Metabolic pathways don’t really have end products

The end product of glycolysis is pyruvate

This, and equivalent statements about other metabolic pathways:

The products of Krebs cycle are ATP/GTP, NADH and carbon dioxide

are not exactly wrong, but they are easily over-interpreted in a way that leads to misunderstanding. They are also  easily swallowed as explanations without considering quite what ‘end product’ is supposed to mean.

Glycolysis is the metabolic pathway in cells that converts glucose to pyruvate

In ‘simplified’ form, glycolysis looks like:

Glucose → Glucose phosphate → Fructose phosphate → Fructose bisphosphate ⇉

Triose phosphate → Bisphosphoglycerate → Phosphoglycerate → Phosphoenolpyruvate → Pyruvate

When written down like this, it looks very much as if pyruvate is the end product of a nice linear sequence of reactions. However, glycolysis has a messy metabolic context:

Many of the intermediates of glycolysis can enter into other metabolic pathways, and vice versa. For example, some of the glucose-phosphate can enter the pentose phosphate pathway (represented by “Ribulose-5P” and “Fructose” in the diagram above):

Glucose phosphate → Phosphogluconate (+CO₂) → Ribulose phosphate →

3 ribulose phosphate → [Big ball of mud including ribose phosphate] → Triose phosphate + 2 Fructose phosphate

If a cell is making lots of DNA, it will need a lot of ribose phosphate, and much of the glucose entering glycolysis will end up as ribose phosphate, not as pyruvate. The question to ask is therefore:

If a cell is synthesising DNA, is ribose phosphate the product of glycolysis?

The knee-jerk response to this is “no”; that ribose phosphate is a product of the pentose phosphate pathway, not of glycolysis. But this begs the question. The two pathways have the same initial steps:

Glucose → Glucose phosphate

The reaction (technically, reactions) above is generally considered part of glycolysis, and it is generally taught that the pentose phosphate pathway is a ‘shunt’ that bleeds off glycolytic intermediates, as though it were some parasitic excrescence to the side of the True Path of Glycolysis. If not a completely arbitrary way of looking at these two pathways, it is at least quite arbitrary.

The choice of which pathway owns these (or any other) reactions depends on what you’re trying to use the pathways to explain. Glycolysis is a convenient shorthand in cells that are channelling a lot of glucose to respiration; it may not be such a helpful or unifying shorthand under other circumstances.

Divvying up the metabolic pathways of a cell into discrete subunits like “glycolysis”, “Krebs cycle” and “pentose phosphate pathway” is largely a matter of convenience. This seems – and indeed, is – very obvious and uncontroversial. Of course metabolic pathways are mere conveniences. Of course they are an imperfect exercise in pigeon-holing. Of course they interact in complex ways that blurs their edges. What’s the problem?

The problem lies in not explicitly acknowledging this. When looking at the ‘end products’ of metabolic pathways, forgetting that glycolysis is just a shorthand can lead to significant misunderstandings of why metabolic pathways are regulated (which will be the subject of a later post), and what they are for (which is the subject of the rest of this one).

Does pyruvate accumulate when glycolysis is running?

It is true that pyruvate is the ‘end product’ of glycolysis, but only in the same sense that the M1 motorway’s destination is junction 21 of the M25 that surrounds London. The cars travelling along the M1 from Leeds to London do not simply pile up at junction 21 of the M25, or at least – if the cars do pile up – something is wrong. The cars filter off onto the M25 and elsewhither. Similarly, the carbon travelling down the glycolytic pathway from glucose does not simply pile up at pyruvate, or at least – if pyruvate does pile up – something is wrong. The carbon filters off to the Krebs cycle or elsewhither.

The end product of glycolysis is the starting material for some other bit of metabolism, as indeed are all of its intermediates. If you don’t have that in mind, you may get the misleading impression that when glycolysis is running normally, pyruvate is accumulating. It shouldn’t, and it usually doesn’t.

It is also true that the purpose of glycolysis is to convert glucose to pyruvate, but only in the same sense that the purpose of the M1 is to move cars from Leeds to London (and vice versa). This is a purpose, but there are higher-level purposes for both highways. For the motorway, this purpose is probably the easy movement of cars across the whole road network: from Derby to York, as well as from London to Leeds. At a higher level, it might conceivably also include employment and economic growth: the mere milling about of cars is a detail of a larger picture.

Do metabolic pathways really have end products?

or to put it another way

What is the larger picture for the milling about of carbon in a metabolic pathway?

The usual fate of the pyruvate made by glycolysis in aerobically respiring cells is to be ‘burnt’ with oxygen to form carbon dioxide, water and ATP. Carbon dioxide certainly has a good claim to be the ultimate end product of glycolysis in humans, as it is exhaled as a waste product. Conversely, the ATP has no better claim than pyruvate to be an end product of these pathways: it is mostly used to power growth and movement, including the walking and chewing and swallowing involved in getting the glucose into your body in the first place. The ATP generated by respiration is recycled to obtain more glucose to make more ATP, which is recycled to obtain more glucose to make more ATP, and so on and so on. The only ‘true’ end product of human metabolism would appear to to be the warm, damp carbon dioxide you exhale.

This is almost – but not quite – true.

There is one other important end product of glycolysis (and Krebs cycle and oxidative phosphorylation and all the other metabolic gubbins) and that is more metabolism. Metabolic pathways in humans have the unusual properly that whilst creating an awful lot of warm, damp carbon dioxide waste, they also produce more of the components needed to run that metabolism.

The ultimate, bigger-picture ‘end product’ of glycolysis is not pyruvate, but babies.

If you think of named metabolic pathways as distinct entities with particular purposes and set start and end points, rather than convenient shorthands for navigation, you may miss the forest for the trees journey for the roads.