Alpha oxidation

Alpha oxidation (α-oxidation) is a process by which certain fatty acids are broken down by removal of a single carbon from the carboxyl end. This is generally applied to fatty acids resistant to beta-oxidation, the other process for fatty acid breakdown. In humans, alpha-oxidation is used:

• In peroxisomes to break down dietary phytanic acid, which cannot undergo beta-oxidation due to its β-methyl branch, into pristanic acid. Pristanic acid can then acquire CoA and subsequently become beta oxidized, yielding propionyl-CoA.
• In the endoplasmic reticulum to break down phytosphingosine, which cannot undergo beta-oxidation due to its 4-hydroxy group, into pentadecanoic acid, which can then be beta-oxidized after acquiring CoA.

Alpha-oxidation of phytanic acid is believed to take place entirely within peroxisomes.

1. Phytanic acid is first attached to CoA to form phytanoyl-CoA.
2. Phytanoyl-CoA is oxidized by phytanoyl-CoA dioxygenase (PHYH), in a process using Fe²⁺ and O₂, to yield 2-hydroxyphytanoyl-CoA.
3. 2-hydroxyphytanoyl-CoA is cleaved by 2-hydroxyphytanoyl-CoA lyase (specifically HACL1) in a TPP-dependent reaction to form pristanal and formyl-CoA (in turn later broken down into formate and eventually CO₂).
4. Pristanal is oxidized by aldehyde dehydrogenase (specifically ALDH3A2) to form pristanic acid.

(Propionyl-CoA is released as a result of beta oxidation when the beta carbon is substituted)

Alpha-oxidation of phytosphingosine and other sphingolipid components can entirely happen in the endoplasmic reticulum (ER), as all components of the main pathway are found in the ER.¹

1. Phytosphingosine (PHS) is phosphorylated to PHS 1-phosphate by SPH kinase. This is mainly catalyzed by SPHK2.
2. PHS-1P is converted to 2-hydroxypalmital (2-OH C16:0-CHO) by SGPL1.
3. 2-OH C16:0-CHO is converted to 2-hydroxypalmitate (2-OH C16:0-COOH) by ALDH3A2.
4. 2-OH C16:0-COOH is converted to 2-hydroxypalmityl-CoA (2-OH C16:0-CoA) by one of the long-chain acyl-CoA synthetases (ACSs).
5. 2-OH C16:0-CoA is converted to pentadecanoal (C15:0-CHO) by HACL2 (with HACL1 being able to compensate if knocked out).
6. C15:0-CHO is converted to pentadecanoic acid (C15:0-COOH) by ALDH3A2.
7. C15:0-COOH is converted to pentadecanoyl-CoA by one of the long-chain ACSs.

Enzymatic deficiency in phytanic acid alpha-oxidation (most frequently in phytanoyl-CoA dioxygenase) leads to Refsum's disease, in which the accumulation of phytanic acid and its derivatives leads to neurological damage. Other disorders of peroxisome biogenesis also prevent alpha-oxidation from occurring.

ALDH3A2 deficiency is known to cause the neurocutaneous disorder Sjögren–Larsson syndrome, in which accumulated aldehydes damage skin and nerve cells: cells that have the most sphingolipid turnover.¹