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Synthesis of d-Methylmalonyl CoA: Initially, propionyl CoA is carboxylated, resulting in the formation of D-methylmalonyl CoA. The enzyme propionyl CoA carboxylase requires biotin and ATP as coenzymes, just like ACC and most other carboxylases.

Formation of l-Methylmalonyl CoA: Following that, the D-isomer is converted into the L-form by the enzyme methylmalonyl CoA racemase.

Synthesis of Succinyl CoA: Finally, the carbons of L-methylmalonyl CoA undergo rearrangement, leading to the formation of succinyl CoA. Succinyl CoA can then enter the TCA cycle. It's important to note that this is the only example of a glucogenic precursor generated from fatty acid oxidation. The enzyme methylmalonyl CoA mutase necessitates the presence of a coenzyme form of vitamin B12, specifically deoxyadenosylcobalamin. This mutase reaction, along with another reaction in the body, is dependent on vitamin B12. It should be mentioned that in patients with vitamin B12 deficiency, both propionate and methylmalonate are excreted in the urine. There are two types of heritable methylmalonic acidemia and aciduria, one caused by a missing or deficient mutase (or one with reduced affinity for the coenzyme), and another in which the patient is unable to convert vitamin B12 into its coenzyme form. Both types result in metabolic acidosis and neurologic manifestations.

Unsaturated fatty acid β-oxidation: The oxidation of unsaturated fatty acids produces intermediates that cannot serve as substrates for 2,3-enoyl CoA hydratase. Therefore, additional enzymes are required. Oxidation of a double bond at an odd-numbered carbon, such as 18:1(9) (oleic acid), requires the presence of an additional enzyme called 3,2-enoyl CoA isomerase. This enzyme converts the 3-cis derivative, obtained after three rounds of β-oxidation, into the 2-trans derivative required by the hydratase. On the other hand, oxidation of a double bond at an even-numbered carbon, such as 18:2(9,12) (linoleic acid), necessitates the presence of an NADPH-dependent 2,4-dienoyl CoA reductase in addition to the isomerase. It is worth noting that due to unsaturated fatty acids being less reduced than saturated fatty acids, their oxidation produces fewer reducing equivalents.

Peroxisomal β-oxidation: Fatty acids with a length of VLCFA ≥22 undergo a preliminary β-oxidation process in peroxisomes. This is because peroxisomes, and not mitochondria, are the primary site of the synthetase responsible for activating fatty acids of this length. The shortened fatty acid, linked to carnitine, diffuses to a mitochondrion for further oxidation. In contrast to mitochondrial β-oxidation, the initial dehydrogenation in peroxisomes is catalyzed by a FAD-containing acyl CoA oxidase. The FADH2 produced is oxidized by O2, resulting in the reduction of hydrogen peroxide (H2O2). This step does not generate ATP. The H2O2 is then reduced to H2O by catalase. Genetic defects affecting the ability to target matrix proteins to peroxisomes (leading to Zellweger syndrome, a peroxisomal biogenesis disorder) or to transport VLCFA across the peroxisomal membrane (resulting in X-linked adrenoleukodystrophy) cause the accumulation of VLCFA in the blood and tissues.

C. Peroxisomal α-oxidation

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d-Methylmalonyl CoA synthesis: First, propionyl CoA is carboxylated, forming D-methylmalonyl CoA. The enzyme propionyl CoA carboxylase has an absolute requirement for the coenzymes biotin and ATP, as do ACC and most other carboxylases.
b.
l-Methylmalonyl CoA formation: Next, the D-isomer is converted to the L-form by the enzyme methylmalonyl CoA racemase.
c.
Succinyl CoA synthesis: Finally, the carbons of L-methylmalonyl CoA are rearranged, forming succinyl CoA, which can enter the TCA cycle (see p. 113). [Note: This is the only example of a glucogenic precursor generated from fatty acid oxidation.] The enzyme methylmalonyl CoA mutase requires a coenzyme form of vitamin B12 (deoxyadenosylcobalamin). The mutase reaction is one of only two reactions in the body that require vitamin B12 (see p. 379). [Note: In patients with vitamin B12 deficiency, both propionate and methylmalonate are excreted in the urine. Two types of heritable methylmalonic acidemia and aciduria have been described: one in which the mutase is missing or deficient (or has reduced affinity for the coenzyme) and one in which the patient is unable to convert vitamin B12 into its coenzyme form. Either type results in metabolic acidosis and neurologic manifestations.] 7.
Unsaturated fatty acid β-oxidation: The oxidation of unsaturated fatty acids generates intermediates that cannot serve as substrates for 2,3-enoyl CoA hydratase (see Fig. 16.17). Consequently, additional enzymes are required. Oxidation of a double bond at an odd-numbered carbon, such as 18:1(9) (oleic acid), requires one additional enzyme, 3,2-enoyl CoA isomerase, which converts the 3-cis derivative obtained after three rounds of β-oxidation to the 2-trans derivative required by the hydratase. Oxidation of a double bond at an even-numbered carbon, such as 18:2(9,12) (linoleic acid), requires an NADPH-dependent 2,4-dienoyl CoA reductase in addition to the isomerase. [Note: Because unsaturated fatty acids are less reduced than saturated fatty acids, fewer reducing equivalents are produced by their oxidation.] 8.
Peroxisomal β-oxidation: VLCFA ≥22 carbons in length undergo a preliminary β-oxidation in peroxisomes, because peroxisomes and not mitochondria are the primary site of the synthetase that activates fatty acids of this length. The shortened fatty acid (linked to carnitine) diffuses to a mitochondrion for further oxidation. In contrast to mitochondrial βoxidation, the initial dehydrogenation in peroxisomes is catalyzed by a FAD-containing acyl CoA oxidase. The FADH2 produced is oxidized by O2, which is reduced to hydrogen peroxide (H2O2). Therefore, no ATP is generated from this step. The H2O2 is reduced to H2O by catalase (see p. 148). [Note: Genetic defects in the ability either to target matrix proteins to peroxisomes (resulting in Zellweger syndrome, a peroxisomal biogenesis disorder) or to transport VLCFA across the peroxisomal membrane (resulting in X-linked adrenoleukodystrophy) lead to accumulation of VLCFA in the blood and tissues.]
C. Peroxisomal α-oxidation