Although the fatty acid oxidation scheme works neatly for even‐ numbered chain lengths, it can't work completely for fatty acids that contain an odd number of carbons. β‐oxidation of these compounds leads to propionyl‐CoA and acetyl‐CoA, rather than to two acetyl‐CoA at the final step. The propionyl‐CoA is not a substrate for the TCA cycle or other simple pathways. Propionyl‐CoA undergoes a carboxylation reaction to form methylmalonyl‐CoA. This reaction requires biotin as a cofactor, and is similar to an essential step in fatty acid biosynthesis. Methylmalonyl‐CoA is then isomerized by an epimerase and then by methylmalonyl‐CoA mutase—an enzyme that uses Vitamin B 12 as a cofactor—to form succinyl‐CoA, which is a TCA‐cycle intermediate.
Branched‐chain fatty acids present a problem of a similar kind. For example, phytanic acid, found in animal milk, can't be oxidized directly by β‐oxidation because the addition of water is a problem at the branched β‐carbon.
The first step in the digestion of this compound is the oxidation of the χ carbon by molecular oxygen. Then the original carboxyl group is removed as CO 2, leaving a shorter chain. This chain can now be accommodated by the β‐oxidation reactions, because the new β‐carbon now lacks a methyl group. (Note that the branch points yield propionyl‐CoA, and must enter the TCA cycle through methylmalonate.