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.

Pathway

Phytanic acid

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

Phytanic acid is first attached to CoA to form phytanoyl-CoA.
Phytanoyl-CoA is oxidized by phytanoyl-CoA dioxygenase (PHYH), in a process using Fe²⁺ and O₂, to yield 2-hydroxyphytanoyl-CoA.
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).
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)

Phytosphingosine

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.

Phytosphingosine (PHS) is phosphorylated to PHS 1-phosphate by SPH kinase. This is mainly catalyzed by SPHK2.
PHS-1P is converted to 2-hydroxypalmital (2-OH C16:0-CHO) by SGPL1.
2-OH C16:0-CHO is converted to 2-hydroxypalmitate (2-OH C16:0-COOH) by ALDH3A2.
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).
2-OH C16:0-CoA is converted to pentadecanoal (C15:0-CHO) by HACL2, which is also TPP-dependent (HACL1 can compensate if HACL2 is knocked out).
C15:0-CHO is converted to pentadecanoic acid (C15:0-COOH) by ALDH3A2.
C15:0-COOH is converted to pentadecanoyl-CoA by one of the long-chain ACSs.

Deficiency

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.

References

1 2 Kitamura, T; Seki, N; Kihara, A (28 March 2017). "Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum". Proceedings of the National Academy of Sciences of the United States of America. 114 (13): E2616–E2623. doi:10.1073/pnas.1700138114. PMC 5380038. PMID 28289220.

Casteels, M; Foulon, V; Mannaerts, GP; Van Veldhoven, PP (2003), "Alpha-oxidation of 3-methyl-substituted fatty acids and its thiamine dependence", European Journal of Biochemistry, 270 (8): 1619–1627, doi:10.1046/j.1432-1033.2003.03534.x, PMID 12694175
Quant, Patti A.; Eaton, Simon, eds. (1999), Current views of fatty acid oxidation and ketogenesis : from organelles to point mutations, vol. 466 (2nd ed.), New York, NY: Kluwer Acad./Plenum Publ., pp. 292–295, ISBN 0-306-46200-1

[Kitamura17-1] 1 2 Kitamura, T; Seki, N; Kihara, A (28 March 2017). "Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum". Proceedings of the National Academy of Sciences of the United States of America. 114 (13): E2616–E2623. doi:10.1073/pnas.1700138114. PMC 5380038. PMID 28289220.