyruvate
ATP
GTP
ADP
GDP
Pyruvate carboxylase
Phosphoenolpyruvate carboxykinase
Energy derived from fatty acid oxidation
GTP derived from succinate thoikinase
Step 1:
(Mitochondria)
(cytosol)
CO2
CO2
Problem --Mitochondrial membrane is impermeable to OAA!!
USMLE CONCEPT!!!
ABC carboxylase
BIOTIN
Oxaloacetate formed in the mitochondria enters cytosol through Malate
Oxaloacetate
Malate
Malate
Oxaloacetate
Mitochondria
cytosol
Malate dehydrogenase
Malate dehydrogenase
NAD
NADH
NAD
NADH
The next few steps are reversal of Glycolysis till Fructose 1,6 bisphosphate is formed.
Fructose -6-PO4
Fructose 1,6 Bisphosphate
PFK -1 Fructose 1,6 bisphosphatase
ADP, AMP
(+)
ATP
(-)
Fructose 2,6 Bisphosphate
(+)
Fructose 2,6 Bisphosphate
Step 2: Conversion of fructose 1,6 bisphosphate to fructose 6-PO-4
(+)
GluconeogenesisGlycolysis
Glucose
Pyruvate
Step 3: Conversion to Glucose
Glucose
Glucose-6-po4
Glucose-6-phosphatase
Glucokinase
Glycolysis Gluconeogenesis
ATP
ADP
PO4
1.Pyruvate & Phosphoenolpyruvate
Fructose 1,6-Bisphosphate & Fructose 6-Phosphate
Glucose 6-Phosphate & Glucose& Glucose to glycogen(not shown)
G L U C O N E O G E N E S I S
Regulation
• Glycolysis and Gluconeogenesis are regulated reciprocally.
Regulation
Induction /Repression
Covalent modification
Allosteric
• Induction & Repression of Key Enzymes Requires Several Hours.
Table 20.1
Harper 29th page 190
Covalent Modification by Reversible Phosphorylation Is Rapid
Glucagon and epinephrine inhibit glycolysis and stimulate gluconeogenesis in the liver by increasing the concentration of cAMP.
cAMP cAMP-dependent protein kinase
phosphorylation and inactivation of pyruvate kinase.
They also affect the concentration of fructose 2,6-bisphosphate which is the most potent positive allosteric effector of of Phosphofructokinase -1 and inhibitor of Fructose 1,6 bisphosphatase .
Fructose -6-po4
Fructose -1,6- Bisphosphate
Fructose -2,6- Bisphosphate
PFK-1
PFK-2
Insulin
Glucagon
Regulation of PFK -1 :
USMLE concept!!!
Allosteric Regulation is Instantaneous !!
Pyruvate
Acetyl Co-AOxaloacetate
Pyruvate dehydrogenase
Pyruvate Carboxylase
(-)(+)
Acetyl Co-A is the allosteric activator of pyruvate carboxylase
What is the source of acetyl Co-A during starvation ?
Glucagon (+) Source of pyruvate ?
= allosteric regulation
Allosteric Modification Is Instantaneous
• Acetyl -CoA as an is an allosteric activator of Pyruvate carboxylase.
• Phosphofructokinase (phosphofructokinase-1 )is inhibited by
citrate and by normal intracellular concentrations of ATP and is activated by 5'AMP. (5'AMP acts as an indicator of the energy status of the cell. )
– When ATP is used AMP increases sensitive signal for energy state of the cell.
ATP ADP
A B
Pi H20
NET FLUX OF B = 0 +heat
Substrate cycles allow fine tuning , rapid response & generate heat
At rest the activity of PFK IS 10x greater than F1,6BPhosphatase .During Muscle contraction , PFK activity increases and F1,6BPhosphatase falls so that rate of Glycolysis becomes 1000 fold higher than resting state.
Futile cycle may occur physiologically for generation of heat.It takes place to a great extent in animals undergoing arousal from hibernation, when body temp is much lower .
100
100
120
80
40
Other factors that favor AB
Clinical aspects 1. Pyruvate carboxylase deficiency (A.R)- 1 in 25,000 births –characterized
by Hypoglycemia , lactic acidosis and Mental retardation .
2. Fructose 1,6bisphosphatase deficiency – lactic acidosis and hypoglycemia .Treatment – feed high carb. Diets and avoidance of fasting .
3. Hypoglycemia during pregnancy and in neonates – Increased risk of maternal hypoglycemia if there are long intervals b/w meals .
Premature babies are more susceptible to hypoglycemia. They have immmature non functional enzymes for gluconeogenesis and low adipose tissue mass.
Pyruvate carboxylase deficiency:
• Malfunctioning of citric acid cycle – def of oxaloacetate
• Malfunctioning of gluconeogenesis – def of oxaloacetate - Hypoglycemia
• Malfunctioning of urea cycle – Def of Aspartate• Acetyl Co-A forms ketone bodies-KETOGENESIS
ALCOHOL DEHYDROGENASE
• Alcohol Acetaldehyde Acetate
• Excess NADH – EXCESS LACTATE from PYRUVATE – Excess Malate FROM OAA– Excess Glycerol 3 P from DHAP– No or less Gluconeogenesis!!Hypoglycemia
NAD NADH NAD NADH
• Immediately after completing a 25-mile marathon race, a healthy 24-yr old man was extremely dehydrated and thirsty. He quickly consumed a 6-pack of ice-cold beer and shortly thereafter became very weak and light-headed and nearly fainted. He complained of muscle cramping and pain. What is the most probable cause ?
1. Excess lactate in blood2. Excess Alcohol in blood 3. Excess NADH 4. Dehydration5. Electrolyte imbalance
• Which of the following enzymes can be induced genetically by hormones in a person with prolonged history of fasting?
A. Glucokinase B. Pyruvate Carboxylase C. PFK-1D. Acetyl co-A Carboxylase E. Phosphofructokinase
• In the citric acid cycle, succinate thiokinase catalyzes the cleavage of the succinyl –Co-A to succinate with formation of a high energy compound. This compound can then be used by the body in which of the following biochemical pathways?
– Oxidative phosphorylation– Gluconeogenesis– Formation of creatine phosphate– Cholesterol synthesis– Fatty acid synthesis
Thank you