August 19, 2006

The Means of Production of Energy in Living Organisms

Hans Krebs and W. A. Johnson, The Role of Citric Acid in Intermediate Metabolism in Animal Tissues, 1937

In the era of DNA sequencing and proteomics, it's sometimes difficult to remember that only in the past century have biologists finally put to rest the idea that living matter obeys different laws than nonliving matter. Biochemistry proved to be the key to detailed understanding of the internal processes of living organisms. Rather than being animated by some sort of life-force present only in living tissue, cells and tissues turn out to run on chemical reactions that obey the same laws that govern non-organic chemical reactions.

What is a chemical reaction, precisely? In short, if one or more molecules have their bonds rearranged, a chemical reaction has occurred. This usually happens when the molecules involved collide, disturbing the delicate balances of repulsion and attraction that form the bonds. During the resulting chaos, bonds are rearranged and energy is transferred between bonds and molecular motion. As you might expect, stable arrangements are more likely to result than unstable ones. Things get interesting when you realize that the word "energy" is being used here as a synonym for "unstability". The more energy needed to construct a molecule, the more unstable, and unlikely, it is. By comparing the energy contained in the molecules on each side of a reaction, you can figure out which way the reaction is going to go (towards the stable, lower energy side), how much heat is going to be released (the difference between the two sides), and even precise equilibrium concentrations.

That last deserves elaboration. Every reaction is, in theory, reversible. Although the lower energy side of the reaction is more likely, if molecules collide hard enough, the stable configurations can be bumped up into higher energy configurations. For example, if you start with a beaker full of substance AB, and conditions are right for it to begin breaking down into A + B, as soon as the products appear in the beaker, some of them will start colliding and reforming into substance AB. This reaction may still favour A + B over AB, but as the concentrations change, the forward and backwards reactions will eventually be proceeding at the same rate, and equilibrium will be achieved; e.g. 10% AB and 90% A + B. Chemists can predict exactly what the equilibrium concentrations will be if they know the energy needed to construct the molecules A, B, and AB.

Things get even more interesting when you consider interactions between lots of chemical reactions. If the products of a reaction get sucked away into another reaction, or moved across a membrane, or removed from the picture in any other way, the reactions will shift to replace the lost products until equilibrium is achieved again. Similarly, when reactants are added, they will react until there are enough products to balance them.

Living systems are, at bottom, a vast network of interconnected chemical reactions. The products of one reaction feed into the next; membranes block the movement of some molecules, let others through, and actively pump still others to one side or the other; catalysts make highly unlikely reactions possible, even probable, greatly speeding up the rate at which equilibrium is reached.

Hans Krebs helped figure out one of the most important and wide-spread chains of reactions present in living tissue, an eight-step cycle that breaks down food and stores its energy in a form a cell can use. Previous work had demonstrated that two three-step chains existed:
citrate→aconitate→isocitrate→α-oxoglutarate, and

These reactions all add or remove H2O, H+, and CO2 from the main molecules, and can all be replicated in a test tube. However, in a test tube, they quickly reach equilibrium, effectively grinding to a halt. Krebs showed that both these sets of reactions will continue for far longer than expected in living tissue (specifically, pigeon flight muscles), implying that the reactants are regenerated somehow. It was already known that α-oxoglutarate will react with an atom of oxygen to form succinate and CO2, and Krebs showed that a known inhibitor of the succinate→fumarate step in the second chain causes the citrate chain to grind to a halt in living tissues. This strongly implies that there is a single continuous chain from citrate to oxaloacetate. He then showed that pigeon muscle creates new citrate in the presence of oxaloacetate, closing the circle.

Krebs didn't know the precise nature of the final step of the pathway, but he knew that it had to involve adding C2H4O2 to the oxaloacetate. As it turns out, the Krebs cycle forms the last two thirds of glucose breakdown, the part that requires oxygen. The first third is a more ancient, anaerobic, metabolic pathway that breaks glucose into C2H3O, which then feeds into the Krebs cycle along with HO-.

What, then, is the purpose of this cycle of reactions? Its net effect seems to be to break C2H3O, 2H2O, and HO- into 2CO2 and 8H+. The whole purpose of the cycle turns out to be to generate those H+ ions. The Krebs cycle occurs inside mitochondria, and there's a protein complex embedded in mitochondrial cell walls that acts like a miniature turbine as H+ ions flow through it. The "turbine" is ATP synthase, which generates the primary energy-carrying molecule in known life.

More than just glucose feeds into this cycle: carbohydrates get broken down into glucose, and proteins and fats get broken down into C2H3O, so that practically all food we eat gets funnled into this reaction. In addition, the oxygen entering the Krebs cycle turns out to enter our cells from our blood, and, ultimately, our lungs. We die when we stop breathing because this metabolic pathway grinds to a halt, and we stop producing ATP. Every cell in every aerobic organism requires oxygen just to power this reaction.

Lots of other metabolic pathways have been discovered, but the Krebs cycle usually shows up in the center of any serious diagram. In my opinion, the only other metabolic pathway that even approaches its importance is photosynthesis, the pathway that put all that free oxygen into our atmosphere in the first place.


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