Biology, physiology, and allied health biochemistry textbooks cover metabolic pathways such as glycolysis; however, most do not include much discussion of how these pathways are regulated within the cell. Because the details of these complex regulatory processes can be difficult for students to learn, we have developed a robust teaching analogy that compares the glycolytic synthesis of ATP to the generation of electrical power. Analogies comparing glucose catabolism to coupled industrial engines (1) and to family finances (2) have been published, but these do not include any notion of regulation. A detailed analogy comparing an enzyme to a butcher (5) deals with enzyme structure, mechanism, and regulation, but only for a single enzyme. Thus we feel that our glycolysis/power generation analogy, which envisions the regulation of an entire metabolic pathway, is uniquely useful.
In our scheme, we identify three key regulatory enzymes in glycolysis: hexokinase, phosphofructokinase, and pyruvate kinase, along with some of their activators and inhibitors. Our analogy compares three key parts of the electric power generation system with these three major regulatory enzymes in the glycolytic pathway. The target audience for this analogy is lower-division undergraduates studying metabolism in courses such as introductory biology, physiology (especially human physiology), introductory biochemistry, and nursing/allied health courses.1
where NAD+ is nicotinamide adenine dinucleotide (oxidized) and NADH is nicotinamide adenine dinucleotide (reduced). Even though glycolysis is a spontaneous process, the glycolytic “pump” must first be “primed” before it can work; ATP is initially consumed in steps 1 and 3 (see Fig. 1A) to eventually produce even more ATP in steps 7 and 10. Similarly, in a power plant, energy must be expended initially to either ignite fuel in the combustion chamber or to reposition dam gates for hydroelectricity (Fig. 1B). In either case, energy must first be spent before it can be created. However, power companies don’t have to generate electricity all the time. Instead, they match energy production to energy need. Cells also perform the same function.
Regulation of glycolysis.
The three glycolytic enzymes that control the critical steps of ATP consumption and ATP production (steps 1, 3, and 10, respectively, in Fig. 1A), often play a significant regulatory role in the glycolysis pathway (4). It would be wasteful for the cell to expend the free energy drops in these highly spontaneous steps unless there were a demonstrable need for ATP. Hence, the enzymes that catalyze these three steps are sensitive to the energy “needs” of the cell. Just as we turn a faucet off when we no longer need water, cells turn glycolysis off when their need for ATP is low. Biochemical “faucets” (or regulatory enzymes) are controlled by small molecules that can either increase (activate) or decrease (inhibit) their activity (4).
Hexokinase catalyzes the first step in glycolysis, the phosphorylation of glucose by ATP (Fig. 1A). Most forms of this enzyme are inhibited by high concentrations of the reaction product, glucose-6-phosphate (feedback inhibition). Phosphofructokinase (PFK) catalyzes the phosphorylation of fructose-6-phosphate by ATP (step 3). Along with hexokinase, PFK is an important regulatory enzyme in glycolysis because it is influenced by a wide range of inhibitors (mainly cytosolic ATP) and activators (e.g., ADP, AMP, Pi). Pyruvate kinase (step 10), which dephosphorylates phosphoenolpyruvate by ADP → ATP, can be found in several forms, all of which are inhibited by high concentrations of either ATP or acetyl-CoA (another high-energy metabolic intermediate). In general, glycolysis inhibitors signal adequate levels of ATP and prevent further use of glucose, preserving the fuel stores within the cell, whereas activators indicate a need for ATP and promote the breakdown of glucose.
Glycolysis/power generation teaching analogy.
To generate electrical power (Fig. 1B), fuel is ignited and combusted, creating gaseous products at high temperature and pressure. These are then used to turn a turbine and generate electron flow to a capacitor. The capacitor stores potential energy in the form of high voltage. Finally, a transformer converts high voltage potential energy to usable 120 or 220 V alternating current electricity.
Parallels between glycolysis (Fig. 1A) and power generation (Fig. 1B) are robust and clear. First, both processes must be “primed.” They consume energy at step 1 (ATP splitting, or fuel ignition or dam gate repositioning) to create more energy farther down the line. Second, both processes demonstrate feedback inhibition in step 1; glucose-6-phosphate inhibits hexokinase (Fig. 1A), and high temperature and pressure decrease fuel flow into the combustion chamber (Fig. 1B). Third, sufficient energy stores trigger a slowdown of both energy generation processes, i.e., high ATP concentrations inhibit pyruvate kinase and PFK (Fig. 1A), just as a highly charged capacitor inhibits discharge of the capacitor and turning of the turbine/generator (Fig. 1B). Conversely, insufficient energy stores rev up energy generation, i.e., high concentrations of the ATP consumption products ADP and Pi activate PFK (Fig. 1A), just as a depleted electrical grid activates the turbine/generator (as well as fuel combustion and electricity generation by the transformer, Fig. 1B).
Effectiveness of the analogy.
Our teaching analogy offers two advantages in the teaching of metabolic regulation in glycolysis: 1) it specifically addresses three important regulatory steps of glycolysis, and 2) it includes analogs of intracellular activators and inhibitors that control the flow through the pathway. Although power generation is not exactly common knowledge, the general concepts of electricity production and consumption are familiar to most students. Judicial use of photographs during classroom instruction can help to further clarify the analogy.
Course surveys administered over the past two semesters (2003 –2004) have shown this analogy to be effective in helping students understand how glycolysis is regulated (data available upon request). The analogy offers students a useful way to simplify and visualize a complex metabolic pathway, as summarized in the words of a student who wrote, “What I like about the analogy and schematics is that they relate to things outside of the difficult terminology and complex structures involved with glycolysis and energy-yielding mechanisms. This eases the learning process and facilitates further speculation…” We could not have said it better ourselves!
↵ 1 Analogies are only useful if they are clear and intuitively descriptive. It is thus very difficult to devise an analogy that can describe fully the exquisite detail found in most biological systems. Our analogy focuses on the three glycolytic regulatory enzymes crucial in most, but certainly not all, tissues. Furthermore, glycolytic flux may be controlled by mechanisms other than enzyme regulation. In particular, studies using metabolic control analysis (described in Ref. 3 and references therein) have shown that regulatory enzymes do not control flux through metabolic pathways in a simple, direct fashion. Even so, hexokinase, phosphofructokinase, and to a lesser extent, pyruvate kinase, have been demonstrated by metabolic control analysis to exert considerable control over the flux of glucose through glycolysis in most tissues.
- © 2005 American Physiological Society