Breakdown of 2-hydroxylated straight chain fatty acids via peroxisomal 2-hydroxyphytanoyl-CoA lyase: a revised pathway for the alpha-oxidation of straight chain fatty acids

J Biol Chem. 2005 Mar 18;280(11):9802-12. doi: 10.1074/jbc.M413362200. Epub 2005 Jan 11.


2-Hydroxyfatty acids, constituents of brain cerebrosides and sulfatides, were previously reported to be degraded by an alpha-oxidation system, generating fatty acids shortened by one carbon atom. In the current study we used labeled and unlabeled 2-hydroxyoctadecanoic acid to reinvestigate the degradation of this class of lipids. Both in intact and broken cell systems formate was identified as a main reaction product. Furthermore, the generation of an n-1 aldehyde was demonstrated. In permeabilized rat hepatocytes and liver homogenates, studies on cofactor requirements revealed a dependence on ATP, CoA, Mg(2+), thiamine pyrophosphate, and NAD(+). Together with subcellular fractionation data and studies on recombinant enzymes, this led to the following picture. In a first step, the 2-hydroxyfatty acid is activated to an acyl-CoA; subsequently, the 2-hydroxy fatty acyl-CoA is cleaved by 2-hydroxyphytanoyl-CoA lyase, to formyl-CoA and an n-1 aldehyde. The severe inhibition of formate generation by oxythiamin treatment of intact fibroblasts indicates that cleavage through the thiamine pyrophosphate-dependent 2-hydroxyphytanoyl-CoA lyase is the main pathway for the degradation of 2-hydroxyfatty acids. The latter protein was initially characterized as an essential enzyme in the peroxisomal alpha-oxidation of 3-methyl-branched fatty acids such as phytanic acid. Our findings point to a new role for peroxisomes in mammals, i.e. the breakdown of 2-hydroxyfatty acids, at least the long chain 2-hydroxyfatty acids. Most likely, the more abundant very long chain 2-hydroxyfatty acids are degraded in a similar manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / chemistry
  • Animals
  • Binding, Competitive
  • Brain / metabolism
  • Carbon-Carbon Lyases / chemistry*
  • Carbon-Carbon Lyases / physiology
  • Coenzyme A / metabolism
  • Dose-Response Relationship, Drug
  • Fatty Acids / chemistry*
  • Fatty Acids / metabolism
  • Fibroblasts / metabolism
  • Formates / chemistry
  • Hepatocytes / metabolism
  • Humans
  • Kinetics
  • Lipid Metabolism
  • Liver / metabolism
  • Magnesium / chemistry
  • Male
  • Mice
  • Models, Chemical
  • NAD / chemistry
  • Oxygen / metabolism
  • Oxythiamine / chemistry
  • Peroxisomes / metabolism*
  • Phytanic Acid / chemistry
  • Rats
  • Rats, Wistar
  • Recombinant Proteins / chemistry
  • Subcellular Fractions
  • Thiamine Pyrophosphate / chemistry
  • Time Factors


  • Aldehydes
  • Fatty Acids
  • Formates
  • Recombinant Proteins
  • NAD
  • Oxythiamine
  • Phytanic Acid
  • Carbon-Carbon Lyases
  • 2-hydroxyphytanoyl-coenzyme A lyase
  • Magnesium
  • Thiamine Pyrophosphate
  • Oxygen
  • Coenzyme A