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
[edit]Phytanic acid
[edit]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
[edit]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]
- 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
[edit]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]
References
[edit]- 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. 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