Can enzymes catalyze thermodynamically unfavorable reactions?

Question

Can biological enzymes catalyze thermodynamically unfavorable reactions? I read that an enzyme lowers the activation energy of a reaction by offering an alternative reaction pathway with a lower activation energy, however the ΔG of the reaction is unchanged. If enzymes can do this, then how exactly does this work?

Answer 1

Enzymes can catalyze a thermodynamically unfavorable reaction by coupling it with a thermodynamically favorable reaction. Most often, enzymes use ATP hydrolysis reaction (energetically favorable) as a source of energy (in simple terms) to drive the unfavorable reaction forward. One important point to keep in mind here is that enzymes don't drive a reaction equilibrium forward or backward; they just help in achieving the reaction equilibrium faster. Also pay attention that enzyme itself does not change the thermodynamics of a reaction (as you say, ∆G of the concerned reaction remains the same, except at equilibrium), coupling of a favorable reaction with an unfavorable one only helps in making the overall reaction favorable. This phenomenon, of one reaction changing the rate of another reaction, is called induced catalysis and has nothing to do with the enzyme itself.

I will talk about how enzymes do this using examples, while the other answer talks about the semantics. An example which will help you understand this concept is ATP synthase. It is an enzyme found in the inner mitochondrial membrane which allows the movement of H⁺ from the inter-membrane space towards the mitochondrial matrix, using the energy of movement (since this is favorable and exergonic) to generate ATP. The reaction would look like this:

$$\ce{ADP + P_i + 3 H^+_{IMS} \rightarrow ATP + 3 H^+_{matrix}}$$ (remember that exactly 3 H⁺ are not required, this is a simplified version)

But, ATP synthase does not drive the reaction forward; it just helps in reaching the following equilibrium faster: $$\ce{H^+_{IMS} \leftrightharpoons H^+_{matrix}}$$ i.e. keeping the amount of H⁺ in inter-membrane space and matrix the same. This is why a constant gradient is required to keep them in working condition. For this, the electron transport chain continuously throws H⁺ into the inter-membrane space to maintain an electrochemical gradient. Along with this, enzymes ATP-ADP translocase and phosphate carrier continuously take out ATP from the matrix and throw in ADP and P_i. However, this lowers the electrochemical gradient (exchanging ADP^3- for ATP^4- in inter-membrane space, while phosphate carrier catalyzes electroneutral reaction), making the final reaction: $$\ce{ADP + P_i + 4 H^+_{IMS} \leftrightharpoons ATP + 4 H^+_{matrix}}$$

However, since the enzyme just helps in maintaining equilibrium, it can also work backwards i.e. it can also transport H⁺ against electrochemical gradient (unfavorable), coupling it with ATP hydrolysis (favorable) to reach equilibrium. The enzyme is now called ATPase and the reaction becomes: $$\ce{ATP + 4 H^+_{matrix} \rightarrow ADP + P_i + 4 H^+_{IMS}}$$

There are many more such enzymes which couple ATP hydrolysis (or other favorable reactions) to catalyze reactions which are either unfavorable or very slow (i.e. require a source of activation energy) under normal cellular conditions. Another factor, as the other answer explains, which helps in this is changing the concentration of products. As seen above, ATP-ADP translocase and phosphate carrier continuously decrease the concentration of products (ATP) and increase concentration of reactants (ADP and P_i) so that the overall equilibrium shifts forward and the enzyme keeps on driving the reaction forward (this, again, has nothing to do with with the enzyme itself, it is called Le Chatelier's Principle). Again, the other answer focuses on this issue.

References:

• Enzyme - Wikipedia

• Cellular Respiration

Answer 2

Can enzymes catalyze thermodynamically unfavourable reactions?

Enzymes don't change the equilibrium of a reaction, but the fact that an equilibrium exists means that the reaction proceeds in both the forward and reverse directions. Before equilibrium is attained, ΔG for the reaction is not 0. Thus, by definition, one direction is thermodynamically favourable (ΔG<0) while the other is thermodynamically unfavourable (ΔG>0). Since an enzyme lowers the activation energy of a reaction, it is catalysing both the forward and reverse reactions. This is a semantic argument since the reaction will still proceed in the direction which is thermodynamically favourable.

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How can enzymes catalyze thermodynamically unfavourable reactions?

Other than in the sense I described above, enzymes do not catalyze thermodynamically unfavourable reactions. However, biological systems can make unfavourable reactions favourable. In addition to the reaction coupling discussed in the other answer (sometimes referred to as pushing) thermodynamically unfavourable reactions can be made favourable by pulling. In this case, for reactions where ΔG°>0 (ie the reaction under standard conditions is unfavourable), the reaction can be made favourable by decreasing the concentration of products relative to reactants, such as by immediately using them in a subsequent, thermodynamically favourable reaction. Mathematically, the relationship between the free energy change of the reaction under standard conditions and the actual reaction is given by:

$$\Delta G=\Delta G^{\circ} +R T\ln\left(\frac{[P]}{[R]}\right)$$

As the ratio of product to reactant concentrations decreases, the actual free energy change of the reaction decreases and can be made thermodynamically favourable.

To be clear, it is not the enzyme that makes an unfavourable reaction favourable (again, it only lowers activation energy). Rather, the enzyme is catalyzing a reaction that is now thermodynamically favourable.