Glycolysis and the Citric Acid Cycle: The Control of Proteins and Pathways

Automobiles have incredible engines, cooling systems, drive trains, and so forth, but all of this must be controlled. The accelerator, gears and brakes are essential in automobile design. This is even more true in biology where regulation and control at all levels is crucial and incredibly complex, particularly since so much of the control is performed automatically. At the cellular level, the cell’s machines—the proteins—are controlled at several levels. As one leading textbook describes:

A living cell contains thousands of enzymes, many of which operate at the same time and in the same small volume of the cytosol. By their catalytic action, these enzymes generate a complex web of metabolic pathways, each composed of chains of chemical reactions in which the product of one enzyme becomes the substrate of the next. In this maze of pathways, there are many branch points where different enzymes compete for the same substrate. The system is so complex that elaborate controls are required to regulate when and how rapidly each reaction occurs.

Regulation occurs at many levels. At one level, the cell controls how many molecules of each enzyme it makes by regulating the expression of the gene that encodes that enzyme. The cell also controls enzymatic activities by confining sets of enzymes to particular subcellular compartments, enclosed by distinct membranes. The rate of protein destruction by targeted proteolysis represents yet another important regulatory mechanism. But the most rapid and general process that adjusts reaction rates operates through a direct, reversible change in the activity of an enzyme in response to specific molecules that it encounters.

So the cell controls its proteins by controlling how many it creates and destroys, and by confining them to certain compartments. But most directly it controls them directly, as one controls an automobile with the accelerator and brake.

Glycolysis and the citric acid cycle

A great example of all this is the nearly universal glycolysis pathway and citric acid cycle which team up to process food intake. In the glycolysis pathway about a dozen protein enzymes break down the six-carbon sugar known as glucose into two three-carbon molecules. Like a factory production line, each enzyme catalyzes a specific reaction, using the product of the upstream enzyme, and passing the result to the downstream enzyme. If just one of the enzymes is not present or otherwise not functioning then the entire process doesn’t work.

In addition to breaking down glucose, glycolysis also produces energy-carrying molecules called ATP. These are in constant demand in the cell as they are used wherever energy is needed. Like most pathways, glycolysis is interconnected with other pathways within the cell. The molecular products of glycolysis are used elsewhere and so the rate at which the glycolysis pathway proceeds is important. Too fast and its products won’t be useful, too slow and other pathways have to slow down.

Glycolysis is regulated in a number of ways. The first enzyme in the glycolysis pathway is regulated by its own product. This enzyme alters glucose to form an intermediate product, but if the rest of the pathway is not keeping up then the intermediate product will build up, and this will cause the enzyme to shut down temporarily. The enzyme is designed to be controlled by the presence of its product.

Two other enzymes in the pathway have even more sophisticated regulation. They are sensitive to a number of different molecules which either increase or decrease the enzyme activity. For example, these enzymes are partly controlled by the energy level of the cell. This makes sense since glycolysis helps supply energy to the cell. A good indicator of the cell’s energy level is the relative concentrations of ATP and spent ATP. High levels of ATP indicate a strong energy supply. Hence the enzyme activity is inhibited (and therefore the glycolysis pathway is slowed) when ATP is abundant. But high levels of spent ATP counteract this effect.

How do these molecules control enzyme activity? The molecules are tiny compared to the big enzymes they control. Just as a small key is used to start up and turn off a big truck, so too these small molecules have big effects on their target enzyme. And just as the truck has an ignition lock that can be turned only by the right key, so too the enzyme has several docking sites that are just right for a particular small molecule, such as ATP.

Not only does ATP fit just right into its docking site, but it perturbs the enzyme structure in just the right way so as to diminish the enzyme activity. There is another docking site that only a spent ATP will fit into. And if this occurs then the enzyme structure is again perturbed just right so as to encourage activity and reverse the ATP docking effect.

Glycolysis and the rest of the cell

Glycolysis and the citric acid cycle do not merely create energy for the cell. Just as an oil refinery also produces a range of petroleum products, glycolysis and the citric acid cycle, in addition to producing energy, spin off a series of essential biochemical components needed by the cell. This figure illustrates how these pathways produce nucleotides, lipids, amino acids, cholesterol and other molecules.

In fact glycolysis and the citric acid cycle exist within a complex web of chemical pathways within the cell. These many pathways interaction with each other in many ways, as shown in this wire chart (glycolysis and the citric acid cycle are shown in red).

Sometimes a three dimensional view, that can be rotated, helps to understand the interactions between these many pathways.

This design is complex at many levels. At the molecular level, there is the precise control of the protein enzymes. At the pathway level, there is the interaction between the enzymes. And at the cellular level there is interactions between the different pathways. And all of this has nothing in common with evolution’s naïve, religiously-driven, dogma that biology must be one big fluke. As one evolutionist admitted (one of the textbook authors):

We have always underestimated cells. Undoubtedly we still do today. But at least we are no longer as naive as we were when I was a graduate student in the 1960s. Then, most of us viewed cells as containing a giant set of second-order reactions: molecules A and B were thought to diffuse freely, randomly colliding with each other to produce molecule AB—and likewise for the many other molecules that interact with each other inside a cell. This seemed reasonable because, as we had learned from studying physical chemistry, motions at the scale of molecules are incredibly rapid. … But, as it turns out, we can walk and we can talk because the chemistry that makes life possible is much more elaborate and sophisticated than anything we students had ever considered. Proteins make up most of the dry mass of a cell. But instead of a cell dominated by randomly colliding individual protein molecules, we now know that nearly every major process in a cell is carried out by assemblies of 10 or more protein molecules. And, as it carries out its biological functions, each of these protein assemblies interacts with several other large complexes of proteins. Indeed, the entire cell can be viewed as a factory that contains an elaborate network of interlocking assembly lines, each of which is composed of a set of large protein machines. […]

Why do we call the large protein assemblies that underlie cell function protein machines? Precisely because, like the machines invented by humans to deal efficiently with the macroscopic world, these protein assemblies contain highly coordinated moving parts. Within each protein assembly, intermolecular collisions are not only restricted to a small set of possibilities, but reaction C depends on reaction B, which in turn depends on reaction A—just as it would in a machine of our common experience. […]

We have also come to realize that protein assemblies can be enormously complex. … As the example of the spliceosome should make clear, the cartoons thus far used to depict protein machines vastly underestimate the sophistication of many of these remarkable devices. [Bruce Alberts, “The Cell as a Collection of Protein Machines: Preparing the Next Generation of Molecular Biologists,” Cell 92 (1998): 291-294.]

But the dogma remains. Evolutionists insist that evolution must be a fact and they use dozens of religious arguments to make their case. In the next moment they turn around and insist it is all about science. The result is pathetic science, such as the journal paper that tried to explain the citric acid cycle as “evolutionary opportunism.” Religion drives science, and it matters.