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In glycolysis, glucose is converted to fructose-6-phosphate before further breakdown. However fructose, instead of being phosphoryated to fructose-6-phosphate by glucokinase (and thereafter to pyruvate via glycolysis), yields fructose-1-phosphate in the reaction catalysed by fructokinase.

Why is this so?

It should be just as easy to phosphorylate fructose to both compounds. Wouldn’t it be more economical to use a single reaction, so everything would be easier to regulate? As there are several disorders that arise from the deficiency of enzymes used in fructolysis, wouldn’t there be a selection pressure against two separate metabolic pathways?

Edit:

Thanks for David's criticism; I see the confusion, I actually meant that it is mainly metabolized in the liver. I don't really have any real sources as I do not have access to much and quite a large portion of online resources is behind paywall. After a bit of digging I was able to find an overview that reiterates most of my claims. Sorry for not being able to provide more.

In the liver, fructose is rapidly converted to fructose 1-phosphate via fructokinase. Fructose 1-phosphate is then converted into the trioses dihydroxyacetone phosphate and glyceraldehyde via aldolase B.

The liver can extract 40–70% of dietary fructose in both rats and humans. The high efficiency of fructose extraction by the liver is due to the fact that the liver is the main source of GLUT-5. Anatomically, the liver is the first organ to receive absorbed nutrients via the portal vein; in that way, it contributes to fructose extraction. In contrast, the liver accounts for a smaller percentage of glucose extraction for glycogen restoration

Above are two excerpts from Chapter 19 - Fructose-Induced Hypertriglyceridemia: A Review. This source also (albeit vaguely) states that the resulting triose phosphates (glyceraldehyde and dihydroxyacetone phosphate) can and will enter pathways like glyconeogenesis, gluconeogenesis etc.

Up until this point in fructose metabolism, there have been no rate-limiting steps and, as a result, there is an increased amount of substrate leading to metabolic pathways from triose phosphate (i.e. glycolysis, glycogenesis, glyconeogenesis, lipogenesis, and fatty acid esterification).

Another source for my assertion that fructose is mainly metabolized to fructose-1-phosphate (Elsevier's Integrated Biochemistry):

Unique Characteristics—Aldolase B Specificity Fructokinase, like glucokinase, is found primarily in the liver. Unlike hexokinase and glucokinase, it phosphorylates the sugar at the C-1 position. Aldolase B, which is specific to the liver, works on both F1,6-BP and F1P. In extrahepatic tissues such as muscle or adipose tissue, fructose is phosphorylated to F6P by hexokinase.

Also, a possible lead, from Fructose: Absorption and Metabolism. Encyclopedia of Human Nutrition:

The allosteric inhibition of PFK effectively reduces the rate of glycolysis and decreases hepatic glucose uptake overall. In contrast, the entry of fructose carbons through the pathway proceeds without this limitation.

Using different enzymes (and therefore a different pathway) allows regulation of glycolysis in the liver without unnecessarily affecting fructolysis.

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  • $\begingroup$ I have edited your question to make it more readable. You need to learn to keep to the point. Written communication requires you to work to decrease the number of words to those that are necessary and then make sure you use the right words. Irrelevant asides inhibit comprehension and the reader will become confused or give up. This is meant as constructive criticism. I shall try to answer your question in due course. Are you sure you meant to write "Fructose is first converted to glucose phosphate before glycolysis"? Do you mean glycogenesis? And which glucose phosphate? Please edit. $\endgroup$ – David Apr 23 at 13:45
  • $\begingroup$ And while you are editing your question please give the sources of your assertions, particularly that fructose is not phosphorylated to F 6-P (and do you mean not or only a small proportion is?) and that fructose is is only metabolized in the liver. My text discusses the metabolism of fructose in adipose tissue. Let's try to construct a good question to justify a good answer. $\endgroup$ – David Apr 23 at 13:49
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    $\begingroup$ @David Thanks for your helpful edit! Granted, that question was written in a panic and I didn't really proofread it, so it just read like a continuous stream of thought. I have tried my best to add relevant sources; most of my assertions are usually taken for granted, so I didn't think of doing it initially. Glad I did, though! Helped to clear some of the confusion behind this monster of a topic. Also, sorry if the sources aren't up to par, I really can't find anything better. $\endgroup$ – chematwork Apr 23 at 15:21
  • $\begingroup$ Thanks for updating your question. I'll try to find time to research an answer over the weekend, although if someone gets in before me, all well and good. $\endgroup$ – David Apr 23 at 16:50
  • $\begingroup$ "Also, why is fructose mainly metabolized in the liver while glucose generally is not?" There are newer evidence suggesting that most of ingested fructose is converted into glucose by intestine cells. If ingested in small amounts it probably never reaches the liver in fructose form. cell.com/cell-metabolism/fulltext/S1550-4131(17)30729-5 $\endgroup$ – payman z Apr 23 at 18:28
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Summary

  • The mechanistic reason why fructose is converted to fructose 1-phosphate by fructokinase rather than fructose 6-phosphate by hexokinase is explained in terms of the Km values of fructose and glucose for the latter enzyme.
  • A possible general rationale for the two distinct pathways of metabolism is to allow them to operate and be regulated independently of one another. Although plausible, I am unaware of further data support this idea.
  • The manner in which the fructokinase pathway evolved is a matter for conjecture. I discuss what types of approaches to this question may be valid, and the types of arguments that I consider invalid.

“Why?” Questions — A Note of Caution

Before addressing this question I think it important to consider what is meant by a “Why?” question in biology. This can be a trap for the unwary if one is not clear whether a question is answerable objectively or only speculatively. There are two main types of “Why?”questions:

  • Mechanistic “Why?” questions. For this SE Question this would seem to be: “What is the mechanistic explanation of the fact that fructose is converted to fructose 1-phosphate, rather than to fructose 6-phosphate, in liver?”
  • Rationalization “Why?” questions. In this case it would seem to be “How can one rationalize the fact that a separate pathway for fructose metabolism exists?”

Mechanistic questions can be answered objectively if there are sufficient experimental observations. Rationalization questions cannot.

Rationalization is helpful to try to make sense of observations — to provide a framework for further experimental work. It is useful in teaching and learning, which is why one encounters it frequently in text books. But just because it is in text books it should not be regard as on a par with the facts described therein. It is just an opinion, an interpretation, which should be regarded critically. There is a danger in accepting an inadequate explanation, just because it is the only one that has been proposed for something that is difficult to understand but we think that must have an explanation.

Rationalization “Why?” questions are often confused with questions about how something Evolved. These should be clearly distinguished. Rationalization explanations refer to the functional utility of a system, not its evolutionary history. If the only explanation is in terms of evolution, then there may be a plausable evolutionary explanation but no rationale.

An Answer to the Mechanistic Question

Fructose is not converted to fructose 6-phosphate in the liver because it has a much higher Km for hexokinase than glucose does. Furthermore, glucose is present normally at a higher concentration and will therefore act as a competitive inhibitor. Instead, as the poster writes, there is a specific fructokinase, which converts it to fructose 1-phosphate and a further enzyme converting to the fructose 1-phosphate to glyceraldehyde and dihydroxyacetone phosphate. The glyceraldehyde is phosphorylated to glyceraldehyde 3-phosphate.

Fructose metabolism

Trying to Answer the Rationalization Question

“How can one rationalize the fact that a separate pathway for fructose metabolism exists?” The explanation given in the Encyclopedia of Human Nutrition — that it allows separate regulation of glucose and fructose utilization — seems possible, but fails to explain the circumstances in which it would be advantageous for fructose to be converted to pyruvate, but glucose to, say, glycogen. In the absence of this I would say that there is no convincing explanation, and that one should carefully consider a number of different possibilities:

  • It is chemically difficult to create a enzyme specific for fructose to catalyse the formation of fructose 6-phosphate. This seems unlikely — we are not dealing with two molecules as similar as serine and threonine.
  • Fructose 1-phosphate has functions (metabolic fates or regulatory roles) other than energy generation in the latter stages of glycolysis. The Kegg pathway map doesn’t suggest anything in the former respect, but the entry in the Encyclopedia of Human Nutrition states: “As fructose-1-phosphate is formed, it feeds forward and enhances the activation of pyruvate kinase thereby facilitating the passage of fructose carbon to pyruvate and lactate.” I do not have access to the book, so cannot say whether this argument is developed further. However as pyruvate kinase is also activated by fructose-1,6-bisphosphate (generated from fructose 6-phosphate) there would seem to be no regulatory difference between fructose and glucose metabolism in this respect.
  • Fructose 1-phosphate lacks some regulatory role of fructose 6-phosphate (or fructose-1,6-bisphosphate) and hence results in different flux of fructose and glucose through glycolysis. This is the converse of the previous possibility. It is true that phosphofructokinase is activated by fructose 2,6-bisphosphate, which is formed from fructose 6-phosphate, and so there is a feed-forward effect when the concentration of fructose 6-phosphate is high. However the fact that fructose 1-phosphate does not have this effect would not seem to have any significance as it does not use phosphofructokinase. Another possibility is proposed in the Encyclopedia of Human Nutrition: “Since fructose enters the glycolytic pathway [later than the phosphofructokinase reaction] it does not exert an inhibitory effect on the gluconeogenic rate-limiting enzyme, fructose-1,6-bisphosphatase” As the only relevant molecule that regulates fructose-1,6-bisphosphatase is fructose 2,6-bisphosphate — inhibiting it — the argument would seem to be that the entry of fructose into glycolysis through fructose 1-phosphate allows more glucose production for other tissues. Why this would be a “good thing”, however, is not clear to me.
  • Unphosphorylated glyceraldehyde has other roles in metabolism, so its production independently of glyceraldehyde 3-phosphate is more energy-efficient. Unfortunately the other metabolic fates of glyceraldehyde are specialized and minor, and do not seem to support this possibility.

In conclusion, I personally cannot see a rationale for the separate pathway of fructose metabolism to pyruvate, although I believe that there must be one.

The Evolutionary Question

Let us use the question to consider arguments in this area. The approaches that I suggest may — in principle — be valid are those relating to actual mechanism. One can consider the number of evolutionary events that need to occur for a new pathway to evolve — the more steps, the more difficult. (I have used a similar argument in another SE answer). In this question the implicit argument is:

“The evolution of the pathway from fructose to glyceraldehyde phosphate via fructose 1-phosphate requires three steps, whereas that for a highly specific enzyme that converted fructose to fructose 6-phosphate would require only one.”

If one accepts this argument, it would suggest that there is some rationale for the fructose 1-phosphate pathway that has escaped us. Although this also seems likely for other reasons, one needs to ask whether the argument is correct. Did three separate enzymes really evolve to accomplish this, or were perhaps some of the enzymes already present and serving other purposes?

Two examples of common type of argument that I think are invalid are in the original question.

“As there are several disorders that arise from the deficiency of enzymes used in fructolysis, wouldn’t there be a selection pressure against two separate metabolic pathways?”

Selection pressure against causes of a human disease require them to have a severe effect on the survival of the species, to cause death before the individual is of a reproductive age, and to be relevant to early humans. Minor enzyme deficiency disorders of fructose metabolism, or even disorders arising from modern over-consumption of sucrose would exert absolutely no selective pressure. As it turns out fructokinase (EC 2.7.1.3) is widely distributed in nature — If one looks up fructose metabolism in fruit flies on KEGG one can follow a trail to a long list of species in which the enzyme is present. The point that I think this demonstrates is that for biochemical evolution, one needs to think when and where the pathway might have evolved.

The second example of argument that I think are invalid is

“Wouldn’t it be more economical to use a single reaction, so everything would be easier to regulate?”

I refer to this type of argument as “playing God” or “second guessing Nature” as to me it presumes that one is in a position of such knowledge and wisdom that one is able to propose the optimal design for life.

Economical in what sense? Is our concept of economy the over-riding feature driving mammalian evolution? Multiple reactions and isoenzymes abound in the metabolism of animals. Apparently ‘wasteful’ energy- or material-consuming reactions like splicing are everywhere. And the regulation of intermediate metabolism is mind-boggling in its complexity. Regulation clearly evolved after the pathways, and “ease” of doing this does not seem to have been a driving force in evolution.

The lesson I draw from this is that even the most knowledgeable molecular scientist is in a poor position to say what is economical or efficient, and to predict the outcome from the cost/benefit tradeoff Nature will make or has made to do things “better”. And it is difficult to say what is “better”.

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