Gluconeogenesis

INTRODUCTION:
  • The synthesis of glucose from non-carbohydrate compounds is known as gluconeogenesis.
  • The major substrates/precursors for gluconeogenesis:v Lactate, pyruvate, glucogenic amino acids, propianate and glycerol.
  • Tyrosine enters gluconeogenesis by forming Fumarate substrate
IMPORTANCE:
  • Brain & CNS, erythrocytes, testes & kidney medulla are dependent on glucose for continuous supply for energy.
  • Human brain alone requires about 120 g of glucose per day, out of about 160 g needed by the entire body.
  • Glucose is the only source that supplies to the skeletal muscle, anaerobic conditions
  • During starvation gluconeogenesis maintains the blood glucose level.
  • During prolonged starvation, the rate of gluconeogenesis depends on Increased alanine levels in liver
  • Major contribution towards gluconeogenesis is by alanine
  • The stored glycogen is depleted within the first 12-18 hours of fasting.
  • After 50 gm of glucose is feed orally Decreased gluconeogenesis
  • In well fed state gluconeogenesis in liver is inhibited by ADP level
  • On prolonged starvation, the gluconeogenesis is speeded up & protein catabolism provides the substrates, namely glucogenic amino acids.
REACTIONS:
  • Gluconeogenesis closely resembles the reversed pathway of glycolysis.
  • During gluconeogenesis reducing equivalents from mitochondria to cytosol are transported by Malate
  • Lactate and alanine can both serve as substrates causing hyperglycemia in diabetes
  • The 3 irreversible steps of glycolysis are catalysed by the 3 enzymes.
  1. Hexokinase
  2. PFK
  3. Pyruvate kinase
  • These three stages by passed by alternate enzymes specific to gluconeogenesis.
  • These are:
  1. Pyruvate carboxylase:Gluconeogenesis in Fasting state is indicated by Pyruvate Carboxylase activation by Acetyl CoA
  2. Phosphoenol pyruvate carboxy kinase
  3. Fructose-1-6-bisphosphatase:Fructose-1,6-bisphosphatase and pyruvate carboxylase pairs of enzymes is required for the process of gluconeogenesis
  4. Glucose-6-phosphatase


Gluconeogenesis Enzymes
  • The enzymes that are same as that of glycolysis are
  1. Phosphoglucoisomerase
  2. Enolasev Phosphoglycerate mutase
  3. Phosphoglycerate kinase
  4. G3P dehydrogenase
  5. Triosephosphate isomerase
  6. Fructose 1,6 bisphosphate aldolase:Aldolase is the glycolytic enzyme used in gluconeogenesis
  • The key enzymes of Gluconeogenesis are
  1. Pyruvate carboxylase:Biotin is the cofactor of pyruvate carboxylase. The carboxylation of pyruvate occurs in the mitochondria whereas the other reactions of gluconeogenesis occur in the cytosol. Glucagon stimulates gluconeogenesis. Lactate is not an intermediate in the conversion of pyruvate to glucose.
  2. Phosphoenol pyruvate carboxykinase
  3. Fructose 1,6 bisphosphatase
  4. Glucose 6 phosphatase:Muscle cannot take part in gluconeogenesis due to absence of Glucose 6 phosphatase
Gluconeogenesis Regulation:
  • There are 3 types of regulation which takes place at different speed. They are
1. Change in the rate of enzyme synthesis – occurs over several hours
  • Availability of substrate –
  • Increased availability of Glucogenic amino acid like Alanine released from muscle stimulates Gluconeogenesis.
  • High glucose increases the synthesis of enzymes of Glycolysis so that the glucose level is brought down.
  1. The synthesis of gluconeogenic enzymes are decreased so that there is less formation of new glucose.
  2. Through hormones – 

  • Gluconeogenesis is increased by the Glucogenic hormones like glucagon, epinephrine and glucocorticoids.v Glucagon stimulates phosphoenolpyruvate carboxykinase while insulin reduces the synthesis of these enzymes.
2. Covalent modification by reversible phosphorylation – rapid
  • Phosphorylation is the process of addition of a phosphate group to an enzyme. On phosphorylation, some enzymes are activated while some are inactivated. The gluconeogenic hormones like glucagon and epinephrine leads to the phosphorylation of a key enzyme of glucose breakdown, pyruvate kinase which gets inactivated.
  • This leads to inhibition of glycolysis and stimulation of Gluconeogenesis. This type of regulation acts as a rapid response to the presence of low glucose
3. Allosteric modification – instantaneous
  • In addition to the enzymes that speeds up a reaction, other substances called allosteric activators further increase the rate of reaction. Acetyl coA is one such allosteric activator.

Exam Question
  • During gluconeogenesis reducing equivalents from mitochondria to cytosol are transported by Malate
  • Lactate and alanine can both serve as substrates causing hyperglycemia in diabetes
  • Aldolase is the glycolytic enzyme used in gluconeogenesis
  • Muscle cannot take part in gluconeogenesis due to absence of Glucose 6 phosphatase
  • Hormone that stimulates gluconeogenesis is Epinephrine
  • Gluconeogenesis is important in maintaining blood glucose during the normal overnight fast
  • The synthesis of glucose from pyruvate by gluconeogenesis Requires the participation of biotin
  • Fructose-1,6-bisphosphatase and pyruvate carboxylase pairs of enzymes is required for the process of gluconeogenesis
  • Alanine released from muscles is an important substrate for gluconeogenesis
  • During prolonged starvation, the rate of gluconeogenesis depends on Increased alanine levels in liver
  • Major contribution towards gluconeogenesis is by alanine
  • Lactate, pyruvate, glucogenic amino acids, propianate and glycerol are the precursors of gluconeogenesis
  • In well fed state gluconeogenesis in liver is inhibited by ADP level
  • Gluconeogenesis in Fasting state is indicated by Pyruvate Carboxylase activation by Acetyl CoA
  • After 50 gm of glucose is feed orally Decreased gluconeogenesis
  • Phosphohexose isomerase, Aldolase,Phosphotriose isomerase,Glyceraldehyde 3-phosphate dehydrogenase,Phosphoglycerate kinase,Phosphoglycerate mutase,Enolase are the common enzymes of gluconeogenesis & glycolysis
  • Tyrosine enters gluconeogenesis by forming Fumarate substrate

Don't Forget to Solve all the previous Year Question asked on Gluconeogenesis