15.5: Regulation of Gluconeogenesis
- Page ID
- 91312
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\(\newcommand{\avec}{\mathbf a}\) \(\newcommand{\bvec}{\mathbf b}\) \(\newcommand{\cvec}{\mathbf c}\) \(\newcommand{\dvec}{\mathbf d}\) \(\newcommand{\dtil}{\widetilde{\mathbf d}}\) \(\newcommand{\evec}{\mathbf e}\) \(\newcommand{\fvec}{\mathbf f}\) \(\newcommand{\nvec}{\mathbf n}\) \(\newcommand{\pvec}{\mathbf p}\) \(\newcommand{\qvec}{\mathbf q}\) \(\newcommand{\svec}{\mathbf s}\) \(\newcommand{\tvec}{\mathbf t}\) \(\newcommand{\uvec}{\mathbf u}\) \(\newcommand{\vvec}{\mathbf v}\) \(\newcommand{\wvec}{\mathbf w}\) \(\newcommand{\xvec}{\mathbf x}\) \(\newcommand{\yvec}{\mathbf y}\) \(\newcommand{\zvec}{\mathbf z}\) \(\newcommand{\rvec}{\mathbf r}\) \(\newcommand{\mvec}{\mathbf m}\) \(\newcommand{\zerovec}{\mathbf 0}\) \(\newcommand{\onevec}{\mathbf 1}\) \(\newcommand{\real}{\mathbb R}\) \(\newcommand{\twovec}[2]{\left[\begin{array}{r}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\ctwovec}[2]{\left[\begin{array}{c}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\threevec}[3]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\cthreevec}[3]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\fourvec}[4]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\cfourvec}[4]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\fivevec}[5]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\cfivevec}[5]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\mattwo}[4]{\left[\begin{array}{rr}#1 \amp #2 \\ #3 \amp #4 \\ \end{array}\right]}\) \(\newcommand{\laspan}[1]{\text{Span}\{#1\}}\) \(\newcommand{\bcal}{\cal B}\) \(\newcommand{\ccal}{\cal C}\) \(\newcommand{\scal}{\cal S}\) \(\newcommand{\wcal}{\cal W}\) \(\newcommand{\ecal}{\cal E}\) \(\newcommand{\coords}[2]{\left\{#1\right\}_{#2}}\) \(\newcommand{\gray}[1]{\color{gray}{#1}}\) \(\newcommand{\lgray}[1]{\color{lightgray}{#1}}\) \(\newcommand{\rank}{\operatorname{rank}}\) \(\newcommand{\row}{\text{Row}}\) \(\newcommand{\col}{\text{Col}}\) \(\renewcommand{\row}{\text{Row}}\) \(\newcommand{\nul}{\text{Nul}}\) \(\newcommand{\var}{\text{Var}}\) \(\newcommand{\corr}{\text{corr}}\) \(\newcommand{\len}[1]{\left|#1\right|}\) \(\newcommand{\bbar}{\overline{\bvec}}\) \(\newcommand{\bhat}{\widehat{\bvec}}\) \(\newcommand{\bperp}{\bvec^\perp}\) \(\newcommand{\xhat}{\widehat{\xvec}}\) \(\newcommand{\vhat}{\widehat{\vvec}}\) \(\newcommand{\uhat}{\widehat{\uvec}}\) \(\newcommand{\what}{\widehat{\wvec}}\) \(\newcommand{\Sighat}{\widehat{\Sigma}}\) \(\newcommand{\lt}{<}\) \(\newcommand{\gt}{>}\) \(\newcommand{\amp}{&}\) \(\definecolor{fillinmathshade}{gray}{0.9}\)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 \(\PageIndex{1}\). 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 \(\PageIndex{1}\): Conversion of Pyruvate to Phosphoenolpyruvate during Gluconeogenesis. Image modified from Principles of Biochemistry (2019) Wikibooks
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 \(\PageIndex{2}\). 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 \(\PageIndex{2}\): Allosteric Regulation of Pyruvate Carboxykinase. Figure modified from Liu, Y., et al (2018) Nat Commun 9:1384
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 \(\PageIndex{3}\). 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.
Figure \(\PageIndex{3}\): Regulation of Phosphoenolpyruvate Carboxykinase at the Transcriptional and Allosteric Levels. Image from ProteinBoxBot
Fructose 1,6-Bisphosphatase
Fructose 1,6-bisphosphatase is both competitively and allosterically regulated, as shown in Figure \(\PageIndex{4}\). 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 \(\PageIndex{14}\): Regulation of Fructose 1,6-Bisphosphatase by Competitive Inhibition and Allosteric Effectors. Image from Jslipscomb