Are there irreversible metabolic reactions that can happen in opposite ways depending on the cellular conditions?

Question

Irreversible reactions are thermodynamically irreversible, not microscopically irreversible. "Irreversible" here means the reaction happens "out-of-equilibrium". It is a macroscopic property.

Being (thermodynamically) irreversible doesn't mean that a reaction cannot be inverted if conditions (temperature, pressure, concentration of species) change so that the reaction then spontaneously proceeds in the opposite direction as in the previous conditions. In other words, a reaction can happen irreversibly (spontaneously) in one direction in given conditions, and happen irreversibly (spontaneously) in the opposite direction in other conditions.

Are there any known (reported) examples of metabolic reactions that are found to happen in opposite directions depending on the conditions in which a given cell or cell type is found, and that happen thermodynamically irreversibly in either case? I have found reactions that happen irreversibly in opposite directions in different cell types (although I am not sure the reactions are irreversible in the respective cases):

Lactate dehydrogenase catalyzes the interconversion of pyruvate and lactate with concomitant interconversion of NADH and NAD+. It converts pyruvate, the final product of glycolysis, to lactate when oxygen is absent or in short supply, and it performs the reverse reaction during the Cori cycle in the liver.

Ref.: Lactate dehydrogenase (Wikipedia)

But I am wondering about a case where such inversion can happen in different conditions or states for a given cell or cell type.

[Note: see also the discussion in the comments for clarifications if needed.]

Answer 1

Reversibility of biochemical reactions

The general view of the way “irreversibility” is regarded in biochemistry is well summarized by the respected enzymologist, Athel Cornish-Bowden:

“Mathematically and thermodynamically there are no irreversible reactions in chemistry, and all enzymes catalyse reversible reactions. All reactions have finite standard Gibbs energies, which is just another way of saying that they all have finite equilibrium constants. Nonetheless, for an enzyme like pyruvate kinase, with an equilibrium constant of the order of 10⁵, one may feel that this is just a mathematical nicety and that the thermodynamic necessity for the reverse reaction to be possible has no practical consequences for cell physiology, and in practice many metabolic reactions are conventionally regarded as irreversible. This typically means that they have equilibrium constants of the order of 1000 or more, though when the mass action ratio in the cell also strongly favours the forward direction a reaction with a substantially smaller equilibrium constant than this can be regarded as irreversible.“

[my emphases]

The standard textbook example of this is the three reactions of glycolysis — hexokinase, phosphofructokinase and phosphoenolpyruvate carboxykinase — that are regarded as effectively irreversible, a view supported by the fact that gluconeogenesis (the overall reverse process to glycolysis) employs separate enzymes for these steps. To quote one such text, Biochemistry by Berg et al.:

“However gluconeogenesis is not a reversal of glycolysis. Several reactions must differ because the equilibrium of glycolysis lies far on the side of pyruvate formation.“

The text then elaborates on the enzymes and lists the standard free energy changes of the reactions they catalyse (ΔG^0′) as in the table below, to which I have added the equilibrium constants (K′_eq) calculated for the same ‘standard’ conditions.

Reaction	K′eq	ΔG0′ (kcal/mol)
Hexokinase	1.32 x 10–6	–8.0
Phosphofructokinase	1.25 x 10–5	–5.3
PEP carboxykinase	1.11 x 10–3	–4.0

The PEP carboxykinase value is consistent with the border value of Cornish-Bowden, above.

So, in my opinion, the question becomes whether there are any examples of reactions at this thermodynamic borderline that are reversed under certain physiological circumstances.

Examples of reversal of very thermodynamically unfavourable reactions

I feel that there are probably other examples I should know of, but will be happy to add any that others can supply to make a community answer. However at the moment the only one that comes to mind is the carbonic anhydrase reaction:

HCO₃⁻ + H⁺ → CO₂ + H₂O

which has an equilibrium constant of the order of 10^–3. (I have found values of 1.7–2.7 x 10^–3.)

The situation is complicated because of the equilibrium between bicarbonate and carbonic acid, and between dissolved and gaseous carbon dioxide. However, the striking fact is that in the tissues the enzyme catalyses the conversion of carbon dioxide produced in metabolism to bicarbonate:

Tissues: CO₂ → HCO₃⁻

whereas in the lungs the reverse occurs in order to allow the carbon dioxide to be removed from the blood:

Lungs: HCO₃⁻ → CO₂

What drives the ‘unfavourable’ conversion of carbon dioxide to carbonate in the tissues? One factor must be the high concentration of CO₂; another must be the lower pH, which, of course, represents an increase in the concentration of hydrogen ions. Both of these are a result of oxidative metabolism in the tissues.

Footnote: Lactate Dehydrogenase

I see that the poster has edited his question to refer to lactate dehydrogenase. The value of ΔG^0′ for LDH is –6 kcal/mol, so it falls into the ‘irreversible’ category biochemical reactions, although, strangely, this is seldom, if ever, mentioned. I don’t see what the poster has against this example. Liver cells can perform glycolysis and form pyruvate and they certainly convert lactate to pyruvate, so the same cell is subject to different circumstances (high blood lactate concentration v. low blood lactate concentration) when catalysing the reaction in opposite directions.