The precursors to gluconeogenesis including acetyl Co -A and pyruvate can act as

Question

The precursors to gluconeogenesis including acetyl Co -A and pyruvate can act as allosteric effect s modulate the activity of PK, PEPCK, and pyruvate carboxylase. Describe the metabolic effects and the impact on a whole animal if the following mutations were present in the liver isoforms of the enzymes listed below. a. The allosteric binding site for alanine on pyruvate kinase is mutated, decreasing affinity for alanine. b. The regulatory phosphorylation site on pyruvate kinase is eliminated through a single amino acid mutation. c. The allosteric binding site for acetyl-CoA on pyruvate carboxylase is mutated, decreasing affinity for acetyl-CoA. d. The pyruvate carboxylase gene is mutated resulting in an enzyme that is catalytically inactive. (HINT: Is there another cellular source of OAA?) The PEPCK gene is mutated resulting in an enzyme that is catalytically inactive.

Explanation / Answer

a.) The pyruvate kinase isozyme has decreased affinity for PEP when allosterically inhibited by alanine. When the alanine binding site is getting mutated and the enzyme is showing less affinity for alanine thenn it will show increased affinity for PEP. So regulation of glycolysis at this step will not be possible and no allosteric inhibition of Pyruvate kinase will take place.

b.) If the regulatory phosphorylation site on pyruvate kinase was eliminated bi single point mutation then it will affect the enzyme's activity by decreasing the effectiveness of phosphoenolpyruvate binding (PEP) with the enzyme as phosphorylation of serine residue increases it's affinity for PE. Although there will be no influence on the binding effectiveness of the ADP.

c.)  The activation of pyruvate carboxylase by acetyl Co A is a cooperative processes. Acetyl CoA activates pyruvate carboxylase enzyme by biotin carboxylation and ATP cleavage. So in this way it enhances the rate of reaction and the binding of some substrates (HCO3?). So any mutation at this site will inhibit the process of biotin carboxylation and ATP cleavage leading decreased efficiency for HCO3-. Thus the process of gyconeogenesis will be affected.

d.) If the gene of pyruvate carboxylase is mutated then there will be no conversion of pyruvate to oxaloacetate. But there are other sources of oxaloacetate in the cell, as it is also produced during kreb cycle from malate.

e.) If PEPCK gene is mutated then the conversion of oxaloacetate to phosphoenol pyruvate will inhibited and so gyconeogenesis will not take place.

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