By: Dr Hadi Mozafari 1
Gluconeogenesis is the process of converting noncarbohydrate precursors to glucose or glycogen. The major substrates are the glucogenic amino acids, and lactate, glycerol, and propionate. Liver (90%) and kidney (10%) are the major gluconeogenic tissues. In addition, gluconeogenesis clears lactate produced by muscle and erythrocytes and glycerol produced by adipose tissue. 2
Gluconeogenesis involves Glycolysis, the Citric Acid Cycle, plus some special reactions Thermodynamic barriers prevent a simple reversal of Glycolysis 3
Gluconeogenesis Pathway Biotin 4
At first, Mitochondrial pyruvate carboxylase catalyzes the carboxylation of pyruvate to oxaloacetate, an ATP-requiring reaction in which the vitamin biotin is the coenzyme. A second enzyme, phosphoenolpyruvate carboxykinase, catalyzes the decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate using GTP as the phosphate donor. Then, glycolysis reaction reverses until fructose 1,6- bisphosphate production. The conversion of fructose 1,6-bisphosphate to fructose 6- phosphate, for the reversal of glycolysis, is catalyzed by fructose 1,6-bisphosphatase. The conversion of glucose 6-phosphate to glucose is catalyzed by glucose 6-phosphatase. It is present in liver and kidney, but absent from muscle and adipose tissue, which therefore, cannot export glucose into the bloodstream. 5
GLUCOSE G-6-Pase GK G-6-P Gluconeogenesis F-6-P Glycolysis FBPase 1 PFK 1 F-1,6-P 2 Increase Hepatic Glucose production Increase Hepatic Glucose Utilization P-ENOLPYRUVATE PEPCK PK OXALOACETATE PYRUVATE 6
Gluconeogenesis substrate entrance 7
Propionate esterify with CoA, propionylcoa is carboxylated to D-methylmalonylCoA, catalyzed by propionylcoa carboxylase, a biotin-dependent enzyme. MethylmalonylCoA racemase catalyzes the conversion of D-methylmalonylCoA to L-methylmalonylCoA. Then undergoes isomerization to succinylcoa catalyzed by methylmalonyl-coa isomerase. In humans, propionate arises from the oxidation of odd chain fatty acids that occur in ruminant lipids, oxidation of isoleucine and the side-chain of cholesterol, and is a (relatively minor) substrate for gluconeogenesis. Methylmalonyl CoA mutase is a vitamin B 12 dependent enzyme, and in deficiency methylmalonic acid is excreted in the urine (methylmalonicaciduria). 8
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The most potent positive allosteric activator of phosphofructokinase-1 and inhibitor of fructose 1,6-bisphosphatase in liver is fructose 2,6-bisphosphate. It inhibits fructose 1,6- bisphosphatase. Fructose 2,6-bisphosphate is formed by phosphorylation of fructose 6-phosphate by phosphofructokinase-2. The same enzyme protein is also responsible for its breakdown, since it has fructose 2,6-bisphosphatase activity. This bifunctional enzyme is under the allosteric control of fructose 6-phosphate, which stimulates the kinase and inhibits the phosphatase. 11
lactate, formed by glycolysis in skeletal muscle and erythrocytes, is transported to the liver and kidney where it reforms glucose, which again becomes available via the circulation for oxidation in the tissues. This process is known as the Cori cycle, or the lactic acid cycle 12
Liver cells are freely permeable to glucose (via the GLUT 2 transporter), whereas cells of extrahepatic tissues (apart from pancreatic -islets) are relatively impermeable, and their glucose transporters are regulated by insulin. The role of various glucose transporter proteins found in cell membranes is shown in Table. 13
Epinephrine and norepinephrine block the release of insulin. Glucagon opposes the actions of Insulin. In the liver it stimulates glycogenolysis by activating phosphorylase. Glucagon also enhances gluconeogenesis from amino acids and lactate. In all these actions, glucagon acts via generation of camp(hyperglycemic effect ) 14
Fructose 2,6-bisphosphatase deficiency led to Lactic acidosis & Hypoglycemia. Hypoglycemia May Occur during Pregnancy & in the Neonates. Glucose tolerance is the ability to regulate the blood glucose concentration after the administration of a test dose of glucose (normally 1 g/kg body weight). This test is disturbed in Diabetes type I & II, liver damage, infection, metabolic syndrome, hyperactivity of the pituitary or adrenal cortex. 15
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