Introduction of Glucose Metabolism Lecture4 GLUCONEOGENESIS GLUCONEOGENESIS Gluconeogenesis

Introduction of Glucose Metabolism Lecture-4 GLUCONEOGENESIS

GLUCONEOGENESIS Gluconeogenesis is the synthesis of glucose from glucogenic precursors which are not of carbohydrate origin (gluconeogenic precursors) It occurs during prolonged fasting to synthesize glucose for tissues requiring continuous supply of glucose as a source of energy: Brain, RBCs, Kidney medulla, Lens, Cornea, Testes, sk. ms Gluconeogenesis occurs ONLY in the liver & kidneys

Gluconeogenesis: An Overview • Both mitochondria and Cytosol Exception: Glycerol, only cytosol • Gluconeogenic substrates: Glycerol Lactate and Pyruvate Glucogenic amino acids

Gluconeogenesis Pathway Dephosphorylation of G-6 -P Dephosphorylation of F 1, 6 -P Transport of OAA Carboxylation of pyruvate

Gluconeogenic precursors 1 - Intermediates of glycolysis by reverse of steps of glycolysis (except 4 steps that need 4 different enzymes) 2 - Intermediates of citric acid cycle are converted to oxalacetate then to glucose 3 - Lactate Lactic acid formed of anaerobic glycolysis in cells as RBCs & skeletal muscles are transported in blood to liver to be converted to pyruvate then to glucose (Cori cycle) 4 - Glycerol is derived from the lipid triacylglycerol in adipose tissue. Glycerol is converted into dihydroxyacetone phosphate (intermediate of glycolysis) then to glucose. 5 - Glucogenic amino acids of proteins Glucogenic amino acids are deaminated to form a-ketoacids a-keto acids are converted to pyruvate or intermediates of citric acid cycle then to glucose

Precursors of Gluconeogenesis Oxalacetate Intermediate of CITRIC ACID CYCLE GLUCOSE Triacylglycerol in adipose tissue Fatty acids Gluconeogenesis Glycerol Pyruvate Lactate Glucogenic amino acids in proteins as sk. ms.

Glycerol as a gluconeogenic Substrate Glycerol Kinase ATP Glycerol 3 -phosphate ADP NAD+ Glycerol 3 -phosphate dehydrogenase Glucose NADH Dihydroxyacetone phosphate GK: Glycerol kinase only in liver & kidneys

Glucogenic Amino Acids Pyruvate Aspartate Aspargine Phenylalanine Tyrosine Amino acids Glycine, Alanine Glutamate Glutamine Methionine Valine

Cori Cycle Lactate is a gluconeogenic precursor

Gluconeogenesis Pathway Dephosphorylation of G-6 -P Dephosphorylation of F 1, 6 -P Transport of OAA Carboxylation of pyruvate

Pruvate Carboxylase and PEP-CK Pyruvate carboxylase + PEP-CK = Pyruvate kinase

Fructose 1, 6 -Bisphosphatase Fructose 1, 6 -bisphosphatase = PFK-1

Glucose 6 -Phosphatase Glucose 6 -phosphatase = Glucokinase

Gluconeogensis: EConsumed Six High-Energy Phosphate Bonds From Pyruvate to Glucose 2 ADP 2 ATP

Gluconeogenesis: Regulation • Reciprocal control Gluconeogenesis & Glycolysis • Allosteric: Acetyl Co. A (Pyruvate carboxylase) Glucagon (I/G ratio) Induction (PEP-CK)

Unique enzymes of gluconeogenesis Reactions 1, 2, 3 & 4 are catalyzed by enzymes NOT used in glycolysis GLUCOSE 1 - Pyruvate to oxalacatate by pyruvate carboxylase 2 - oxalacetate to phosphoenol pyruvate by PEP carboxykinase 3 - Fructose 1, 6 bisphosphate to fructose 6 phosphate by fructose 1, 6 bisphosphatase 4 - Glucose 6 -phosphate to glucose by glucose 6 -phosphatase Other reactions of gluconeogenesis are catalyzed by same enzymes of glycolysis in the reverse direction GLUCONEOGENESIS