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Regulation of glycolysis and gluconeogenesis

Topic: Principles Of Metabolic Regulation Mcat Wiki

Glycolysis and gluconeogenesis can be regulated by the enzymes and the molecules that help the enzymes in catalyzing the reactions. Glycolysis can be regulated by enzymes such as hexokinase, phosphofructokinase and pyruvate kinase. Gluconeogenesis can be regulated by fructose 1,6-bisphosphatase.

The control of glycolysis begins with the first enzyme in the pathway, hexokinase. This enzyme catalyzes the phosphorylation of glucose, which helps to prepare the compound for cleavage in a later step. The presence of the negatively-charged phosphate in the molecule also prevents the sugar from leaving the cell. When hexokinase is inhibited, glucose diffuses out of the cell and does not become a substrate for the respiration pathways in that tissue. The product of the hexokinase reaction is glucose-6-phosphate, which accumulates when a later enzyme, phosphofructokinase, is inhibited.


Phosphofructokinase is the main enzyme controlled in glycolysis. High levels of ATP, citrate, or a more acidic pH decrease the enzyme’s activity. Specifically, ATP binds an allosteric site on the enzyme to inhibit its activity. An increase in citrate concentration can occur because of a blockage in the citric acid cycle. Fermentation, with its production of organic acids like lactic acid, frequently accounts for the increased acidity in a cell; however, the products of fermentation do not typically accumulate in cells.

The last step in glycolysis is catalyzed by pyruvate kinase. The pyruvate produced can proceed to be catabolized or converted into the amino acid alanine. If no more energy is needed and alanine is in adequate supply, the enzyme is inhibited. The enzyme’s activity is increased when fructose-1,6-bisphosphate levels increase. (Recall that fructose-1,6-bisphosphate is an intermediate in the first half of glycolysis. ) The regulation of pyruvate kinase involves phosphorylation, resulting in a less-active enzyme. Dephosphorylation by a phosphatase reactivates it. Pyruvate kinase is also regulated by ATP (a negative allosteric effect).

If more energy is needed, more pyruvate will be converted into acetyl CoA through the action of pyruvate dehydrogenase. If either acetyl groups or NADH accumulates, there is less need for the reaction and the rate decreases. Pyruvate dehydrogenase is also regulated by phosphorylation: a kinase phosphorylates it to form an inactive enzyme, and a phosphatase reactivates it. The kinase and the phosphatase are also regulated.

The gluconeogenesis involves the enzyme fructose 1,6-bisphosphatase that is regulated by the molecule citrate (an intermediate in the citric acid cycle). Increased citrate will increase the activity of this enzyme. Gluconeogenesis needs ATP, so reduced ATP or increased AMP inhibits the enzyme and thus gluconeogenesis.

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Key Points

• Glycolysis control begins with hexokinase, which catalyzes the phosphorylation of glucose; its product is glucose-6- phosphate, which accumulates when phosphofructokinase is inhibited.

• Gluconeogenesis can be controlled by regulating the enzyme fructose 1,6-bisphosphatase, which is activated by citrate and inhibited by AMP.

Key Terms

Phosphofructokinase: any of a group of kinase enzymes that convert fructose phosphates to biphosphate

Glycolysis: the cellular metabolic pathway of the simple sugar glucose to yield pyruvic acid and ATP as an energy source

Kinase: any of a group of enzymes that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific target molecules (substrates); the process is termed phosphorylation

Phosphorylation: the addition of a phosphate group to a protein

Glucose: a simple monosaccharide (sugar) with a molecular formula of C6H12O6; it is a principal source of energy for cellular metabolism

Hexokinase: an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate

Pyruvate: a biological molecule that consists of three carbon atoms and two functional groups – a carboxylate and a ketone group

Dephosphorylation: removal of a phosphate group

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