Information for clinicians
6a Alpha-oxidation of phytanic acid
Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is derived from dietary sources only, mainly from dairy and ruminant fats. Phytanic acid is a 3-methyl branched chain fatty acid, which cannot undergo straightforward beta-oxidation like other fatty acids since the presence of the methyl group at the 3-position blocks beta-oxidation. Nature has resolved this problem by creating an alpha-oxidation mechanism in which the terminal carboxyl group is released as CO2. Accordingly, phytanic acid first undergoes alpha-oxidative chain shortening to produce pristanic acid (2,4,6,10-tetramethylpentadecanoic acid) and CO2. All steps from phytanoyl-CoA to pristanic acid occur in peroxisomes [Wanders et al 2001]:
- Activation of phytanic acid to phytanoyl-CoA.
- Hydroxylation of phytanoyl-CoA to 2-hydroxyphytanoyl-CoA by the enzyme phytanoyl-CoA hydroxylase, encoded by PHYH. Phytanoyl-CoA hydroxylase is equipped with a PTS2 signal, and is targeted to the peroxisome by means of the PTS2 receptor, encoded by the PEX7 gene.*
- Conversion of 2-hydroxyphytanoyl-CoA into pristanal and formyl-CoA via the enzyme 2-hydroxyphytanoyl-CoA lyase** encoded by 2-HPCL.
- Conversion of pristanal into pristanic acid via an ill-defined aldehyde dehydrogenase [Jansen et al 2001].
- Conversion of pristanic acid into pristanoyl-CoA via the peroxisomal very-long-chain acyl-CoA synthetase**, which has its catalytic site facing the lumen of the peroxisome [Smith et al 2000].
*In case of a deficiency at the level of the PTS2 receptor, phytanoyl-CoA hydroxylase cannot be properly imported into the peroxisome leading to its functional deficiency.
**The other enzymes from the phytanic acid alpha-oxidation route, including 2-hydroxy phytanoyl-CoA lyase and very-long-chain acyl-CoA synthetase, are PTS1 proteins, which are targeted to the peroxisome by means of the PTS1 receptor, encoded by the PEX5 gene.
Once pristanic acid has been activated to pristanoyl-CoA it undergoes three cycles of beta-oxidation in the peroxisomes to generate 4,8-dimethylnonanoyl-CoA, which then is transported to mitochondria for final oxidation to CO2 and H2O in the form of its carnitine ester.
Page last updated 26 June 2006