ATP, NADH and FADH2 are high energy molecules. The second half of glycolysis is known as the pay-off phase, characterised by a net gain of the energy-rich molecules ATP and NADH.

In fermentation, for example, pyruvate still has energy into it. If you had oxygen around, you could have cellular respiration, you could go into the Krebs cycle, the citric acid cycle, and derive more ATP from pyruvate. But the term 'high energy' or 'energy-rich' is not commonly used to describe pyruvate. Is it wrong to use such terms to describe pyruvic acid?


2 Answers 2



Do not use the term ‘high-energy’ to refer to biochemical intermediates because many people (including the OP) do not understand what it is supposed to mean. However, if you insist in using it in its historic biochemical sense, pyruvate does not qualify,

The terms ‘high-energy’ and ‘energy-rich’, although traditional in biochemistry, are best avoided. This is because they are meaningless to a chemist and misleadingly imprecise to a biochemist. This question is a good example of the misunderstanding of the term.

What is important is not to stick ‘labels’ on molecules (leave that to undergraduate politics) but to understand and articulate the energetic role molecules have in metabolism. As regards ATP and NADH, I have already provided such an explanation in the answer to another question. I will only summarize here to make a comparison with pyruvate.

However one thing should be emphasized at the start. Statements about molecules containing ‘energy’ are sloppy:

  • A change in Gibbs Free Energy only occurs when a molecule reacts with other molecules, and the magnitude of this change depends on which molecule(s) it reacts with.
  • The biochemical usefulness of a molecule participating in a reaction with a negative change in free energy depends on the availability and ubiquity of reacting partners and the magnitude of the free energy change compared with that of the reacting partners.

Historic use of the term ‘energy-rich’ with respect ot ATP, NADH and pyruvate

  • In the case of ATP, the hydrolysis reaction to ADP + Pi has a high enough negative change in Gibbs Free Energy to drive many biochemical reactions that have a positive Gibbs Free Energy change, and enzymes have evolved to couple ATP hydrolysis to such reactions. The latter is key — there must be a way of using this energy!

  • In the case of NADH, its oxidation to NAD+ has a standard redox potential of +0.32V, which is, in effect, a negative standard free-energy change. However it can only occur in conjunction with another redox ‘half-reaction’ with a redox potential that will result in an overall negative free-energy change. In fact the redox potential of the NADH oxidation half-reaction sufficient to drive many biochemical reductions, and enzymes have evolved to couple NADH (and NADPH) oxidation to such reactions. Furthermore the oxidative phosphorylation system has evolved to allow production of ATP from NADH.

  • In the case of pyruvate, its reduction to lactate has a standard redox potential of –0.19V, so it has a positive standard free-energy change. Clearly quite a different situation to NADH, with which it reacts to regenerate NAD+. So pyruvate could only be considered in relation to half reactions of even higher redox potential. In fact, it plays no general role in metabolism for driving thermodynamically disfavoured reactions.

The cause of the confusion

The explanation above shows that pyruvate does not conform to the description ‘energy-rich‘ in its (discouraged) historic biochemical usage. What caused the OP to think so? He states:

…pyruvate still has energy into it. If you had oxygen around, you could have cellular respiration, you could go into the Krebs cycle, the citric acid cycle, and derive more ATP from pyruvate.

What this is actually saying is that pyruvate is a metabolic source of energy in the form of ATP because it can be metabolized aerobically (in the pyruvate dehydrogenase reaction) like glucose and a host of other intermediates. This is not the usage of the term ‘energy-rich’. All one is saying here is that when pyruvate, glucose, fatty acids etc. etc. are oxidized to carbon dioxide and water the C–C bond energy etc. can be utilized in biochemical reactions (reductions) rather than being released as heat.

Appendix 1: Other phospho-compounds with a high group-transfer potential

An alternative to ‘energy-rich‘ for compounds such as ATP is that they have a high ‘group-transfer potential‘ — the free energy change in a particular reaction. The student of biochemistry will be aware that particular reactions in glycolysis and the tricarboxylic acid cycle can phosphorylate ADP to ATP, and so must have a high group transfer potential. Some examples (taken from Berg et al.) are listed below. These are all ΔG0′ (kJ/mol) for the hydrolysis of the phospho/phosphate group.

Phosphoenolpyruvate        –61.9
1,3-bisphosphoglycerate    –49.9
Creatine phosphate         –43.1
ATP (to ADP)               –30.5  ------------------
Glucose 1-phosphate        –20.9
Glucose 6-phosphate        –13.8
Glycerol 3-phosphate        –9.2

Thus, phosphoenolpyruvate, 1,3-bisphosphoglycerate and creatine phosphate have a higher group transfer potential than ATP, as expected from their role in phosphorylating ADP. They can be considered ‘energy-rich‘ in the historical usage of the term. However, unlike ATP, they play specific — rather than general — roles in biochemical energy transfer.

Appendix 2: Other biochemical reducing agents

Although biochemical reducing agents play a central role in overcoming the energy barriers to synthesizing reduced compounds such as fatty acids and steroids, the historical term ‘energy-rich‘ has not been applied widely to them. To provide a perspective on the reducing power of different biochemical compounds, some examples (again taken from Berg et al.) are listed below. The standard redox potential (E0′) is expressed in volts, and n is the number of electrons transferred in the oxidation/reduction

Succinate (+ CO2)   α-ketoglutarate   2       –0.67
Ferrodoxin (Ox)     Ferrodoxin (Red)  1       –0.43
NAD+                NADH              2       –0.32
Glutathione (Ox)    Glutathione (Red) 2       –0.23
FAD                 FADH2             2       –0.22  ---------
Pyruvate            Lactate           2       –0.19
Cytochrome c (+3)   Cytochrome c (+2) 1       +0.22
Oxygen (O + 2H+)    Water             2       +0.82
  • 1
    $\begingroup$ Oxygen to water is a 4 electron process $\endgroup$ Feb 14, 2022 at 14:02
  • 1
    $\begingroup$ @VincentFourmond — Not with reference to one atom with the product 1 molecule of water. I've clarified. (The problem is that if you try to lay out a table you have to use pre formatting that renders everything literally. Hence you can't use subscripts or superscripts etc.) $\endgroup$
    – David
    Feb 14, 2022 at 15:25

This is a related conversation between me and David Harrison, Course Director of Biochemistry for Pharmacy since 2009:


Amir, There is a problem with your nomenclature. I would describe NADH as an electron carrier not as a high energy molecule. Its reductive potential is only relevant in the presence of a molecule that has oxidative potential (say pyruvate). Similarly, I would say that ATP has a high energy phosphate bond meaning that the free energy of hydrolysis of ATP to ADP and phosphate is -7.3 kcal/mol (-30 kJ/mol) whereas a typical phosphate bond’s hydrolysis (glucose 6-phosphate) is closer -3 kcal/mol (-12 kJ/mol). Pyruvate has a higher reduction potential (-0.19V) than NAD+ (-0.32V) which explains why it is readily reduced by NADH, but the free energy for the reaction producing lactate is only -2.5 kcal/mol. So, no pyruvate is not a particularly high energy molecule under reductive condition. However, when you consider the reaction of pyruvate and oxygen to give CO2 and water the free energy is huge. But again, if you want to talk about high energy bonds neither pyruvate nor NADH have them.


Thank you. I know my question is semantic. I don’t think that terms like ‘energy-rich molecules’ and ‘high energy molecules’ are exclusively used to describe molecules that contain high energy bonds. For example, I read this in Wikipedia: The second half of glycolysis is known as the pay-off phase, characterised by a net gain of the energy-rich molecules ATP and NADH.


The reason the NADH is considered high energy in this context is that, in the presence of oxygen, NADH can be restored to NAD+ via the electron transport system (Complex I, III, and IV) to produce a proton gradient across the inner mitochondrial membrane. That gradient is then responsible for driving the F0F1-ATPase (complex V) to produce ATP from ADP and phosphate. [I should mention that there are two different mechanisms for delivering the reduction potential of NADH from the cytosol to the mitochondrial matrix, but that is a different story] But again, the energy of NADH is dependent on context. In an anaerobic environment, it is the NAD+ that is necessary for the formation of ATP and the NADH is restored to NAD+ by converting pyruvate to waste products (lactate or ethanol).

  • $\begingroup$ Three cheers for David Harrison $\endgroup$
    – user338907
    Feb 15, 2022 at 12:46

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