Further studies on the substrate spectrum of phytanoyl-CoA hydroxylase

Foulon, Veerle; Asselberghs, Stanny; Geens, Wendy; Mannaerts, Guy P.; Casteels, Minne; Veldhoven, Paul P. Van

doi:10.1194/jlr.m300230-jlr200

Cited by 21 publications

(19 citation statements)

References 31 publications

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“…The nature of the enzyme responsible for synthesis of HFA sphingolipids in keratinocytes is not known. The peroxisomal phytanoyl-CoA hydroxylase is involved in the degradation of branched fatty acids by ␣-oxidation (43), but it is not clear whether phytanoylCoA hydroxylase also hydroxylates straight chain acyl-CoA (44,45). Likely candidate enzyme(s) involved in the synthesis of HFA sphingolipids in keratinocytes include members of the cytochrome P450 family, some of which are strongly expressed in skin (46), although there is currently no experimental evidence to support this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

Maier

Meixner

Hartmann

et al. 2011

Journal of Biological Chemistry

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2-Hydroxylated fatty acid (HFA)-containing sphingolipids are abundant in mammalian skin and are believed to play a role in the formation of the epidermal barrier. Fatty acid 2-hydroxylase (FA2H), required for the synthesis of 2-hydroxylated sphingolipids in various organs, is highly expressed in skin, and previous in vitro studies demonstrated its role in the synthesis of HFA sphingolipids in human keratinocytes. Unexpectedly, however, mice deficient in FA2H did not show significant changes in their epidermal HFA sphingolipids. Expression of FA2H in murine skin was restricted to the sebaceous glands, where it was required for synthesis of 2-hydroxylated glucosylceramide and a fraction of type II wax diesters. Absence of FA2H resulted in hyperproliferation of sebocytes and enlarged sebaceous glands during hair follicle morphogenesis and anagen (active growth phase) in adult mice. This was accompanied by a significant up-regulation of the epidermal growth factor receptor ligand epigen in sebocytes. Loss of FA2H significantly altered the composition and physicochemical properties of sebum, which often blocked the hair canal, apparently causing a delay in the hair fiber exit. Furthermore, mice lacking FA2H displayed a cycling alopecia with hair loss in telogen. These results underline the importance of the sebaceous glands and suggest a role of specific sebaceous gland or sebum lipids, synthesized by FA2H, in the hair follicle homeostasis.

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Section: Discussionmentioning

confidence: 99%

Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

Maier

Meixner

Hartmann

et al. 2011

Journal of Biological Chemistry

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“…A bulky group at the -end (e.g., 5-phenyl-3-methylpentanoyl-CoA) is tolerated, but free 3-methyl FAs are not substrates. Both the length and the position of the branch are important; extending the branch to a 3-ethyl group lowers the activity considerably and 2-methyl-and 4-methylbranched acyl-CoAs are not hydroxylated ( 38 ). With an excess of enzyme, a low activity with straight chain acyl-CoAs can be seen ( 41 ).…”

Section: Acsl1mentioning

confidence: 99%

“…In vitro, substrate inhibition is seen with phytanoyl-CoA (and longchain 3-methylacyl-CoA) already starting around 10 µM. This can be counteracted by albumin ( 38 ). Others have claimed that the enzyme prefers substrate bound to sterol carrier protein 2 (SCP2) ( 39 ), which indeed has a good affi nity for phytanoyl-CoA ( 40 ).…”

Section: Acsl1mentioning

confidence: 99%

Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism

Veldhoven

2010

Journal of Lipid Research

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“…The resulting adaptor sequence was cloned between the KpnI-BamHI sites of yVF3 (yVF7), and S. cerevisiae CB80 cells, transformed with yVF7, were grown for 18 h in 400 ml of Sc-ura containing 0.5% (w/v) glucose. The fusion protein was purified from cell lysate (prepared as described before in 8 ml of lysis buffer) on nickel nitrilotriacetic acid-agarose essentially as described for the purification of phytanoyl-CoA hydroxylase (16). Analysis of the purified fraction by SDS-PAGE (12% polyacrylamide, w/v) and subsequent immunoblotting with anti-His antibody (Clontech) revealed one single polyhistidine-tagged protein with a molecular mass of ϳ63 kDa.…”

Section: Fatty Acids and Derivatives-[1-mentioning

confidence: 99%

“…According to our data PAHX does not act on straight chain fatty acids or their CoA esters (15,16) and, hence, cannot be involved in the formation of 2-hydroxyfatty acids; others claim, however, that PAHX can hydroxylate straight chain acyl-CoAs (17). Regardless of this discrepancy, a recently described fatty acid 2-hydroxylase, highly abundant in brain and encoded by the FA2H gene (18), is likely responsible for the formation of 2-hydroxyfatty acids in man.…”

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confidence: 99%

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

Foulon

Sniekers

Huysmans

et al. 2005

Journal of Biological Chemistry

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2-Hydroxyfatty acids, constituents of brain cerebrosides and sulfatides, were previously reported to be degraded by an ␣-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 ␣-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.

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Further studies on the substrate spectrum of phytanoyl-CoA hydroxylase

Cited by 21 publications

References 31 publications

Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism

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

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