Breakdown of 2-Hydroxylated Straight Chain Fatty Acids via Peroxisomal 2-Hydroxyphytanoyl-CoA Lyase

2-Hydroxyfatty acids, constituents of brain cerebrosides and sulfatides, were previously reported to be degraded by an α-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, Mg2+, 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 α-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. 2-Hydroxyfatty acids, constituents of brain cerebrosides and sulfatides, were previously reported to be degraded by an α-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, Mg2+, 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 α-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. In mammals, 2-hydroxyfatty acids (2-OH-FA) 1The abbreviations used are: 2-OH-FA, 2-hydroxyfatty acids; 2-HPCL, 2-hydroxyphytanoyl-CoA lyase; ν, substrate/BSA ratio; PAHX, phytanoyl-CoA hydroxylase; TPP, thiamine pyrophosphate; Mops, 4-morpholinepropanesulfonic acid; BSA, bovine serum abumin; HPLC, high performance liquid chromatography.1The abbreviations used are: 2-OH-FA, 2-hydroxyfatty acids; 2-HPCL, 2-hydroxyphytanoyl-CoA lyase; ν, substrate/BSA ratio; PAHX, phytanoyl-CoA hydroxylase; TPP, thiamine pyrophosphate; Mops, 4-morpholinepropanesulfonic acid; BSA, bovine serum abumin; HPLC, high performance liquid chromatography. are present in several tissues but are most abundant in brain, where they represent ∼6% of the total fatty acids. The 2-hydroxy derivatives of C18 to C26 straight chain saturated and/or mono-unsaturated fatty acids appear to be present exclusively in cerebrosides, cerebroside sulfates, and ceramides, most of which are found in myelin (1Kishimoto Y. Radin N.S. J. Lipid Res. 1963; 58: 139-143Abstract Full Text PDF Google Scholar). Furthermore, in brain cerebrosides even more than half of the fatty acids are 2-OH-FA, and also odd-numbered fatty acids are present in an unusually large proportion (2Hajra A.K. Radin N.S. J. Lipid Res. 1963; 58: 270-278Abstract Full Text PDF Google Scholar). The ratio of 2-OH-FA to normal fatty acids increases during myelination, whereas the percentage of odd-numbered fatty acids continues to increase up to the age of 10–15 years (3Svennerholm L. Stallberg-Stenhagen S. J. Lipid Res. 1968; 9: 215-225Abstract Full Text PDF PubMed Google Scholar). In 1964 Levis and Mead (4Levis G.M. Mead J.F. J. Biol. Chem. 1964; 239: 77-80Abstract Full Text PDF PubMed Google Scholar) reported for the first time the existence of an α-oxidation system for the degradation of the C20 to C26 straight chain fatty acids of rat brain sphingolipids. It was postulated that this pathway would consist of two steps, generating first 2-hydroxy even-numbered fatty acids, and subsequently odd-numbered fatty acids one carbon atom shorter. Later, it was reported that in rat brain the decarboxylation reaction was performed by a microsomal enzyme and that a 2-keto fatty acid, found only in small amounts, was formed as an intermediate (5Lippel K. Mead J.F. Biochim. Biophys. Acta. 1968; 152: 669-680Crossref PubMed Scopus (16) Google Scholar). α-Oxidation of straight chain fatty acids has also been studied in plants, and the formation of an n – 1 aldehyde was reported by several authors (6Gerhardt B. Prog. Lipid Res. 1992; 31: 417-446Crossref PubMed Scopus (94) Google Scholar, 7Andersen Borge G.I. Slinde E. Nilsson A. Biochim. Biophys. Acta. 1998; 1394: 158-168Crossref PubMed Scopus (2) Google Scholar, 8Koeduka T. Matsui K. Akakabe Y. Kajiwara T. J. Biol. Chem. 2002; 277: 22648-22655Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). α-Oxidation has also been described in yeast (9Fulco A.J. J. Biol. Chem. 1967; 242: 3608-3613Abstract Full Text PDF PubMed Google Scholar) and in protozoa (10Kaya K. Ramesha C.S. Thompson Jr., G.A. J. Biol. Chem. 1984; 259: 3548-3553Abstract Full Text PDF PubMed Google Scholar). More recently, the involvement of peroxisomes in the α-oxidation of cerebronic acid (2-hydroxytetracosanoic acid) was described. The decarboxylation of 2-hydroxytetracosanoic acid was apparently independent of the preceding formation of an acyl-CoA and was supposed to be distinct from the α-oxidation of 3-methyl-branched fatty acids such as phytanic acid (11Sandhir R. Khan M. Singh I. Lipids. 2000; 35: 1127-1133Crossref PubMed Scopus (11) Google Scholar). The latter pathway is currently thought to proceed as follows; 1) activation to a CoA ester, 2) hydroxylation of carbon 2 by phytanoyl-CoA hydroxylase (PAHX), and 3) cleavage of the hydroxylated CoA-ester by 2-hydroxyphytanoyl-CoA lyase (2-HPCL) to formyl-CoA (12Croes K. Van Veldhoven P.P. Mannaerts G.P. Casteels M. FEBS Lett. 1997; 407: 197-200Crossref PubMed Scopus (44) Google Scholar) and a 2-methyl-branched fatty aldehyde (13Croes K. Casteels M. Asselberghs S. Herdewijn P. Mannaerts G.P. Van Veldhoven P.P. FEBS Lett. 1997; 412: 643-645Crossref PubMed Scopus (43) Google Scholar) in a TPP-dependent manner (14Foulon V. Antonenkov V.D. Croes K. Waelkens E. Mannaerts G.P. Van Veldhoven P.P. Casteels M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 10039-10044Crossref PubMed Scopus (92) Google Scholar). Both PAHX and 2-HPCL are peroxisomal enzymes. According to our data PAHX does not act on straight chain fatty acids or their CoA esters (15Croes K. Foulon V. Casteels M. Van Veldhoven P.P. Mannaerts G.P. J. Lipid Res. 2000; 41: 629-636Abstract Full Text Full Text PDF PubMed Google Scholar, 16Foulon V. Asselberghs S. Geens W. Mannaerts G.P. Casteels M. Van Veldhoven P.P. J. Lipid Res. 2003; 44: 2349-2355Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar) and, hence, cannot be involved in the formation of 2-hydroxyfatty acids; others claim, however, that PAHX can hydroxylate straight chain acyl-CoAs (17Mukherji M. Kershaw N.J. Schofield C.J. Wierzbicki A.S. Lloyd M.D. Chem. Biol. 2002; 9: 597-605Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Regardless of this discrepancy, a recently described fatty acid 2-hydroxylase, highly abundant in brain and encoded by the FA2H gene (18Alderson N.L. Rembiesa B.M. Walla M.D. Bielawska A. Bielawski J. Hama H. J. Biol. Chem. 2004; 279: 48562-48568Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar), is likely responsible for the formation of 2-hydroxyfatty acids in man. The current study was undertaken to elucidate the degradation of 2-hydroxyfatty acids and to highlight a possible role of 2-HPCL in this process. Hereby, we made use of 2-hydroxyoctadecanoic acid, labeled and and unlabeled CoA are to and than the more abundant very long chain 2-hydroxyfatty acids. 2-hydroxyoctadecanoic acid is a abundant 2-hydroxyfatty acid, it a more than of the 2-hydroxyfatty acids in brain cerebrosides in in and and (3Svennerholm L. Stallberg-Stenhagen S. J. Lipid Res. 1968; 9: 215-225Abstract Full Text PDF PubMed Google Scholar). and acid was from and acid were from acid was from The of most fatty has been described acid, labeled and unlabeled acid, and K. α-Oxidation of a acid and Van Veldhoven P.P. Mannaerts G.P. J. Biol. Chem. Full Text PDF PubMed Google (14Foulon V. Antonenkov V.D. Croes K. Waelkens E. Mannaerts G.P. Van Veldhoven P.P. Casteels M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 10039-10044Crossref PubMed Scopus (92) Google Scholar), H. Asselberghs S. Van Veldhoven P.P. Mannaerts G.P. J. Biol. Chem. Full Text PDF PubMed Google and (13Croes K. Casteels M. Asselberghs S. Herdewijn P. Mannaerts G.P. Van Veldhoven P.P. FEBS Lett. 1997; 412: 643-645Crossref PubMed Scopus (43) Google Scholar). acid was from or as from (11Sandhir R. Khan M. Singh I. Lipids. 2000; 35: 1127-1133Crossref PubMed Scopus (11) Google Scholar) and R. R. J. Chem. Scopus Google acid with was in in a for at ratio of the was to the and the acid acid, acid was The was to a in two The was in acid and at for with the acid was and in n for 2 The was and the formed 2-hydroxyoctadecanoic acid was and by was acid and acid were in a similar from acid and acid The CoA esters of 2-OH-FA were by of their ester, with in and on a was on CoA and were on a and a and were studies were by the fibroblasts and fibroblasts from were by for fibroblasts from with acyl-CoA chain acyl-CoA and were by J. Van 1 fibroblasts and rat were from The of fibroblasts from and has been described M. P. E. P. Casteels M. M. P. Van Veldhoven P.P. Mannaerts G.P. 1997; PubMed Scopus Google Scholar). were at and in and a of and and with serum or hepatocytes were as described by Mannaerts G.P. J. J. Biol. Chem. Full Text PDF PubMed Google Scholar) and permeabilized as described by Croes K. Casteels M. Van Veldhoven P.P. Mannaerts G.P. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). hepatocytes were as from and P. M. J. 1998; PubMed Scopus Google Scholar), in at and used an of and of rat liver and brain were in and fractionation of rat liver and brain was as described previously Van Veldhoven P. Van Mannaerts G.P. J. Biol. Chem. 1984; 259: Full Text PDF PubMed Google Scholar) for rat with for the of a rat brain at was in and with an of and for at to most of the myelin G.A. J. PubMed Scopus Google Scholar). were of the peroxisomal a and of and by and and protein were as described previously Van Veldhoven P. Van Mannaerts G.P. J. Biol. Chem. 1984; 259: Full Text PDF PubMed Google Scholar, Veldhoven P.P. Croes K. Asselberghs S. Herdewijn P. Mannaerts G.P. FEBS Lett. PubMed Scopus Google Scholar). to in were by with and by in 1 of by and of fatty acid in intact rat were for in of and of the with permeabilized and hepatocytes were by a cell to of labeled and the and and rat were to in and hepatocytes for R. I. K. A. M. Van Veldhoven P.P. M. Google Scholar), for with labeled in in the of Veldhoven P.P. S. Mannaerts G.P. J. PubMed Scopus Google Scholar). in and subcellular were in BSA, and the were by to a of The and the of and were as described K. α-Oxidation of a Scholar). of acyl-CoA esters was in BSA, ATP, CoA, and were by the of 2 of n fatty acids were with of and an of the the was in a liquid 2-hydroxyphytanoyl-CoA lyase was by and M. Croes K. Van Veldhoven P.P. Mannaerts G.P. PubMed Scopus Google Scholar), the 2-HPCL is to formate (12Croes K. Van Veldhoven P.P. Mannaerts G.P. Casteels M. FEBS Lett. 1997; 407: 197-200Crossref PubMed Scopus (44) Google Scholar). were performed in a of BSA, and to as with acid, acid, acid, or the a of was and a of a was unlabeled 2-HPCL was by the formation of the n – 1 aldehyde. Lipid of the CoA esters was on the formation of derivatives by by and to with up to a of from and J. PubMed Google unlabeled were by the of of 1 n the of of the the were with of and the was The was in of and to a was the were in the at for and on of the was a C18 on a The acyl-CoA esters were with a of in 2 2 2 was performed on a the and of were with of 2 n the of of the and of a of in of 2 n the were for at this and were from of the were 2 of of the was the was in of and of was on a C18 with was at and of 2-HPCL was from a liver with and and with and the was in R. A. J. 1997; PubMed Scopus Google Scholar) was were and on essential yeast acids, and a of and acids as were at in as the carbon from of were by and broken with in of 1 1 TPP, and a of was by and lyase was on a of 2-HPCL, two and were to to a small The was the of and S. with were for in of The protein was from cell as described in of on as described for the of phytanoyl-CoA hydroxylase V. Asselberghs S. Geens W. Mannaerts G.P. Casteels M. Van Veldhoven P.P. J. Lipid Res. 2003; 44: 2349-2355Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). of the by and with revealed one protein with a of The was of protein with a of of protein of the of fibroblasts and rat with acid for possible labeled degradation revealed formate as the In intact rat and on the the of was than the of formate that in from was as the reaction or that was subsequently intact rat hepatocytes were in the of of unlabeled the of from acid was by a increase in the generation of as was for acid K. Casteels M. E. Mannaerts G.P. Van Veldhoven P.P. J. PubMed Scopus Google also whereas the of straight chain fatty acids was the formate the that 2-hydroxyfatty acids are shortened by a the α-oxidation of phytanic acid not but is the that is subsequently and of 2-hydroxyoctadecanoic acid in intact rat hepatocytes hepatocytes fibroblasts in a new a first in the the of acid was in fibroblasts from with fatty acid In with the fatty acid chain acyl-CoA or acyl-CoA characterized by a in the chain or acyl-CoA in was data a role of in the degradation of straight chain fatty acids. the of the 2-hydroxyfatty acids were not in from characterized by a in the peroxisomal of very long chain fatty acids, or in from a 1 with a of the for peroxisomal a peroxisomal in fibroblasts from a with with a in the peroxisomal of a peroxisomal was a in similar was in fibroblasts from a for data that peroxisomes are and that peroxisomal with a peroxisomal are involved in the degradation of fatty acids. The to the of or acid, of and, hence, of fatty acyl-CoA the not the of acid not that are likely not of 2-hydroxyoctadecanoic acid in and fibroblasts fibroblasts fibroblasts fibroblasts fibroblasts fibroblasts fibroblasts fibroblasts in a new study the rat permeabilized with to the K. Casteels M. Van Veldhoven P.P. Mannaerts G.P. Biochim. Biophys. Acta. PubMed Scopus Google Scholar), were with of In hepatocytes the of acid was on ATP, Mg2+, and CoA and was by of in a increase of total requirements for of 2-hydroxyoctadecanoic acid in permeabilized of Mg2+, Mg2+, CoA, CoA, Mg2+, CoA, Mg2+, TPP, CoA, Mg2+, in a new The dependence on was by fibroblasts and in the of the thiamine The of this to the for several cell the of 2-hydroxyoctadecanoic acid by and in and data the involvement of a TPP-dependent enzyme and are similar to the of oxythiamin on α-oxidation of acid. The of oxythiamin on the of long chain fatty acids. M. M. and P. P. Van in The that and CoA are essential that the of 2-hydroxyfatty acids an activation The dependence of the pathway on to a reaction similar to that of the TPP-dependent cleavage of esters during the α-oxidation of 3-methyl-branched fatty acids. In rat liver similar as in permeabilized hepatocytes were not breakdown of acid in rat liver was on the of CoA, ATP, Mg2+, and the in the of were of with ATP, was the of or Furthermore, CoA not be by or In the main was formate of total The of not the of acid not as a of and of rat liver were with acid in the of ATP, CoA, and Mg2+, labeled acyl-CoA esters were of the esters revealed a with at with the The of of on the with the total of labeled CoA on of of two the generation of a intermediate was also in rat brain and in from rat In the of and TPP, was formed by rat liver with at of of data that esters are in the degradation of 2-hydroxy straight chain fatty acids. to the of the formation of the n – 1 aldehyde not be in with brain of the acyl-CoA the of rat liver the activation of 2-hydroxyoctadecanoic acid was to be for up to The formation of an at a ratio of the generation of at in a from of the data to the of an of in rat liver and subcellular performed at a of and a ratio of and were of in of rat were a ratio of and an time of The activation of 2-hydroxyoctadecanoic acid in subcellular of rat liver a with the in and the microsomal In the the to be of the on a revealed an with peroxisomes not In rat brain a was as the microsomal most not the acyl-CoA responsible for the activation of 2-hydroxy straight chain fatty acids, of from with acid were performed with and the of a of unlabeled fatty acids. acid, acid, and acid on the activation of 2-hydroxyoctadecanoic acid, acid and acid the activation not that the of the enzyme involved long chain fatty acids. of 2-HPCL as the the of the formation of from in subcellular of rat liver that the responsible enzyme has a peroxisomal Both this subcellular and the thiamine dependence point 2-HPCL as the enzyme the cleavage In the of ATP, CoA, Mg2+, and TPP, of the recombinant 2-HPCL with in with the formation of from The reaction of recombinant 2-HPCL were by the generation of and The cleavage of the was for up to whereas for the straight chain it was for up to at least not a from was for whereas for a was from and of and be Furthermore, the of aldehyde with with the of recombinant protein up to at least The of 2-HPCL was labeled of the recombinant 2-HPCL with in of at of of protein n but the lyase or acid, acid, acid, and acid. Furthermore, the of from was not in the of acid, acid, or The of or to with however, the cleavage to a that 2-hydroxy straight chain acyl-CoA esters with acyl-CoAs for cleavage by In the current study 2-hydroxyoctadecanoic acid was used as a to the degradation of 2-hydroxy straight chain fatty acids. is abundant than 2-hydroxytetracosanoic acid acid) in brain cerebrosides and (3Svennerholm L. Stallberg-Stenhagen S. J. Lipid Res. 1968; 9: 215-225Abstract Full Text PDF PubMed Google Scholar), but it the very long chain in and The that acid to the generation of labeled formate in intact as as in broken cell systems was a first that 2-hydroxyfatty acids can be degraded a the α-oxidation of fatty acids. was by the of ATP, Mg2+, CoA, and in permeabilized and by the that as a for recombinant 2-HPCL, to The in of the pathway was by the of the thiamine oxythiamin in our data led to the following 2-hydroxy fatty acid is first activated to CoA in an The is cleaved by 2-HPCL an n – 1 aldehyde and The latter is to formate and subsequently to for the n – 1 formed during α-oxidation of 3-methyl-branched fatty acids, the n – 1 aldehyde is most to the odd-numbered fatty acid, which can be degraded we cannot that 2-hydroxyfatty acids can be degraded by the inhibition by oxythiamin that the main at least in the and tissues we is the TPP-dependent In we not for the formation of a 2-keto fatty acid, formed as an intermediate an acid J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In but not in an long chain acid has been described A. J. PubMed Scopus Google Scholar). as for α-oxidation not been described in or but in n – 1 as a of α-oxidation been reported (6Gerhardt B. Prog. Lipid Res. 1992; 31: 417-446Crossref PubMed Scopus (94) Google Scholar). The of 2-HPCL to the α-oxidation of 2-hydroxy straight chain fatty acids in is at to the of the we not are The 2-hydroxyfatty acids a but 2-hydroxyoctadecanoic acid has been The that in of the was that can or that are 2-HPCL is to possible of K. Casteels M. M. Mannaerts G.P. Van Veldhoven P.P. J. Lipid Res. 1999; Full Text Full Text PDF PubMed Google Scholar), the latter is more of the activation of 2-hydroxyoctadecanoic acid in subcellular from rat liver revealed that the is with the peroxisomal and with the with the the fatty acids only acid and acid the activation of 2-hydroxyoctadecanoic acid, point the long chain acyl-CoA as the it is that the of long chain and very long chain acyl-CoA Van J. 2002; PubMed Scopus Google Scholar, J. A.K. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), can be as to the enzyme it be that the chain of the the involved long chain 2-hydroxyfatty acids 2-hydroxyoctadecanoic acid) be activated by a long chain acyl-CoA and very long chain 2-hydroxyfatty acids be activated by a very long chain acyl-CoA The of 2-HPCL involved in the degradation of 2-hydroxyfatty acids was by the of formation from in subcellular in the that 2-HPCL (14Foulon V. Antonenkov V.D. Croes K. Waelkens E. Mannaerts G.P. Van Veldhoven P.P. Casteels M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 10039-10044Crossref PubMed Scopus (92) Google Scholar). The inhibition of 2-hydroxyoctadecanoic acid degradation by the of oxythiamin to the thiamine dependence of the pathway in the intact The that in rat liver and permeabilized by the of was only can be by the that in is to the 2-HPCL only during to the of (14Foulon V. Antonenkov V.D. Croes K. Waelkens E. Mannaerts G.P. Van Veldhoven P.P. Casteels M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 10039-10044Crossref PubMed Scopus (92) Google Scholar). The that 2-hydroxyfatty acid degradation is by only in fibroblasts from and an for M. P. E. P. Casteels M. M. P. Van Veldhoven P.P. Mannaerts G.P. 1997; PubMed Scopus Google Scholar), that 2-HPCL, a peroxisomal enzyme (14Foulon V. Antonenkov V.D. Croes K. Waelkens E. Mannaerts G.P. Van Veldhoven P.P. Casteels M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 10039-10044Crossref PubMed Scopus (92) Google Scholar), in the where peroxisomal protein is is in with most peroxisomal enzymes, which are in the their is but in with our of 2-HPCL in liver of and as V. α-Oxidation of of the in the Scholar). the of 2-hydroxyfatty acid degradation to an of 2-hydroxyfatty acids in tissues from is increases in cerebrosides and/or been described in fibroblasts or but their 2-hydroxyfatty acid was not M. M. B. A. Y. S. M. Y. Biochim. Biophys. Acta. 1999; PubMed Scopus Google Scholar, K. M. B. M. H. S. T. Y. Biochim. Biophys. Acta. PubMed Scopus (11) Google Scholar). the of this for 2-hydroxyphytanoyl-CoA lyase, one that an of 2-HPCL, not not only to an α-oxidation of phytanic acid but also to an of 2-hydroxyfatty acids. The of 2-HPCL as the cleavage enzyme in the degradation of 2-hydroxyfatty acids is also of for reaction It that the at is not but that the at 2 and the CoA are 2-hydroxy of a 2-keto is an for TPP-dependent enzymes. one the of and in the of first in the of has been reported to with a at 2 Chem. Biol. 2002; PubMed Scopus Google Scholar). In TPP-dependent cleavage described decarboxylation the activation of the of the of to an intermediate is by a at the atom of the 2) K. K. M. FEBS Lett. 1998; PubMed Scopus Google Scholar). Most likely, the formation of a is also for the cleavage of esters by this carbon 1 of the which is highly to the of the this to the formation of formyl-CoA and an n – 1 fatty aldehyde The that of to the in a increase of total be by a inhibition through of the aldehyde. aldehyde is found in peroxisomes and (13Croes K. Casteels M. Asselberghs S. Herdewijn P. Mannaerts G.P. Van Veldhoven P.P. FEBS Lett. 1997; 412: 643-645Crossref PubMed Scopus (43) Google Scholar, FEBS Lett. 1998; PubMed Scopus Google Scholar). It is currently fatty in the are exclusively by the peroxisomal or also by the In our present that 2-hydroxyfatty acids an degradation that apparently cleavage of the aldehyde with the α-oxidation of 3-methyl-branched fatty acids, to n – 1 odd-numbered fatty acids, which can subsequently be degraded It is of to that the enzyme of the α-oxidation of 3-methyl-branched fatty acids peroxisomal PAHX, which to is likely not involved in the of 2-hydroxy straight chain fatty acids the of the be that an hydroxylation of straight chain acyl-CoAs by PAHX would to the breakdown of the acyl-CoAs by 2-HPCL the the of 2-hydroxyfatty acids in brain cerebrosides and sulfatides, supposed to a role in a on of for their and at subcellular be more as was reported in and recently by (18Alderson N.L. Rembiesa B.M. Walla M.D. Bielawska A. Bielawski J. Hama H. J. Biol. Chem. 2004; 279: 48562-48568Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar), hydroxylation of straight chain fatty acids only in which would peroxisomes as a in this hydroxylation process. In this it is of to that 2-hydroxyoctadecanoic acid was to intact V. P. P. Van and M. the α-oxidation of straight chain fatty acids, as has been described for brain, to proceed as follows; 1) hydroxylation of the fatty acid by a fatty acid the 2) activation of the 2-hydroxyfatty acid to a 3) cleavage of the CoA formyl-CoA and an n – 1 fatty and of the aldehyde to the n – 1 odd-numbered fatty acid. for for and Geens and for