Biosynthesis and maturation of peroxisomal beta-oxidation enzymes in fibroblasts in relation to the Zellweger syndrome and infantile Refsum disease.

Schram, A. W.; Strijland, Anneke; Hashimoto, Takashi; Wanders, Ronald J. A.; Schutgens, R. B. H.; Bosch, H. van den; Tager, J. M.

doi:10.1073/pnas.83.16.6156

Cited by 91 publications

(48 citation statements)

References 33 publications

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“…Studies in cultured skin fibroblasts have shown that peroxisomal fl-oxidation enzyme proteins are synthesized normally in Zellweger syndrome but are degraded rapidly due to the absence of peroxisomes (48). The same applies to infantile Refsum disease and neonatal adrenoleukodystrophy in which peroxisomes have also been shown to be strongly deficient in liver (32,(41)(42)(43)(44) and cultured fibroblasts (33,49).…”

Section: Discussionmentioning

confidence: 85%

Peroxisomal fatty acid beta-oxidation in relation to the accumulation of very long chain fatty acids in cultured skin fibroblasts from patients with Zellweger syndrome and other peroxisomal disorders.

Wanders¹,

Roermund²,

Wijland³

et al. 1987

J. Clin. Invest.

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The peroxisomal oxidation of the long chain fatty acid palmitate (C16:0) and the very long chain fatty acids lignocerate (C24:0) and cerotate (C26:0) was studied in freshly prepared homogenates of cultured skin fibroblasts from control individuals and patients with peroxisomal disorders. The peroxisomal oxidation of the fatty acids is almost completely dependent on the addition of ATP, coenzyme A (CoA), Mg2+ and NAD'.However, the dependency of the oxidation of palmitate on the concentration of the cofactors differs markedly from that of the oxidation of lignocerate and cerotate.The peroxisomal oxidation of all three fatty acid substrates is markedly deficient in fibroblasts from patients with the Zellweger syndrome, the neonatal form of adrenoleukodystrophy and the infantile form of Refsum disease, in accordance with the deficiency of peroxisomes in these patients. In fibroblasts from patients with X-linked adrenoleukodystrophy the peroxisomal oxidation of lignocerate and cerotate is impaired, but not that of palmitate. Competition experiments indicate that in fibroblasts, as in rat liver, distinct enzyme systems are responsible for the oxidation of palmitate on the one hand and lignocerate and cerotate on the other hand. Fractionation studies indicate that in rat liver activation of cerotate and lignocerate to cerotoyl-CoA and lignoceroyl-CoA, respectively, occurs in two subcellular fractions, the endoplasmic reticulum and the peroxisomes but not in the mitochondria. In homogenates of fibroblasts from patients lacking peroxisomes there is a small (25%) but significant deficiency of the ability to activate very long chain fatty acids. This deficient activity of very long chain fatty acyl-CoA synthetase is also observed in fibroblast homogenates from patients with X-linked adrenoleukodystrophy. We conclude that X-linked adrenoleukodystrophy is caused by a deficiency of peroxisomal very long chain fatty acyl-CoA synthetase.

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Section: Discussionmentioning

confidence: 85%

Peroxisomal fatty acid beta-oxidation in relation to the accumulation of very long chain fatty acids in cultured skin fibroblasts from patients with Zellweger syndrome and other peroxisomal disorders.

Wanders¹,

Roermund²,

Wijland³

et al. 1987

J. Clin. Invest.

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“…They concluded that part, if not all, of the proteolytic processing of 3-oxoacyl-CoA thiolase takes place within the peroxisomal compartment. Schram et al (29) showed that the conversion of the 44-kD precursor of 3-oxoacyl-CoA thiolase to the mature protein does not take place in fibroblasts from patients with disorders of peroxisome biogenesis. They concluded that functional peroxisomes are required for the proteolytic processing of the precursor of 3-oxoacylCoA thiolase.…”

Section: Resultsmentioning

confidence: 99%

Rhizomelic chondrodysplasia punctata. Deficiency of 3-oxoacyl-coenzyme A thiolase in peroxisomes and impaired processing of the enzyme.

Heikoop¹,

Roermund²,

Just³

et al. 1990

J. Clin. Invest.

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The rhizomelic form of chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized biochemically by an impairment of plasmalogen biosynthesis and phytanate catabolism. We have now found that the maturation of peroxisomal 3-oxoacyl-CoA thiolase is impaired in fibroblasts from RCDP patients.To establish the subcellular localization of the 3-oxoacylCoA thiolase precursor protein, cultured skin fibroblasts were fractionated on a continuous Nycodenz gradient. Only a small amount of 3-oxoacyl-CoA thiolase activity was present in the catalase-containing (peroxisomal) fractions of RCDP fibroblasts in comparison with control fibroblasts. Moreover, the amount of thiolase protein in immunoblots of the catalase-containing fractions was below the limit of detection. Finally, the fl-oxidation of 1'4Cjpalmitoyl-CoA was found to be reduced in these fractions.We conclude that the mutation in RCDP leads to a partial deficiency of 3-oxoacyl-CoA thiolase activity in the peroxisomes and, concomitantly, an impairment in the ability to convert the precursor of this protein to the mature form. The reduction of 3-oxoacyl-CoA thiolase activity results in a decrease in the rate of peroxisomal f-oxidation of palmitoylCoA. However, the capacity of the peroxisomes to oxidize very-long-chain fatty acids must be sufficient to prevent excessive accumulation of these compounds in vivo. (J. Clin. Invest.

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“…peroxisome have little activity (4)(5)(6)(7)(8)(9). When patients with Zellweger syndrome and hyperpipecolic acidemia were given oral loading doses of pipecolic acid, their serum pipecolic acid levels were elevated for a prolonged period of time relative to controls (10)(11)(12)(13)(14).…”

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confidence: 99%

Peroxisomal L-Pipecolic Acid Oxidation Is Deficient in Liver from Zellweger Syndrome Patients

Mihalik

Moser²,

Watkins³

et al. 1989

Pediatr Res

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Biosynthesis and maturation of peroxisomal beta-oxidation enzymes in fibroblasts in relation to the Zellweger syndrome and infantile Refsum disease.

Abstract: The biosynthesis of the peroxisomal enzymes acyl-CoA oxidase, 3-oxoacyl-CoA thiolase (acetyl-CoA acyltransferase, EC 2.3

Cited by 91 publications

References 33 publications

Peroxisomal fatty acid beta-oxidation in relation to the accumulation of very long chain fatty acids in cultured skin fibroblasts from patients with Zellweger syndrome and other peroxisomal disorders.

Peroxisomal fatty acid beta-oxidation in relation to the accumulation of very long chain fatty acids in cultured skin fibroblasts from patients with Zellweger syndrome and other peroxisomal disorders.

Rhizomelic chondrodysplasia punctata. Deficiency of 3-oxoacyl-coenzyme A thiolase in peroxisomes and impaired processing of the enzyme.

Peroxisomal L-Pipecolic Acid Oxidation Is Deficient in Liver from Zellweger Syndrome Patients

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