Module 10: Carbohydrate Metabolism - Gluconeogenesis (Part 02) Flashcards
This is the synthesis of glucose from non-carbohydrate precursors.
Gluconeogenesis
Why is gluconeogenesis important?
(1) Essential for human survival
(2) Maintains blood glucose levels to support metabolism of tissues that use glucose as their primary substrate
(3) Supplies glucose after glycogen has almost been depleted
This is the main site for gluconeogenesis, it is involved in the control of systemic blood glucose.
Liver
What is the main site during fasting and starvation?
Kidneys (Renal Cortex)
How much gluconeogenesis occurs in the liver?
50%
How much percentage of newly synthesized glucose molecules does the Kidneys (Renal Cortex) provide?
10%
What are the sites for gluconeogenesis?
(1) Liver
(2) Kidneys (renal cortex(
(3) Small intestine - epithelial cells
What are the major substrates of gluconeogenesis?
(1) glucogenic AA,
(2) lactate,
(3) glycerol,
(4) fructose, and
(5) propionate
What are the major gluconeogenic tissues?
Liver and kidney
ATP required for gluconeogenesis is supplied by what?
Beta - oxidation of fatty acids
How are Gluconeogenesis & Glycolysis related?
They share 7 reversible steps and enzymes. There are 3 irreversible reactions of glycolysis bypassed by gluconeogenesis
Explain the net equation of gluconeogenesis.
The synthesis of one mol glucose from 2 moles pyruvate requires 2NADH, 4ATP, 2GTP
This is has bypass reactions that circumvent highly exergonic glycolytic processes.
Gluconeogenic pathway
What are the three (3) irreversible steps in glycolysis?
(1) Phosphorylation of glucose by hexokinase: ( glucose —> glucose-6-phosphate)
(2) 2Phosphorylation of fructose-6-phosphate by PFK (fructose-6-phosphate —-> fructose-1,6-bisphosphate)
(3) Hydrolysis of PEP to pyruvate coupled to phosphorylation of ADP to ATP by pyruvate kinase (PEP —-> pyruvate)
What happens in step 01 of gluconeogenesis?
The carboxylation of pyruvate to oxaloacetate from 3 C’s to 4 C’s/
Oxaloacetate is a what?
keto dicarboxylic acid
What is the bypass enzyme for the carboxylation of pyruvate to oxaloacetate from 3 C’s to 4 C’s?
pyruvate carboxylase
What is the location for the carboxylation of pyruvate to oxaloacetate from 3 C’s to 4 C’s?
mitochondria
What does the carboxylation of pyruvate to oxaloacetate from 3 C’s to 4 C’s need?
ATP, BIOTIN*, and CO2,. * Pyruvate carboxylase requires Acetyl CoA as positive modulator or activator
This exist in both cytosol & mitochondria and catalyzes the decarboxylation and phosphorylation of oxaloacetate to PEP with the use of GTP
PEP carboxykinase
What happens in step 02 of gluconeogenesis?
Oxaloacetate undergoes phosphorylation and carboxylation to form PEP with the use of GTP>
What are the two (2) routes by which PEP can be synthesized?
when pyruvate or lactate is the precursor
Mitochondrial membrane has no transporter for oxaloacetate; it is shuttled by ________.
malate
This is the mitochondrial1st regulatory enzyme in gluconeogenesis; requires ACETYL CoA as + allosteric effector
Pyruvate carboxylase
This could be cytosolic or mitochondrial Mg+2 dependent & requires GTP as P grp donor
PEP carboxykinase
This catalyzes the irreversible hydrolysis of C1 phosphate.
Mg2+ dependent fructose 1 biphosphatase base
Where is Fructose-1,6-bisphosphatase present?
liver, kidney, and skeletal muscle
This enzyme is located in the cytosol and dephosphorylates fructose 1,6-bisphosphate to give fructose 6-phosphate. The presence of this enzyme determines if a tissue is capable of synthesizing glucose or glycogen from triose phosphates
Fructose-1,6-bisphosphatase
Where is Fructose-1,6-bisphosphatase absent?
heart and smooth muscle
Fructose-1,6-bisphosphatase can allosterically inhibited by?
AMP
Fructose-1,6-bisphosphatase can allosterically stimulated by?
citrate
How many mole is generated from Fructose-1,6-bisphosphatase?
16.3 kJ/mol
This enzyme catalyzes the irreversible hydrolysis. It is found in the liver and kidney (lumenal side of ER).
Mg2+ activated glucose 6 phosphatase
This enzyme is located in the cytosol and dephosphorylates glucose 6-P to give glucose
glucose 6 phosphatase
Presence of this enzyme in the _________________makes gluconeogenesis possible
ER of liver and kidney cells
Glucose 6 phosphatase is found only?
Enzyme is found only in liver, kidney & small intestine
Why do muscles and brain DO NOT undergo gluconeogenesis
Muscles and brain DO NOT undergo gluconeogenesis because the enzyme is absent
How much moles is generated by glucose 6 phosphatase?
13.8 kJ/mol
This hormone is secreted in response to increased blood glucose enhances the synthesis of key enzymes in glycolysis.
Insulin
It hormones responsive to a decrease in blood glucose, inhibit glycolysis & stimulate gluconeogenesis in the liver by increasing cAMP (2o messenger).
Glucagon & Epinephrine
During the Cori Cycle, glucose in the muscle is used to form __________.
Pyruvate
During the Cori Cycle, in anaerobic metabolism, pyruvate is converted to _________.
Lactate
Explain the Cori Cycle.
(1) Lactate goes to the bloodstream then to the liver
(2) Lactate is converted to pyruvate
(3) Pyruvate is converted to glucose-6P (gluconeogenesis)
(4) Glucose-6P is hydrolyzed to glucose and released to the bloodstream then to the muscles
What is the importance of the Cori Cycle?
(1) Cori cycle prevents lactic acidosis (excessive accumulation of lactate) in muscle under anaerobic conditions.
(2) This cycle is also important for production of energy molecule (ATP) during muscle activity, as muscles get deprived of energy due to insufficient glucose.
These are are amino acids that cannot provide carbon sources for synthesis of glucose, because they will give rise to acetoacetyl CoA or acetyl CoA.
Ketogenic
Acetyl CoA is oxidized to ________in Krebs.
2CO2
These are amino acids that give rise to pyruvate or Krebs intermediates which becomes oxaloacetate which can be converted to glucose.
Glucogenic
These are reactions that lead to net synthesis of TCA cycle intermediates, reactions that will replenish Krebs intermediates.
Anaplerotic reactions
These are reactions that lead to the net synthesis of Krebs intermediates. They support gluconeogenesis because they provide for net synthesis of oxaloacetate
Anaplerotic reactions (anaplerosis)
All amino acids except______________ can provide C for net synthesis of glucose by gluconeogenesis.
Leu and Lys
End product of Lys metabolism:
Acetyl CoA
End product of Leu metabolism:
Acetoacetate and Acetyl CoA
During fasting glucose or glycogen forms pyruvate. The pyruvate undergoes transamination to alanine
Glucose-Alanine Cycle
Explain the glucose-alanine cycle
In the fasting state, alanine accumulates in the cell and the excess is transferred to the liver where it is reconverted back to pyruvate. This reformed pyruvate can therefore undergo gluconeogenesis in the liver.
When muscles degrade amino acids from proteins during starvation, what is transferred?
ammonium is generated which is transferred to pyruvate generating alanine.
What does alanine do?
(1) brings the ammonium group to the liver and converts it to urea
(2) pyruvate from alanine is used to make glucose for energy
