Question

A mutation in the liver enzyme PFK-2/FBPase-2 results in the loss of cAMP-dependent kinase phosphorylation site, thus resulting in a loss of responsiveness to cAMP-dependent kinase. What are the effects of this mutation on blood glucose levels during times of fasting? Please explain your answer.

Answer 1

c-AMP when binds to regulatory site of protein kinase A, its catalytic subunit gets activated, in the active form 1) it inhibits glycogen synthesis and glycolysis. 2) It activates glycogenolysis and gluconeogenesis.

PFK-2/FBPase-2 is bifunctional enzyme. It can synthesize as well as degrade F-2,6BP.

When blood glucose level is low during fasting glucagon secreted by cells of pancreas reaches to surrounding of every cell. It binds to GPCR on liver cell and it activates enzyme adenylate cyclase. It converts ATP to c-AMP. This c-AMP binds to Protein kinase A and activated protein kinase A phosphorylates other kinases.PFK-2 is inactivated by phosphorylation so PFK-2 stops making F-2,6 Biphosphate and PFK-1 is inactivated glycolysis is stopped.Now cell is having low F2,6BP levels. So gluconeogenesis is activated.

Under mutant condition as there is loss of C-AMP dependent kinase phosphorylation site, C-AMP cannot phosphorylate it. Means PFK-2 will be in dephosphorylated form. During fasting when glucagon signalling will occur inside cell . But PFK-2 cannot be inactivated by phosphorylation due to mutation. So Gluconeogenesis will not occur. But PFK-2 is present inside cell in dephosphorylated(Active form)- there is activation of active site responsible for hydrolysis of F-2,6BP and inactivation of active site responsible for synthesis of F-2,6BP. So ultimately Glycolysis will keep on going.

Due to fasting already glucose levels are low. Due to this mutation blood glucose will be drastically low.