Why does long-chain fatty acid synthesis involve the two-carbon precursor, malonyl CoA, rather than the one-carbon acetyl CoA (or even a three-carbon precursor).

Is this because fatty acids with an even number of carbons are somehow ‘better’ than those with an odd number, or does it reflect some aspect of the chemistry involved?

  • $\begingroup$ @kmm I do not think this question is about evolution except in the most tangential sense. There is a tendency of people to bring evolution into questions which just relate to functional utility. In this case there is no evidence that there were ever organisms that had a one-carbon pathway of fatty acid synthesis, so the question of a selective advantage does not come into play. In an effort to make people keep things simple, I have edited the question removing all references to evolution, and distilling it to its essentials, which now seem capable of a factual answer. $\endgroup$
    – David
    Aug 26, 2020 at 12:03
  • $\begingroup$ Thanks for the edit! The new question is pretty much what I'm interested in knowing about! $\endgroup$
    – Sid
    Aug 26, 2020 at 12:30
  • $\begingroup$ @kmm I did give the answer a read and I learnt something new, but it didn't help me exactly with what I wanted to know, thanks for providing the link though! $\endgroup$
    – Sid
    Aug 26, 2020 at 12:32
  • $\begingroup$ @David Now it seems more appropriate for chemistry.SE, as it is about biochem and not biology. $\endgroup$
    – kmm
    Aug 26, 2020 at 14:03
  • $\begingroup$ @kmm It is totally on-topic here as it is about biochemical pathways and metabolism, which are (molecular) biological concepts, not about chemistry per se. You will find dozens of questions in this category on the site. Please withdraw your close vote, I am in the process of answering. You will see my answer is about metabolic strategies, not pure chemistry. $\endgroup$
    – David
    Aug 26, 2020 at 14:13

1 Answer 1


The answer to this question lies in the chemistry of fatty acid synthesis — specifically the chemical energetics of the reactions. For those new to the biochemistry there is a basic concept that must be understood: that a reaction can occur spontaneously only if it involves a negative change in Gibbs Free Energy. This is discussed, among other places, in my answer to another question.

As regards long-chain fatty acid synthesis, the answer can be found in Section 22.4 of Berg et al. Biochemistry some of which I summarize here.

The reactants in fatty acid synthesis are linked to a protein during the cycle of reactions — acyl-carrier protein, ACP:

malonyl CoA + ACP ⇌ malonyl ACP + CoA

The first condensation reaction of a malonyl constituent in the elongation cycle of reactions is shown below.

Fatty Acid Synthesis condensation reaction

The key point to note is that in this step the malonyl carboxylic acid group is released as carbon dioxide with a substantial decrease in free energy that makes the reaction favourable. Without it the reaction would not proceed, which is why the synthesis of acetoacetyl ACP from two molecules of acetyl ACP does not occur.

It is worth adding that this free energy is ultimately derived from ATP, which is needed to drive the reaction in which malonyl CoA is formed from acetyl CoA and carbon dioxide.

Formation of malonyl CoA


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