title: 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.
abstract: 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.
authors.affiliation: Afdeling Farmacologie, Departement Celbiologie, Katholieke Universiteit Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Foulon
authors.forename: Mieke
authors.initials: M
authors.lastname: Sniekers
authors.forename: Els
authors.initials: E
authors.lastname: Huysmans
authors.forename: Stanny
authors.initials: S
authors.lastname: Asselberghs
authors.forename: Vincent
authors.initials: V
authors.lastname: Mahieu
authors.forename: Guy P
authors.initials: GP
authors.lastname: Mannaerts
authors.forename: Paul P
authors.initials: PP
authors.lastname: Van Veldhoven
authors.forename: Minne
authors.initials: M
authors.lastname: Casteels
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D019755:Carbon-Carbon Lyases / Q000737:chemistry* / Q000502:physiology; D003065:Coenzyme A / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000737:chemistry* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005561:Formates / Q000737:chemistry; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008274:Magnesium / Q000737:chemistry; D008297:Male; D051379:Mice; D008956:Models, Chemical; D009243:NAD / Q000737:chemistry; D010100:Oxygen / Q000378:metabolism; D010119:Oxythiamine / Q000737:chemistry; D020675:Peroxisomes / Q000378:metabolism*; D010831:Phytanic Acid / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000737:chemistry; D013347:Subcellular Fractions; D013835:Thiamine Pyrophosphate / Q000737:chemistry; D013997:Time Factors
chemical_list: D000447:Aldehydes; D005227:Fatty Acids; D005561:Formates; D011994:Recombinant Proteins; D009243:NAD; D010119:Oxythiamine; D010831:Phytanic Acid; D019755:Carbon-Carbon Lyases; C121516:2-hydroxyphytanoyl-coenzyme A lyase; D008274:Magnesium; D013835:Thiamine Pyrophosphate; D010100:Oxygen; D003065:Coenzyme A