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Forgotten Aspects of GLYCOLYSIS AND THE KREBS CYCLE

The top three reasons for the existence of these and related pathways are, in order of importance. That ordering will be explained a couple of paragraphs further on.

1. To obtain energy from the environment to power metabolism and growth.
2. To produce this power with a minimum of deleterious byproducts
3. To produce the building blocks for anabolism

Reason for why Glycolysis is NOT the most important pathway!

There is another priority list that should be created because it concerns which energy producing pathway should be studied first. Glycolysis (a la Embden, Meyerhof and Parnas) is the one usually studied first (and only!). But is this based on its superlative merits? Look at your own diet. From which class of biochemicals do you derive most of your calories? Lipids. And within that group, mostly the fats and oils. Carbohydrate metabolism is a distant second. So why is glycolysis the only thing studied in introductory courses? Probably because it is for historical reasons - glycolysis was the first pathway to be elucidated; printed into textbooks and never pushed aside by subsequent discoveries. One of those late-comers was lipid metabolism, which was penetrated rather late because of the inherent problem that most of its intermediates are not water soluble. Just think of trying to do research on glop! Thus it is seen that glycolysis is only one of many energy procuring catabolic pathways that exist in the world. Indeed, plants have a modification of glycolysis called the pentose shunt. But remember that most of the mass of life is out of sight (and out of mind?). A favorite, even more efficient catabolic pathway used by a very widely dispersed group of microbes is the Entner-Douderoff pathway. Others include the glucuronate pathway and a group called collectively the phosphoketolase pathways, It should not be surprising that more organisms use these other pathways than those which use glycolysis. NEVERTHELESS, all use their favorite forms of catabolism for the purpose of gaining energy to drive the other pathways in their metabolism.

So let us redirect our focus to the obviously more important and usually untaught, major purpose, which is energy acquisition or energetics. All of these pathways proceed through a series of steps to which we can give common names:

1. Mobilization (usually attaching a charged group to a monomer detached from a polymer - e.g.: from starch to glucose-6P)
2. Isomerizations and interconversions (converting that charged monomer from a rare form into one that is more common - from, for example, arabinose-5P to ribose-5P, or from galactose-6P to glucose-6P; many of these conversions jack up the energy of the molecule such that finally a form was reached that satisfied the pathway's activation energy)
3. Additional phosphorylations, substitutions and degradations (e.g.: lower glycolysis, and the tangle of pentose- and triose-phosphates)
4. The final degradation to CO2 or making anabolic starting compounds (e.g.: from pyruvate through the Krebs Cycle)

Fortunately, the above strategy tells us to expect that there are a few tools common to all organisms' toolboxes especially as the strategy promotes converting highly disparate starting compounds into more and more "common" intermediates, which in many cases lead into the Krebs Cycle or some derivation of it. Afterall, all organisms are restricted to the laws of chemistry and physics, and so, depending on the nature of the starting material (food), these wrenches, hammers and screwdrivers are applied in very similar ways.

Another item to get out of the way is that we are often tempted to talk about biological oxidation as the equivalent of catabolic energy procurement, but that would overlook all those fermentations in which there is no net oxidation. So, if biological oxidation is "out," then what is the driving force? What is that which promotes a huge ΔG?

The Gibbs-Helmholz Equation has two other factors in it: ΔH and ΔS. Hence, a large change in ΔG means a large change in entropy or enthalpy or both!

How, for instance, is a large entropy manifested? Mostly from taking a single molecule and making several smaller molecules from it. Randomness is increased by going from few to many. For example, one molecule of FDP can only be in one position relative to itself, but when it is split to GAP and DHAP, there are at least two positions each of those have to itself: GAP+DHAP or DHAP+GAP, and that is only one-dimensional. There are three dimensions. Randomness has been increased to at least 6-times over that of FDP, and we have yet to mention how far apart they are from one another. Then consider what the Krebs Cycle does - a single glucose goes to 6 CO₂'s! (How many ways can you shuffle a deck of playing cards, and how distantly dispersed can you make them?) We haven't even mentioned dispersion of the molecules in an environment full of other molecules.

The trick that nature has is the ability to harness the increasing entropy. It does this by linking negative-entropy reactions to the catabolism. (But make no mistake: the net of the two reactions is still positive entropy - just less than it would be if the linked - or coupled - reaction were not there with the result of a "runaway" reaction. (Imagine a hydroelectric dam. The turbine blades in the falling water are the "coupled" reaction. Take away the turbine blades and you have a "runaway". Another example: a small gasoline engine is coupled with a model airplane's propeller and, with considerable resistance, moves the air, and hence the plane. Disconnect the propeller, and the engine can be such a runaway that its speed reaches levels that might explode the engine.)

Okay, all you carbon counters and pushers! Let's see how energy is really procured as we look for those catabolic steps that produce the most energy. Be prepared to look at all this from a very different perspective. But first we need to review a little organic chemistry.

There are four different general structures from which energy can be derived biologically. It is all in how we "pack" the molecules with these forms. Just like gasoline burns in open air, but explodes with "packed;" just like a boiling pot steams uselessly, but if "packed" into a cylinder it can do work; just like gunpowder fizzles if spread upon the ground, it explodes when "packed". Catabolic pathways go through a series of incremental, step-by-step "packing" reactions, then comes the harnessing "explosion" reactions - over and over until there is only CO₂ or other products such as ethanol or lactic acid (pickles, cheeses, silage).

What are those packing reactions in which the molecule is jacked up to higher and higher energy levels? These are listed in decreasing energy content so molecules are jacked up from the bottom of the list upwards. The bottom step is only infrequently used: once each in both glycolysis (PEP) and the Krebs Cycle (fumerate).

1. Asymmetrical acid anhydrides

   

2. Symmetrical acid anhydrides

   

   

3. Esters

   

   

4. (double bonded carbons) as in fumeric acid made from succinic acid

Let's take a look at the first reaction in glycolysis: we take a polyol (glucose) and use the energy of a symmetrical acid anhydride (ATP) to pack a little chemical energy into the polyol - an ester bond is formed. (An ester is the dehydration product of combining an acid (phosphoric acid) with an alcohol.) The G1P is now packed with a little energy. To pack more into the polyol, the molecule is refolded into a tighter form. Then a second ester is made (FDP) at the expense of the driving force of the breakage of a symmetrical acid anydride (ATP). Look at FDP. Look at the energy packed within it! See the two huge, highly negatively charged phosphate groups repelling each other, straining and almost ripping the structure of fructose apart. (These, by the way, are drawn roughly to scale.

Here is a complete graph of energy (based on heats of formation) versus the catabolic intermediates of the pathway. Can you pick out where the various types of anhydrides and esters are on this graph? Note where the Krebs Cycle takes over, and how much more efficient it is versus the two forms of fermentation. Why is ethanolic fermentation more efficient than lactic fermentation? (more entropy)

Substrate Level Energetics Glycolysis through Krebs Cycle	Energetics of NADH
Shown are the relative functional energy contents of all the intermediates of glycolysis and respiration. It is obvious that the Krebs Cycle is far superior to glycolysis in liberating energy. Furthermore, it is seen that ethanolic fermentation releases about 80% more energy than does lactic fermentation.
Electron transport releases more than enough energy needed to couple the phosphorylation of ADP to ATP. (One might wonder if evolution has not yet discovered how to capture much of the remaining energy.)