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The hexokinase, phosphofructokinase and pyruvate kinase steps of glycolysis (1,3 and 10, below) are the only ones that are irreversible, and are also the steps where glycolysis is regulated.

Glycolysis

Is it necessary for a regulatory step in glycolysis to be irreversible, and if so does this apply to metabolic pathways generally?

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    $\begingroup$ Is this a homework question? What is your basis for the generalization from one pathway — namely glycolysis? What have you done to try to answer this question yourself? $\endgroup$ – David Nov 15 '17 at 21:43
  • $\begingroup$ @David I rephrased it-please ignore that generalization. I've tried to find an explanation on Berg's 7th ed. Biochemistry. It (and Mathews' Biochemistry from which my course's lectures are taken) states that the reactions are essentially irreversible on physiological conditions, and go on explaining the control on these reactions' enzymes. We've been told at our course several times (with no explanation) that regulation of pathways usually occurs at irreversible steps. $\endgroup$ – idanp Nov 16 '17 at 19:53
  • $\begingroup$ This is not a homework question; I want to know if and why this is true, and if not are there any counter examples some of you may know. $\endgroup$ – idanp Nov 16 '17 at 19:54
  • $\begingroup$ Ok. I'll answer your question over the weekend if nobody else has stepped in first. Too busy with other things tonight. $\endgroup$ – David Nov 16 '17 at 19:55
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As far as glycolyis is concerned, the answer is straightforward. In certain cells and tissues there is a pathway working in the opposite direction — gluconeogenesis — in which the ‘irreversible’ steps of glycolysis are, in fact (and of necessity), reversed by a different enzymic reaction in which the position of the equilibrium is in the opposite direction.

Glycolyis and Gluconeogenesis

Obviously if it is metabolically appropriate for glycolysis to occur it is inappropriate for gluconeogenesis to occur. The only way of turning e.g. glycolysis off while at the same time turning gluconeogenesis on is by regulating the activity of the different enzymes at these three steps.

Glycolysis is, therefore a special case in sharing many reactions with another pathway working in the reverse direction. What about pathways in which the interconversions only proceed in one direction. Classic examples are biosynthetic pathways that are regulated by what is known as ‘feedback’ or ‘end-product’ inhibition. An example (for which I happen to have my own diagram) is the synthesis of isoleucine from threonine in bacteria:

synthesis of ile

When the concentration of isoleucine increases to a certain amount (sufficient for the cell’s needs) this inhibits the enzyme threonine deaminase, preventing the wasteful conversion of threonine to isoleucine.

The main point is not the position of equilibrium of the threonine deaminase reaction (I haven’t checked it yet) but that it is the first unique step in the synthesis pathway. Hence regulating this step prevents the unnecessary removal of threonine in a way that does not allow the wasteful accumulation of intermediates.

Moral

There is an old party game in which you pass a pair of scissor to your neighbour saying “I pass you these scissors crossed” or “I pass you these scissors uncrossed”. The initiates then tell you whether you have performed the operation correctly. The uninitiated player assumes that what is important is whether the scissors are crossed. In fact, it is whether or not your legs are crossed. Beware of false associations.

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    $\begingroup$ This is useful information, but there is also a different aspect on the question. Regardless of the pathway, I think the thermodynamics of an irreversible reaction make it a good candidate for regulation, in general. I believe this is related to the fact that a reaction with a large free energy difference can "drive" a pathway, while an equilibrium reaction cannot. This is explored in Metabolic Control Analysis, see en.wikipedia.org/wiki/Metabolic_control_analysis I am not an expert in this stuff though ... $\endgroup$ – Roland Nov 22 '17 at 17:37
  • $\begingroup$ After consideration I deliberately avoided posing the question of whether all regulation steps in biosynthetic pathways (e.g. theonine deaminase, above) are thermodynamically irreversible, partly because I did not know if this is so, and partly because I regard it as subsiary to the question of where to control a pathway. For example, if in all cases the first commited step in biosynthetic pathways were irreversible one would conclude that evolution pressures had selected from alternative chemistries. A good question but one I can't answer. The evidence interests me more than theory, though. $\endgroup$ – David Nov 22 '17 at 21:50
  • $\begingroup$ @Roland Thanks that's a nice way of looking at it. $\endgroup$ – idanp Nov 29 '17 at 20:23
  • $\begingroup$ @David This might be a digression but are there other criteria for which steps should be regulated other than the first unique ones? $\endgroup$ – idanp Nov 29 '17 at 20:35
  • $\begingroup$ @idnap — not that I can think of, although others may. I could envisage a situation where A ⇋ B → C ⇋D etc. in which B → C is regulated rather than A ⇋ B. If the A ⇋ B reaction didn't require energy or reducing power (e.g. an isomerization) and the equilibrium was midway between the two it wouldn't really matter if the next step were regulated. As A was drawn off in some other direction, B would be converted back to A. Can't think of any examples off the cuff. $\endgroup$ – David Nov 30 '17 at 14:45

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