What are the three main precursors used in the biosynthesis of glucose?
alanine, lactate, glycerol
How is glycerol utilized in gluconeogenesis
- glycerol (which is obtained from TAG in adipose tissues) is phosphorylated into L-glycerol 3-phosphate by glycerol kinase.
- L-glycerol 3-phosphate is oxidized into dehydroxyacetone phosphate by glycerol 3-phosphate dehydrogenase.
How is alanine utilized n gluconeogenesis?
alanine is converted into pyruvate by alanine transferase
How is lactate utilized in gluconeogenesis?
lactate (produced in the muscle due to the absence of oxygen) is transported into the liver where it is converted back into pyruvate by lactate dehydrogenase.
Describe what happens in the first step of gluconeogenesis.
Pyruvate carboxylase catalyzes the addition of the carbonyl group from bicarbonate into pyruvate to form oxaloacetate. This reaction requires ATP, acetyl-CoA (as an allosteric activator), and biotin (vitamin B7).
Notice that oxaloacetate is produced in the mitochondria, but gluconeogenesis takes place in the cytosol. How is oxaloacetate transported into the cytosol and enters gluconeogenesis?
- oxaloacetate is reduced into malate driven by the oxidation of NADH into NAP+.
- Malate is transported from the mitochondria into the cytosol where is oxidized back to oxaloacetate by the coupling reduction of NAD+ into NADH.
- oxaloacetate is phosphorylated (by releasing CO2) to form phosphoenolpyruvate via phosphoenolpyruvate carboxykinase. This reaction requires GTP (not ATP).
What happens in the seven step of gluconeogenesis?
Fructose 1,6-bisphosphate is dephosphorylated by fructose 1,6-bisphosphatase (FBPase-1) to form fructose 6-phosphate. This reaction utilizes water and releases inorganic phosphate.
What happens in the last step of gluconeogenesis?
Glucose 6-phosphate is decarboxylated by glucose 6-phosphatase to form glucose. This water utilizes water which generates inorganic phosphate.
Remember that glycolysis takes place in the cytosol and while gluconeogenesis also takes place in the cytosol, the first step in which pyruvate is converted into oxaloacetate takes place in the mitochondria.
got it
What is the difference between hexokinase and glucokinase (aka hexokinase 4)?
- hexokinase is present in all cell type whereas glucokinase is only found in liver cells.
- hexokinase has high affinity and low capacity whereas glucokinase has low affinity and high capacity.
- hexokinase is inhibited by the product (remember, high concentrations of G6P inhibit hexokinase). glucokinase is not inhibited by the product.
A mutation on the regulatory protein bonded to hexokinase 4, prevent the molecule from being released even in the presence of glucose. What are the effects of this.
This means that Hexokinase 4 will not be able to phosphorylate glucose into G6P.
What activates PFK-1?
AMP, ADP and F2,6BP
What inhibits PFK-1?
ATP and citrate
What happens when AMP is activated?
It favors glycolysis in which F6P is phosphorylated into F1,6BP. At the same time, it inhibits FBPase-1 to prevent gluconeogenesis.
Suppose that we create a disrupter that expresses PFK-2 at all times. What are the implications of this?
PFK-2 phosphorylates F6P into F2,6BP to activate glycolysis. If the enzyme is constantly turned on, the cells would be depleted of glucose at some point, because we would not be able to make glucose through gluconeogenesis.
How is F2,6BP hormonally regulated in the liver?
Insulin (PP1) dephosphorylate the bifunctional enzyme to activate PFK-2 and inactivate FBPase-2 and drive glycolysis.
Glucagon (PKA) phosphorylates the bifunctional enzyme to inactivate PFK-2 and activate FBPase-2 and drive gluconeogenesis.
How is pyruvate kinase regulated in the tissues in comparison with the liver?
In all tissues (besides the liver) PK is allosterically regulated by ATP. During low levels of ATP, the enzyme is activated but inactivated during high levels of energy.
In the liver, PK is hormonally regulated by insulin and glucagon. Insulin activates PP1 which dephosphorylate and activates PK favoring glycolysis. Glucagon activates PKA which phosphorylates and inactivates PK inhibiting glycolysis
