1. Regulation of glycolysis occurs through 3 enzymes - hexokinase, PFK, and pyruvate kinase. Hexokinase is regulated by substrate-level regulation. PFK is regulated allosterically by ATP (turns off), AMP (turns on), citrate (turns off), and F2,6BP (strongly turns on). Note that ATP and citrate will be present when cells have a lot of energy, so it is logical that they turn off the enzyme. By contrast, AMP is present when cells have little energy and it is logical that it turn on the enzyme under these conditions. F2,6BP can counteract the negative effects of ATP on the enzyme to some extent.
2. Note also that PFK is very unusual in being negatively regulated by a molecule (ATP) that is also a substrate. This is possible because the enzyme has an allosteric binding site for ATP in addition to the substrate binding site and the Km for the allosteric site is higher than the substrate binding site.
3. Pyruvate kinase is regulated both allosterically andby covalent modification (phosphorylation/dephosphorylation). Phosphorylation of the enzyme by a protein kinase turns the enzyme activity down, whereas F1,6BP acts as an allosteric activator. This activation is known as feedforward activation.
4. Feed forward activation is rare in metabolism. It is a term used to describe a metabolic product (such as F1,6BP above) that ACTIVATES an enzyme that catalyzes a reaction further ahead of it in a metabolic pathway. In glycolysis, feedforward activation acts to start the pyruvate kinase reaction and PULLs the reactions forward to get over the energy "hump" of the aldolase reaction.
5. Hypoxia refers to the condition where cells are short of oxygen. Since oxygen is necessary for maximum energy production from glucose, they must respond to this condition. One way they respond is by making a transcription factor known as Hypoxia Induction Factor 1 (HIF-1). HIF-1 activates transcription of genes involved in glucose transport and glycolysis. Cancer cells are frequently hypoxic and induce HIF-1, as well. Another way cancer cells battle hypoxia is to stimulate the growth of blood vessels to them by making another factor known as angiogenin. Blocking HIF-1 and angiogenin are anti-cancer therapies.