explain the \"biochemical logic\" of the following observations re regulation of
ID: 212256 • Letter: E
Question
explain the "biochemical logic" of the following observations re regulation of fuel metabolism 3) (17pts) Succinctly (a) Citratc is a (-) allosteric effiector of phosphofructokinase-1 carboxylase (ACC) PFK-1% but is a () allosteric effector of Ac-CoA (b) 1anine is a (-) allosteric regulator of pyruvate kinase. (e) Insulin binding to liver cells upregulates ACC and PFK-2. What does coordination of these effects achieve? (d) Glucagon binding to liver cells downregulates ACC and PFK-2 in liver, while stimulating hormone-sensitive lip adipose cells. What does coordination of these effects achieve? (e) Aspartate transcarbamoylase is upregulated by ATP, but downregulated by CTPExplanation / Answer
A. Phosphofructokinase-1 (PFK-1) is a key enzyme in the glycolysis pathway that catalyzes an irreversible reaction to form fructose 1,6-bisphosphate from fructose-6-phosphate. PFK-1 is a tetrameric enzyme and exhibits two conformational states; T and R. Each subunits of PFK-1 has two binding site for ATP, one is substrate site and other is regulatory site. ATP binds to the substrate site in both the states (T and R). In the presence of excess ATP, the inhibitor site of PFK-1 is also occupied by ATP. The other substrate, fructose-6-phosphate binds to the substrate site at the R state. Therefore, excess ATP inhibits the functional activity of PFK-1. Citrate enhances the inhibitory effect of ATP, as high citrate level is an indicator of high abundance of biosynthetic precursor. Thus, citrate act as negative allosteric regulator of PFK-1. On the contrary, acetyl-CoA carboxylase (ACC) acts as rate limiting enzyme in the fatty acid biosynthesis pathway. ACC catalyzes an irreversible reaction which convert acetyl-CoA into malonyl-CoA. It is predicted that citrate may increase ACC polymerization that activates the enzymatic activity of ACC. Thus, in this case citrate acts as an allosteric activator of ACC.
B. Pyruvate kinase accomplishes the final step of glycolysis; catalyzes an important irreversible reaction that form pyruvate from phosphophenol pyruvate. Pyruvate kinase is allosterically modulated by certain regulators, such as ATP and alanine. Presence of excess ATP and alanine indicates that energy charge is high and building blocks are abundant, so that both alanine and ATP act as negative allosteric effector of pyruvate kinase.
C. ACC catalyzes the formation of malonyl-CoA from the acetyl-CoA. ACC is present in low activity dimers within cells. While cells secretes insulin, it triggers the polymerization of ACC dimers to form high activity polymers. Therefore, insulin acts as a positive regulator of ACC.
PFK-2/FBPase-2 is a crucial enzyme that regulate the balance between glycolysis and gluconeogenesis.It is a bifunctional enzyme which contains kinase domain at its N-terminal domain and phosphatase domain at its C-terminal end.Insulin activates the PFK-2 activity by activating protein phosphatase that dephosphorylates the PFK-2 complex, which favored PFK-2 activity.Activation of PFK-2 drives the glycolysis pathway by activating the PFK-1 and subsequently inhibits the gluconeogenesis pathway.Therefore, here insulin acts as positive regulator of PFK-2 activity.
D. Glucagon activates the cAMP dependent protein kinase A (PKA), which is reported to phosphorylate ACC to inhibit its lipogenic activity. Therefore, Glucagon binding inhibits the activity of ACC in liver, so that it can be concluded that Glucagon acts as a negative regulator of ACC.
Glucagon is released during fasting state, and it triggers cAMP signal cascade. This cascade reaches Protein kinase A (PKA), which phosphorylates the PFK-2 complex that deactivate the PFK-2 complex. This phosphorylation favors the FBPase-2 activity. FBPase-2 decreases the level of fructose-2,6 bisphosphate, which is allosteric activator of PFK-1. Thus glucagon binding reduces the FBPase-2 activity, so that Glucagon acts as a negative regulator of PFK-2 activity.
E. Aspartate transcarbamoylase catalyzes condensation of l-aspartate and carbamoyl phosphate to form N-carbamyl-L-aspartate and inorganic phosphate, the first step of pyrimidine biosynthesis pathway. Concentration of ATP (purines) and CTP (pyrimidine) regulate the enzymatic activity of aspartate transcarbamoylase. ATCase holoenzyme is composed of two trimers of catalytic subunits and three dimer of regulatory subunits. Catalytic subunits has two distinct domain, responsible for binding of two different substrates; aspartate and carbamoyl phosphate, while the allosteric domain of the regulatory subunits is occupied by the effector molecules, ATP, CTP and /or UTP. This enzyme exists between two states: tensed ‘T’ or less active state and relaxed ‘R’ or more active state. CTP, the end product of the pyrimidine biosynthesis pathway, act as a potent negative regulator of the ATCase. Binding of ATP to the high affinity site of the ATCase activates its enzymatic activity. However, binding of CTP at its binding site of ATCase inhibits ATCase. Binding of UTP at the allosteric site of ATCase causes increased binding affinity of ATCase to the CTP. Therefore, binding of UTP increases the inhibitory effect of ATCase upto 95%, while presence of only CTP accounts for 50% inhibitory effect of ATCase.
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