1. Research in cell biology and metabolism has progressed due to the discovery o
ID: 202606 • Letter: 1
Question
1. Research in cell biology and metabolism has progressed due to the discovery of molecules that artificially stimulate or inhibit glucagon/epinephrine and insulin signaling pathways. Let's say you are working in a lab cataloging the effects of a library of small molecules on these pathways and have a "hit" on molecule 1stAVNGR. Preliminary data on molecule IstAVNGR indicates that the cardiac isoform of PFK2/FBPase2 is doubly phosphorylated when this molecule is present at micromolar concentrations in cell cultures. Given this context answer the following questions.Explanation / Answer
1d) Phosphofructokinase-2 or PFK2/fructose-2,6, bisphosphatase (FBPase-2) is an enzyme that controls synthesis and degradation of fructose 2. 6-bisphosphate. Fructose-2,6 bisphosphate activates PFK-1, which is a key enzyme controlling glycolysis. Heart PFK2/FBase-2 contains a carboxy-terminal regulatory domain that can be phosphorylated on both ser466 and Ser483. Phosphorylation activates PFK-2 but has no effect of FBase-2 activity. Hence, there is formation of fructose 2, 6 bisphosphate but does not cause its degradation. Thus, glycolysis is activated but gluconeogenesis is inhibited.
When the molecule 1stAVNGR is added to a culture of cardiac myocytes, there is phosphorylation of ser466 and ser483 on PFK-2/FBase-2. This results in formation of fructose-2,6 bisphosphate that will activate PFK-1 enzyme. As a result, there will be increased glycolytic flux due to activation of glycolysis.
e) In the liver, the phosphorylation of PFK-2/FBase-2 activates FBase-2 activity but inhibits PFK2 activity. Hence, fructose 2,6 bisphosphate levels will be decreased which inhibits glycolysis. The IstAVNGR molecule phosphorylates the enzyme in the hepatocytes. Hence, FBase-2 activity is activated which causes decreased fructose 2,6 bisphosphate levels. Hence, PFK1 is inhibited thereby inhibiting glycolysis and the glycolytic flux in these cells.
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