Biochem 11.2 Gluconeogenesis Overview

The conversion of pyruvate to lactate in oxygen-poor environments, allowing for ATP production without oxygen.

The breakdown of lactate back into pyruvate in oxygen-rich environments, allowing it to be used for gluconeogenesis.

Direct conversion of substrates to oxaloacetate, bypassing the pyruvate carboxylase step and saving ATP.

The process of synthesizing glucose from non-carbohydrate sources.

A four-carbon molecule that is a key intermediate in both gluconeogenesis and the citric acid cycle.

A cytosolic enzyme responsible for converting oxaloacetate to phosphoenolpyruvate (PEP) in gluconeogenesis.

The movement of malate across the mitochondrial membrane, allowing for the transfer of NADH from the mitochondria to the cytosol.

The oxidation of lactate to pyruvate, directly producing cytosolic NADH, eliminating the need for the malate shuttle.

Bypass reactions are unique to gluconeogenesis, bypassing irreversible steps of glycolysis. These reactions convert pyruvate to phosphoenolpyruvate (PEP) and fructose 1,6-bisphosphate to fructose 6-phosphate.

Two sets of bypass reactions are needed for gluconeogenesis because two irreversible reactions occur in glycolysis: pyruvate kinase and phosphofructokinase-1. These reactions are replaced with different enzymes.

Gluconeogenesis uses mostly the same enzymes as glycolysis, but for reversible reactions only. These shared enzymes operate in either direction based on the concentration of reactants and products.

The net effect of a futile cycle is just ATP hydrolysis without net change in metabolites. In glycolysis and gluconeogenesis, this happens when both pathways run simultaneously. This wastes energy.

To prevent wasteful ATP hydrolysis, the irreversible enzymes in glycolysis and gluconeogenesis are finely regulated. This ensures that only one pathway is active at a time, preventing a futile cycle.

The enzyme catalyzing the bypass of phosphofructokinase-1 in gluconeogenesis. It catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate, a step that releases energy instead of consuming it.

The regulation of metabolic pathways by feedback inhibition. This occurs when the product of a pathway inhibits an enzyme involved in its own synthesis, thus slowing down the pathway.

The irreversible enzymes in a metabolic pathway are often key points for regulation, as their activity affects the overall rate of the pathway.

The liver's ability to sense blood glucose levels and adjust its metabolism accordingly, largely due to the presence of glucokinase, an unregulated hexokinase isoform.

The overall rate of a metabolic pathway, reflecting the rate at which reactants are converted to products. In glycolysis, it refers to the speed at which glucose is broken down.

The enzyme that catalyzes the first committed step of glycolysis, irreversible in most cells, converting glucose to glucose 6-phosphate.

The enzyme that catalyzes the irreversible phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate, a key regulatory step in glycolysis.

The earliest committed step in glycolysis, catalyzed by phosphofructokinase-1 (PFK-1), is highly regulated due to its importance in energy production.

ATP is a product of glycolysis, and high levels of ATP can feedback inhibit PFK-1 activity, slowing down glycolysis when energy levels are high.

High levels of ADP and AMP indicate low energy levels, which activates PFK-1, stimulating glycolysis to increase ATP production.

Citrate, a molecule from the citric acid cycle, inhibits PFK-1. High citrate levels signal energy excess, making glycolysis unnecessary.

Fructose 2,6-bisphosphate (F2,6BP) is a potent activator of PFK-1, ensuring high levels of glycolysis when glucose is readily available.

F2,6BP is synthesized from fructose 6-phosphate by the enzyme phosphofructokinase-2 (PFK-2).

F2,6BP levels are controlled by the enzyme fructose-2,6-bisphosphatase (FBPase-2) which degrades F2,6BP back to fructose 6-phosphate.

F2,6BP, PFK-2, and FBPase-2 are regulators of glycolysis, distinct from the enzymes directly involved in the pathway.

Insulin, a hormone released when blood glucose is high, activates a protein phosphatase that dephosphorylates many enzymes involved in glycolysis and gluconeogenesis.

Glucagon, released when blood glucose is low, activates a protein kinase that phosphorylates many enzymes involved in glycolysis and gluconeogenesis.

Insulin dephosphorylates and activates PFK-2, which produces F2,6BP. This compound stimulates glycolysis by activating PFK-1 and inhibits gluconeogenesis by inhibiting FBPase-1.

The liver responds to high blood glucose by taking up glucose and increasing glycolysis to decrease blood glucose. The liver also inhibits gluconeogenesis to prevent a futile cycle.

Insulin signals the liver to increase F2,6BP levels by activating PFK-2. F2,6BP is a potent allosteric activator of PFK-1 (glycolysis) and inhibits FBPase-1 (gluconeogenesis).

Futile cycles occur when both glycolysis and gluconeogenesis operate simultaneously, resulting in net ATP hydrolysis without a net change in metabolites.

The liver's regulation of glycolysis and gluconeogenesis is essential to prevent wasteful ATP hydrolysis and maintain blood glucose homeostasis.

Hormones like insulin and glucagon control liver glycolysis and gluconeogenesis by influencing the phosphorylation state of key enzymes, affecting their activity and regulating blood glucose levels.

Fructose 2,6-bisphosphate (F2,6BP) is a potent activator of phosphofructokinase-1 (PFK-1), the key regulatory enzyme in glycolysis. It increases glycolysis by signaling that cells need more ATP.

In muscle cells, F2,6BP levels are primarily regulated by substrate levels, specifically the concentration of fructose 6-phosphate (F6P). A build-up of F6P leads to F2,6BP production, which in turn activates PFK-1 and boosts glycolysis.

In the liver, F2,6BP levels are controlled by both substrate levels and hormonal signals. This allows the liver to fine-tune both glycolysis and gluconeogenesis, which are essential for maintaining blood glucose homeostasis.

The enzyme PFK-2 catalyzes the conversion of fructose 6-phosphate (F6P) to fructose 2,6-bisphosphate (F2,6BP). It plays a vital role in regulating glycolysis by controlling the levels of F2,6BP.

In muscle cells, PFK-1 activity is regulated by ATP, ADP, AMP, and F2,6BP. High levels of ATP inhibit PFK-1, while low energy stores (indicated by high ADP or AMP) and F2,6BP activate it.

In the liver, the activity of PFK-1 is further regulated by hormonal signals like glucagon and insulin. These hormones affect the covalent modification of PFK-2, indirectly influencing F2,6BP levels and glycolysis.

The liver's ability to regulate both glycolysis and gluconeogenesis is vital for maintaining blood glucose levels. F2,6BP plays a key role in this process.

F2,6BP, as an activator of PFK-1, plays a key role in the regulation of glycolysis, ensuring adequate energy production in various tissues like muscle.