Identification of phytanoyl‐CoA ligase as a distinct acyl‐CoA ligase in peroxisomes from cultured human skin fibroblasts

Pahan, Kalipada; Cofer, Joseph B.; Baliga, Prabhakar K.; Singh, Inderjit

doi:10.1016/0014-5793(93)81546-c

Cited by 27 publications

(10 citation statements)

References 18 publications

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“…It has been suggested that 3-methyl branched-chain fatty acids are activated by a separate acyl-CoA synthetase distinct from the acyl-CoA synthetases responsible for the activation of long-chain, very long-chain and 2-methyl-branched fatty acids [2,41,421. The uncoupling of formic acid production and the formation of the 2-hydroxy-3-methyl-acyl-CoA intermediate in one of the Percoll gradient fractions (see Fig.…”

Section: Discussionmentioning

confidence: 99%

α‐Oxidation of 3‐Methyl‐Substituted Fatty Acids in Rat Liver

Croes

Casteels

Hoffmann

et al. 1996

European Journal of Biochemistry

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coxidation of 3-methyl-substituted fatty acids in rat liver was studied in intact and permeabilized rat hepatocytes, and in homogenates and subcellular fractions. The experiments revealed that the primary end product of a-oxidation is formic acid, which is then converted to CO,. Rates of a-oxidation identical to those observed in intact hepatocytes were obtained in the permeabilized hepatocytes and liver homogenates when ATP, Mg2+ and CoA, and Fez+, 2-oxoglutarate and ascorbate were added, suggesting that aoxidation involves a fatty acid activation reaction and a dioxygenase reaction. Subcellular fractionation by differential and density gradient centrifugation demonstrated that a-oxidation is confined to peroxisomes, which produce formic acid that is converted to CO,, mainly in the cytosol. a-Oxidation in broken cell systems went hand in hand with the formation of a 2-hydroxy-3-methylacyl-CoA ester. Formation of the metabolite was strictly dependent on the presence of the above-mentioned cofactors, was confined to peroxisomes and was inhibited by fenoprofen and propyl gallate, inhibitors of a-oxidation in intact cells, indicating that the 2-hydroxyacyl-CoA ester is a bona fide intermediate of a-oxidation. Selective omission of cofactors from the reaction mixture and analysis of the incubation mixtures for 3-methyl fatty acids, 3-methyl fatty acyl-CoAs and their respective 2-hydroxy derivatives revealed that the activation reaction precedes the dioxygenase (hydroxylase) reaction.Our experiments demonstrate that a-oxidation is a peroxisomal process that consists of at least three reactions : fatty acid activation, hydroxylation and the reaction(s) involved in the release of formic acid.

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Section: Discussionmentioning

confidence: 99%

α‐Oxidation of 3‐Methyl‐Substituted Fatty Acids in Rat Liver

Croes

Casteels

Hoffmann

et al. 1996

European Journal of Biochemistry

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“…Isoprenoid-derived branched fatty acids can be activated by peroxisomes, mitochondria, and endoplasmic reticulum (112,118), possibly via the long-chain acyl-CoA syn thetases present in these cell compartments. Preliminary evidence that peroxi somes contain a separate branched-chain acyl-CoA synthetase awaits further confIrmation (72). Short and medium straight-chain fatty acids are activated in the mitochondrial matrix (91); medium-chain fatty acids can also be acti vated to a certain extent by long-chain acyl-CoA synthetases present in the mitochondrial outer membrane and in the peroxisomal and endoplasmic retic ulum membranes.…”

Section: Fatty Acid Activation and Penetration Into The Peroxisomementioning

confidence: 99%

Peroxisomal Lipid Metabolism

Reddy

Mannaerts²

1994

Annu. Rev. Nutr.

395

233

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Peroxisomes are present in virtually all eukaryotic cells. At present, they are known to contain more than 50 enzymes, more than half of which play a role in lipid metabolism. During the past two decades, considerable knowledge has been gained about the role of peroxisomes in lipid metabolism, the implications of induction of hepatic peroxisome proliferation and the peroxisomal fatty acid beta-oxidation enzyme system in the development of hepatocellular carcinomas in rats and mice by structurally diverse groups of chemicals designated as peroxisome proliferators, and the biochemical basis for inheritable diseases in humans caused by disturbances and/or deficiencies in peroxisomal lipid metabolism. Nevertheless, many unanswered questions remain. The ontogeny and homeostatic interrelationships between the enzymes of the peroxisomal and mitochondrial lipid metabolism have yet to be fully elucidated. The mechanism(s) by which PPARs are activated also remains unclear. Information about the interplay between PPAR, RXR alpha, HSP72, and other possible regulatory molecules is necessary to elucidate the transcriptional activation of inducible peroxisomal genes. The assumption that multiple signaling pathways may be responsible for the pleiotropic responses induced by structurally different peroxisome proliferators requires further examination. Finally, studies to identify and characterize different PPARs and PPREs from inducible peroxisomal genes from a variety of species are also required for a clear understanding of the role of peroxisomal beta-oxidation enzyme system in the pathogenesis of hepatocellular carcinogenesis induced by peroxisome proliferators.

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“…Candidates, based on cell extract studies, include a non‐specific long chain fatty acyl (LCFA)‐CoA synthetase (Watkins et al . 1996) and a specific enzyme, which has not been cloned (Pahan et al . 1993).…”

Section: Metabolism Of Phytanic Acidmentioning

confidence: 99%

Refsum's disease: a peroxisomal disorder affecting phytanic acid α‐oxidation

Wierzbicki

Lloyd

Schofield³

et al. 2002

Journal of Neurochemistry

176

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Refsum's disease (hereditary motor sensory neuropathy type IV, heredopathia atactica polyneuritiformis) is an autosomal recessive disorder the clinical features of which include retinitis pigmentosa, blindness, anosmia, deafness, sensory neuropathy, ataxia and accumulation of phytanic acid in plasma-and lipid-containing tissues. The transport and biochemical pathways of phytanic acid metabolism have recently been defined with the cloning of two key enzymes, phytanoylCoA 2-hydroxylase (PAHX) and 2-hydroxyphytanoyl-CoA lyase, together with the confirmation of their localization in peroxisomes. PAHX, an iron(II) and 2-oxoglutarate-dependent oxygenase is located on chromosome 10p13. Mutant forms of PAHX have been shown to be responsible for some, but not all, cases of Refsum's disease. Certain cases have been shown to be atypical mild variants of rhizomelic chondrodysplasia punctata type 1a. Other atypical cases with lowplasma phytanic acid may be caused by a-methylacyl-CoA racemase deficiency. A sterol-carrier protein-2 (SCP-2) knockout mouse model shares a similar clinical phenotype to Refsum's disease, but no mutations in SCP-2 have been described to-date in man. This review describes the clinical, biochemical and metabolic features of Refsum's disease and shows how the biochemistry of the a-oxidation pathway may be linked to the regulation of metabolic pathways controlled by isoprenoid lipids, involving calcineurin or the peroxisomal proliferator activating a-receptor.

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Identification of phytanoyl‐CoA ligase as a distinct acyl‐CoA ligase in peroxisomes from cultured human skin fibroblasts

Cited by 27 publications

References 18 publications

α‐Oxidation of 3‐Methyl‐Substituted Fatty Acids in Rat Liver

α‐Oxidation of 3‐Methyl‐Substituted Fatty Acids in Rat Liver

Peroxisomal Lipid Metabolism

Refsum's disease: a peroxisomal disorder affecting phytanic acid α‐oxidation

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