Identification of the cytochrome P450 enzymes responsible for the ω‐hydroxylation of phytanic acid

Komen, J.C.; Wanders, Ronald J. A.

doi:10.1016/j.febslet.2006.05.069

Cited by 22 publications

(18 citation statements)

References 33 publications

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“…Antibody inhibition experiments (13,14) suggest that P450 4F2/4F3B in human liver and kidney microsomes contribute ϳ66% to the formation of 20-HETE. Recently, P450s 4F2 and 4F3B were found to -hydroxylate very long chain saturated fatty acids (15) as well as phytanic acid (16). Our preliminary experiments using com-mercially available Supersomes TM (BD Gentest) indicate that P450 4F2 also -hydroxylates oleic acid, stearic acid, and palmitic acid, but not lauric acid.…”

mentioning

confidence: 98%

Regulation of Human Cytochrome P450 4F2 Expression by Sterol Regulatory Element-binding Protein and Lovastatin

Hsu

Savas

Griffin

et al. 2007

Journal of Biological Chemistry

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The capacity to oxidize the terminal carbon of aliphatic chains is a highly conserved enzymatic activity of cytochrome P450s in plant and animal species. In mammals, the -hydroxylation of fatty acids provides a means to remove potentially toxic excess concentrations of free fatty acids. This is the first step in the formation of dicarboxylic acids that can be more readily excreted or are further degraded by peroxisomal ␤-oxidation. The -hydroxylases also provide pathways for the degradation of signaling molecules such as prostanoids and leukotrienes. On the other hand, -hydroxylation of arachidonic acid forms 20-hydroxyeicosatetraenoic acid (20-HETE), 2 which has been implicated in the regulation of vascular tone and blood pressure (1-3).Cytochrome P450 4F2 (P450 4F2) is a fatty acid -hydroxylase that is expressed in human liver and kidney and contributes to free fatty acid catabolism and the conversion of arachidonic acid to 20-HETE. In humans, the predominant -hydroxylases in liver and kidney are microsomal P450s 4A11, 4F2, and 4F3B (4). The -hydroxylation of saturated fatty acids is generally associated with P450 4A enzymes in non-human species, and human P450 4A11 catalyzes the -hydroxylation of lauric acid Ͼ palmitic acid Ͼ arachidonic acid (5). Selective disruption of the murine Cyp4a10 (6) and Cyp4a14 (7) genes leads to hypertensive phenotypes that are thought to reflect changes in renal 20-HETE production arising through distinct mechanisms. Interestingly, an allelic variant encodes a human CYP4A11 with reduced catalytic activity that is associated with an increased risk for hypertension in studies of three independent cohorts (8, 9). P450s 4F2 and 4F3B are highly similar in amino acid sequence and display overlapping catalytic activity profiles. Both enzymes efficiently oxidize arachidonic acid (10). An alternative transcript of the CYP4F3 gene, 4F3A, arises from differential promoter use leading to the incorporation of an alternative exon that alters substrate preferences to favor the -hydroxylation of leukotrienes (11). P450 4F3A is predominantly expressed in human leukocytes (12). Antibody inhibition experiments (13, 14) suggest that P450 4F2/4F3B in human liver and kidney microsomes contribute ϳ66% to the formation of 20-HETE. Recently, P450s 4F2 and 4F3B were found to -hydroxylate very long chain saturated fatty acids (15) as well as phytanic acid (16). Our preliminary experiments using com-* This work was supported by National Institutes of Health Grant HD004445(to E. F. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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confidence: 98%

Regulation of Human Cytochrome P450 4F2 Expression by Sterol Regulatory Element-binding Protein and Lovastatin

Hsu

Savas

Griffin

et al. 2007

Journal of Biological Chemistry

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“…This phenomenon is thought to reflect the role of P450 4F2 in hepatic clearance of vitamin K (McDonald et al, 2009). Finally, the participation of P450s 4F2 and 4F3B in the biotransformation of very long-chain saturated fatty acid or phytanic acid in patients with X-linked adrenoleukodystrophy (Sanders et al, 2006) or Refsum's disease (Komen and Wanders, 2006), respectively, suggests that factors that modulate CYP4F2 expression may play an important role in alleviating these diseases and possibly other disorders of lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

Genistein, Resveratrol, and 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside Induce Cytochrome P450 4F2 Expression through an AMP-Activated Protein Kinase-Dependent Pathway

Hsu¹,

Savas²,

Lasker³

et al. 2011

J Pharmacol Exp Ther

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Activators of AMP-activated protein kinase (AMPK) increase the expression of the human microsomal fatty acid -hydroxylase CYP4F2. A 24-h treatment of either primary human hepatocytes or the human hepatoma cell line HepG2 with 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR), which is converted to 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranosyl 5Ј-monophosphate, an activator of AMPK, caused an average 2.5-or 7-fold increase, respectively, of CYP4F2 mRNA expression but not of CYP4A11 or CYP4F3, CYP4F11, and CYP4F12 mRNA.

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“…More recent work in which use was made of specific inhibitors has shown that members of the CYP family 4 are responsible for phytanic acid ω-hydroxylation. Incubations with microsomes containing human recombinant CYPs (supersomes) revealed that multiple CYP enzymes of the family 4 class are able to ω-hydroxylate phytanic acid with the following order of efficiency: CYP4F3A>CYP4F3B>CYP4F2>CYP4A11 [35].…”

Section: Phytanic Acid ω-Oxidation An Alternative Mechanism To Degramentioning

confidence: 99%

Peroxisomes, Refsum's disease and the α- and ω-oxidation of phytanic acid

Wanders

Komen

2007

Biochemical Society Transactions

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In the present paper, we describe the current state of knowledge regarding the enzymology of the phytanic acid alpha-oxidation pathway. The product of phytanic acid alpha-oxidation, i.e. pristanic acid, undergoes three cycles of beta-oxidation in peroxisomes after which the products, including 4,8-dimethylnonanoyl-CoA, propionyl-CoA and acetyl-CoA, are exported from the peroxisome via one of two routes, including (i) the carnitine-dependent route, mediated by CRAT (carnitine acetyltransferase) and CROT (carnitine O-octanoyltransferase), and (ii) the free acid route, mediated by one or more of the peroxisomal ACOTs (acyl-CoA thioesterases). We also describe our recent data on the omega-oxidation of phytanic acid, especially since pharmacological up-regulation of this pathway may form the basis of a new treatment strategy for ARD (adult Refsum's disease). In patients suffering from ARD, phytanic acid accumulates in tissues and body fluids due to a defect in the alpha-oxidation system.

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Identification of the cytochrome P450 enzymes responsible for the ω‐hydroxylation of phytanic acid

Cited by 22 publications

References 33 publications

Regulation of Human Cytochrome P450 4F2 Expression by Sterol Regulatory Element-binding Protein and Lovastatin

Regulation of Human Cytochrome P450 4F2 Expression by Sterol Regulatory Element-binding Protein and Lovastatin

Genistein, Resveratrol, and 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside Induce Cytochrome P450 4F2 Expression through an AMP-Activated Protein Kinase-Dependent Pathway

Peroxisomes, Refsum's disease and the α- and ω-oxidation of phytanic acid

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