Gluconeogenesis

• pH is not a metabolic signal in the liver because it does not produce lactic acid
• The formed Citrate is an inhibitor of phosphofructokinase as the metabolite produced from the substrate is already enough
• Fructose 2,6 bisphosphate is formed from a deviation in glycolysis
• Fructose 1,6 bisphosphate stimulates forward to pyruvate by keeping the PK in pace with PFK to prevent any buildup
• In the liver, high concentration of fructose 6 phosphate activates phosphofructokinase through an intermediary fructose 2, 6 bisphosphate
• PFK has a tight and relaxed conformation, and ATP is both an inhibitor and a substrate
• ATP as a substrate favors T and R conformation, while ATP as an inhibitor favors T conformation
• Fructose 2,6 Bisphosphate is formed by phosphorylating with PFK 2 from Fructose 6 phosphate
• Fructose 2,6 Bisphosphate releases its phosphate with the enzyme Fructose 2,6 Bisphosphatase to produce Fructose 6 Phosphate
• Fructose 2,6 Bisphosphate is an allosteric effector which activates PFK 1 to shift conformational equilibrium to the R state
• In the liver, hexokinase has another isozyme called glucokinase which is not inhibited by glucose 6 phosphate
• Glucokinase has a high Km value and a low affinity of glucose
• Glucokinase can phosphorylate glucose if the concentration of glucose in blood is high
• The low affinity of glucokinase allows brain, muscle and RBC to call glucose, without wasting any energy
• Pyruvate kinase has The liver and muscle isozymic forms
• The Liver enzyme behave much like the muscle enzyme
• In the pyruvate, the L form is controlled by covalent modification through phosphorylation
• Glucagon is released when the blood glucose is low, activating the phosphatase function of PFK 2 reducing level of F2,6 Bisphoshate in the cell decreasing PFK 1
• Insulin is released when blood glucose are high. Activates the kinase function of PFK 2, increasing the fructose 2,6 bisphosphate in the cell thereby activating PFK 1
• Gluconeogenesis is an important pathway during a longer period of starvation
• The substrates for gluconeogenesis include Lactate, Glycerol, and Alanine
• Lactate is released by the skeletal muscle from the Cori cycle. Liver lactate It is converted with lactate dehydrogenase requiring NAD+ and becomes pyruvate and NADH
• Glycerol can be converted to Dihydroxyacetone phosphate which can enter into gluconeogenesis
• Pyruvate is the deaminated form of Alanine
• Alanine is generated from pyruvate in exercising muscle, Alanine is converted to pyruvate and then glucose in the liver
• Oxidation of Glycerol 3 phosphate to form Dihydroxyacetone phosphate occurs when cytoplasm NAD+ concentration is high
• Large amounts of pyruvate is produced at exercising muscles, with glutamate and the enzyme alanine transaminase, it is converted to alanine and alpha ketoglutarate
• Noncarbohydrate precursors are converted to Pyruvate or enter glycolysis at a later intermediate of like oxaoacetate or DHAP
• Aspartic acid and NAD+ when deaminated with Aspartate dehydrogenase becomes oxaloacetate and NADH
• Glutamate with NAD+ when trans aminated with glutamate dehydrogenase becomes alpha ketoglutarate and NADH
• Fructose bisphosphatase and Glucose 6 phosphatase releases the energy of inorganic phosphate, an irreversible process
• Gluconeogenesis in the liver and kidney maintain glucose in the blood so that the brain and muscle can extract sufficient glucose to meet their metabolic demands
• Lactate, Pyruvate, citric acid cycle intermediate such as oxaloacetate, and carbon skeletons of most amino acids
• The three high energy compounds or the irreversible reactions in glycolysis are bypassed by gluconeogenesis to be spontaneous
• The three high energy compounds are Fructose 1,6 Bisphosphate, Glucose 6 Phosphate, and Pyruvate
• The first step is in the mitochondria, where pyruvate is carboxylated with ATP and carbonic acid with the enzyme pyruvate carboxylase yielding Oxaloacetate, inorganic phosphate and ADP
• There are 2 generated pyruvate, which needs 2 ATP
• Oxaloacetate must be migrated to the cytosol for the reaction to proceed
• In reaction 2, oxaloacetate used guanosine triphosphate (GTP) as a source of phosphate group with the enzyme PEP carboxykinase by decarboxylation and phosphorylation to yield Phosphoenol pyruvate, GDP and CO2
• The GTP that is used by PEPCK is provided by Succinyl CoA synthetase, an enzyme linked the citric acid cycle