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

Gluconeogenic precursors glycolysis 1- Intermediates of glycolysis by reverse of steps of glycolysis (except 4 steps that need 4 different enzymes) citric acid cycle 2- Intermediates of citric acid cycle are converted to oxalacetate then to glucose Lactate 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) Glycerol 4- Glycerol Glycerol is derived from the lipid triacylglycerol in adipose tissue. Glycerol is converted into dihydroxyactone phosphate (intermediate of glycolysis) then to glucose. amino acids 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

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

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

Glucogenic Amino Acids Glutamate Glutamine MethionineValine PhenylalaninTyrosine Amino acids AspartateAspargine Pyruvate Glycine, Alanine Amino acids

Cori Cycle Lactate is a gluconeogenic precursor

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