15.

5: REGULATION OF GLUCONEOGENESIS
Within the regulation of the gluconeogenic pathway, three of the major enzymatic steps are regulated. The first two are the pyruvate
carboxykinase enzyme and the phosphoenolpyruvate carboxykinase (PEPCK). Recall that these two enzymes are required to convert
pyruvate back into phosphoenolpyruvate via an oxaloacetate intermediate as shown in Figure 15.5.1 . The third enzyme regulated in this
pathway is Fructose 1,6-Bisphosphatase which converts fructose 1,6-bisphosphate into fructose 6-phosphate. We will explore the regulation
of these three enzymes in more detail.

Figure 15.5.1: Conversion of Pyruvate to Phosphoenolpyruvate during Gluconeogenesis. Image modified from Principles of Biochemistry
(2019) Wikibooks

15.5.1: PYRUVATE CARBOXYKINASE

Pyruvatecarboxykinase is one of the primary regulation points. It is primarily regulated by two allosteric effectors, Acetyl-CoA and ADP, as
shown in Figure 15.5.2 . When pyruvate enters into the Kreb Cycle, it is first converted to Acetyl-CoA. If abundant pyruvate is present, an
ample supply of acetyl-CoA will also be available, indicating a high energy load for the cell. Acetyl-CoA, can bind with pyruvate
carboxylase and act as an activator of the protein, stimulating the production of oxaloacetate. ADP, on the other hand, is a low-energy
indicator and an inhibitor of the enzyme. In the next section, we will discover how oxaloacetate moves into the cytoplasm.

Figure 15.5.2: Allosteric Regulation of Pyruvate Carboxykinase. Figure modified from Liu, Y., et al (2018) Nat Commun 9:1384

15.5.2: PHOSPHOENOLPYRUVATE CARBOXYKINASE

Cytoplasmic PEPCK is largely regulated at the transcriptional level. Increases in gene expression are seen in response to elevated cAMP
levels, increased glucocorticoids, and increased thyroid hormone levels, as shown in Figure 15.5.3 . The activated CREB transcription factor
plays a role in this response. Alternatively, decreased gene expression is caused by insulin signaling. ADP also acts as an allosteric effector
of the protein, causing it to have lower activity. This indicates that when energy is low, the cell cannot afford to use its reserves to remake
glucose and inhibits the pathway.

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 Figure 15.5.3: Regulation of Phosphoenolpyruvate Carboxykinase at the Transcriptional and Allosteric Levels. Image from ProteinBoxBot

15.5.3: FRUCTOSE 1,6-BISPHOSPHATASE

Fructose 1,6-bisphosphatase is both competitively and allosterically regulated, as shown in Figure 15.5.4 . Fructose 2,6-bisphosphate serves
as a competitive inhibitor of the enzyme reducing the overall activity of the enzyme for fructose 1,6-bisphosphate. Competitive inhibitors
bind within the active site and compete for binding with the regular substrate. Thus, they lower the overall Km of the reaction and make the
enzyme less effective at lower substrate concentrations. However, the Vmax of the enzyme is not affected during the process.
In addition to competitive inhibition, low energy load (AMP and ADP) also inhibits the enzyme. ADP and AMP will bind allosterically
with the enzyme and inhibit its activity.

Figure 15.5.14: Regulation of Fructose 1,6-Bisphosphatase by Competitive Inhibition and Allosteric Effectors. Image from Jslipscomb

This page titled 15.5: Regulation of Gluconeogenesis is shared under a not declared license and was authored, remixed, and/or curated by Henry
Jakubowski and Patricia Flatt.

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