Carbohydrate Metabolism › Glycolysis

Regulation of Glycolysis Overview

Notes

Regulation of Glycolysis Overview

Sections

REGULATED STEPS IN GLYCOLYSIS

Hexokinase: first step in glycolysis

  • Phosphorylates glucose
  • Consumes ATP
  • Traps glucose within cell
  • Muscle: inhibited by glucose 6-P
  • Liver: glucokinase isozyme

Phosphofructokinase: committed step

  • Most important control element
  • First reaction unique to glycolysis
  • Phosphorylates fructose 6-P to form fructose 1,6-BP
  • Consumes ATP
  • Activated by AMP and fructose 2,6-BP (more important in liver)
  • Inhibited by ATP, citrate and low pH (muscle)

Pyruvate kinase: last step in glycolysis

  • Dephosphorylates phosphenol pyruvate to form pyruvate
  • Generates ATP
  • Activated by fructose 1,6-bisphosphate and AMP
  • Inhibited by: ATP, alanine & Acetyl CoA

MAJOR REGULATION SITES IN GLYCOLYSIS

Muscle

  • Requires energy for contraction
  • ATP: AMP ratio determines whether glycolysis should move forward
  • When ratio is low: glycolysis activated
  • 2 ADP combine to form 1 ATP and 1 AMP (free ADP does not persist)

Liver

  • Uses molecules from glycolysis to start biosynthetic/metabolic reactions
  • High glucose levels: liver stores glucose as glycogen
  • Low glucose levels: liver releases glucose
  • Liver isozymes allow glucose to be prioritized for brain & muscles

Full-Length Text

  • Here we'll learn a general overview of the careful regulation of glycolysis, which is highly important because glycolysis involves many compounds integral to metabolism and biosynthesis.
  • Start a table to denote some key features of glycolysis regulation.
  • Denote that there are 3 regulation steps in glycolysis:
    • Hexokinase, the first step of glycolysis
    • Phosphofructokinase, the committed step of glycolysis (we'll learn what this means later)
    • Pyruvate kinase, the last step of glycolysis
  • Denote that there are two major regulation sites in glycolysis
    • Muscle, which requires energy for contraction
    • Liver, which uses molecules from glycolysis to start many biosynthetic and metabolic reactions.

Now let's draw the representative steps.

  • Write that we'll first address the first step in glycolysis.
  • Although not specifically addressed in this tutorial, write that in this step, we see the importance of regulation via isoenzymes: hexokinase vs glucokinase (in the liver).

Now, draw the step.

  • Draw glucose as six circles (which represent carbons) linked together.
  • Redraw our six circles, with a P attached to the sixth circle to represent the phosphate group.
  • Use an arrow and show that this irreversible reaction is catalyzed by hexokinase.
  • Use another arrow to show that in this step, ATP is converted to ADP, which is an energy-consuming reaction.
  • The phosphorylation of glucose is an irreversible reaction that traps glucose inside the cell.
  • Dash a line between glucose and glucose-6-phospate to represent that this reaction traps glucose in the cell.

Now, let's address the committed step in glycolysis.

  • Write that it's the most important control element of the glycolytic pathway, even though it seems that hexokinase should be the most regulated, since it is the first step.
  • Write that phosphofructokinase (called PFK) catalyzes the first reaction that is unique to glycolysis, which represents a commitment to the glycolysis process.
    • We will learn much more about how PFK does this elsewhere.
  • In this step, draw fructose-6-phosphate as six circles with a phosphate group on the sixth circle.
  • Then, draw fructose-1,6-bisphosphate, which has a phosphate group on the first carbon and sixth carbon.
  • Indicate that it is an irreversible reaction, which phosphofructokinase catalyzes.
  • Show that ATP is converted to ADP, which is an energy-consuming reaction.

Now, let's address the last step in glycolysis.

  • Write that it controls the outflow of the pathway.
    • Because of this, write that pyruvate kinase uses downstream products as a signal to regulate its activity.
  • In this last step, draw phosphoenol pyruvate as three circles with a P on the second circle.
  • Show that it is dephosphorylated to pyruvate in an irreversible reaction by pyruvate kinase.
  • Show this reaction generates energy as ADP is converted to ATP.

Now let's turn our attention to the two major regulation sites: muscle and liver. Let's start with muscle.

  • Write that glycolysis is the energy source for muscle contraction.
  • Also write that the cell uses the ATP–to-AMP ratio to determine whether glycolysis should move forward or come to a standstill; it uses the energy charge of muscle to regulate enzyme activity.
    • Why do we consider AMP instead of ADP?
  • Show that two molecules of ADP can combine to generate one molecule of ATP and one molecule of AMP, which allows the cell to squeeze as much energy as possible out of the system; thus, free ADP doesn't persist, it is converted to ATP and AMP.

To illustrate how this ratio influences glycolysis, draw the following:

  • Show a muscle cell milieu in which the ATP level is high and the AMP level is low and write that it causes glycolysis inhibition.

Next, show another muscle cell milieu.

  • With arrows, show that when AMP is high and ATP is low (when the levels flip), it causes glycolysis activation.
  • Because muscles use glycolysis as an energy source, glycolysis is inhibited when there is a lot of energy and reactivated when the energy levels fall.

Now let's look at what happens in the liver.

  • Write that the liver regulates blood glucose levels, and is an important site for biosynthesis, thus, glucose levels have a significant impact on glycolytic activity.
  • Draw an up arrow as an indication of the level of blood glucose.
  • Label the top of the arrow high glucose and the bottom of the arrow low glucose.
    • Show that at high glucose blood levels, the liver stores glucose as glycogen.
    • Write that at low glucose blood levels, the liver releases glucose.
  • Since liver activity primarily involves glycogen storage and biosynthesis of larger molecules and not use of energy from glycolysis, write that liver isoenzymes allow glycolysis to be prioritized as an energy source for the brain and muscles.

Now let's make a chart to show an overview of the effects of various molecules and conditions on glycolysis enzymes; we'll will learn about each of these in detail, elsewhere.

  • Create a column of the three regulated enzymes: hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK).
  • Show that to one side, we'll list the molecules and conditions that activate the enzymes and on the other, those that inhibit them.
  • Write that glucose -6-phosphate (G6P) inhibits hexokinase (in muscle).
    • Glucokinase in the liver is under hormonal control and is considered a glucose sensor (its activity is highly sensitive to glucose levels). We will not draw these mechanisms here.
  • For phosphofructokinase, write that it is activated by AMP throughout the body and by fructose-2,6-bisphosphate (F26BP) (in the liver).
    • Fructose-2,6-bisphosphate is also an allosteric activator in the muscle, but plays a more significant regulatory role in the liver.
  • And that it is inhibited by ATP throughout the body, by low pH (in muscle), and by citrate throughout the body.
  • For pyruvate kinase, write that throughout the body, fructose-1,6-bisphosphate (F16BP) and AMP activate it and that ATP, alanine and acetyl CoA inhibit it.

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