Biogenesis of peroxisome

MOST CASES OF ZELLWEGER SYNDROME ARE DUE TO MUTATIONS IN GENES INVOLVED IN THE BIOGENESIS OF PEROXISOMES... 

Tanaka A, M Ueda (1993) Assimilation of alkanes by yeasts functions and biogenesis of peroxisomes Mycol Res 98 1025-1044. 

Both the integral membrane proteins of peroxisomes as well as the peroxisomal matrix proteins are synthesised on free polyribosomes and are specifically targeted to peroxisomes via dedicated peroxisomal targeting signals. The biogenesis of peroxisomes follows a sequential pattern, which involves first the insertion of peroxisomal membrane proteins into the membrane of the pre-peroxisomal structure, derived from the endoplasmic reticulum, followed by insertion of the various matrix proteins. 

Missing or defective biogenesis of peroxisomes or L-amino acid oxidase causes generalized hyper-aminoacidemia and hyper-aminoaciduria, generally leading to neurotoxicity and early death. 

Lazarow PB, Fujiki Y. Biogenesis of peroxisomes. Annu Rev Cell Biol 1985 1 489-530. 

Disorders of peroxisome biogenesis 689 Defects of single peroxisomal enzymes 691... 

Barth, P. G., Majoie, C. B., Gootjes, J. et al. Neuroimaging of peroxisome biogenesis disorders (Zellweger spectrum) with prolonged survival. Neurology 62 439-444, 2004. 

Olsen, L. (1998). The surprising complexity of peroxisome biogenesis. Plant Mol. Biol. 38, 163-189. 

UbclO is required for the biogenesis of the peroxisome, an oxidative organelle [75]. This E2 plays a role in peroxisomal protein import [76] and is recruited to the peroxisomal membrane through an interaction with a partner protein [77]. Membrane-localized UbclO also seems to be spatially proximal to PexlO, which has a RING-like domain [78]. Whether PexlO is a cognate E3 of UbclO remains to be determined, as does the mechanistic role of ubiquitin conjugation in peroxisome biogenesis. 

Zellweger syndrome Is a llpid storage disorder caused by impaired peroxisome biogenesis due to deficiency or functional defect of one of eleven proteins involved in the complex mechanism of peroxisomal matrix protein import and assembly of the organelle. 

Unfortunately, a minority of the patients with peroxisomal dysfunction cannot be diagnosed using plasma parameters. In the authors laboratory, patients have been seen with peroxisome biogenesis defects, D-bifunctional protein deficiency, and acyl-CoA oxidase deficiency in whom no abnormalities of plasma VLCFA, phytanic acid, pristanic acid or bile acids could be established. Hence, a strong clinical suspicion of peroxisomal disease should always be verified by fibroblast investigation, regardless of the outcome of plasma analyses. 

Rizzo C, Boenzi S, Wanders RJA, Duran M, Caruso U, Dionisi-Vici C (2003) Characteristic acylcarnitine profiles in inherited defects of peroxisome biogenesis a novel tool for screening diagnosis using tandem-MS. Pediatr Res 53 1-6... 

Subramani, S. (1993). Protein import into peroxisomes and biogenesis of the oiganelle. 

Martinez, M. (1996) Docosahexaenoic acid therapy in docosahexaenoic acid-deficient patients with disorders of peroxisomal biogenesis. Lipids. 31 S145-S152. 

Docosahexaenoic Acid Therapy for Disorders of Peroxisome Biogenesis... 

The rationale for DHA therapy in the disorders of peroxisome biogenesis is compelling at first glance DHA is essential for nonnal function of brain and retina PBD patients cannot synthesize DHA and, thus, have adeficicncy of this substance oral administration of DHA can normalize levels of DHA in plasma and red cells and probably also in brain and retina DHA therapy is simple and not excessively expensive and it appears to be free of significant side effects. Finally, the nonrandomized studies that have been published... 

Lazarow PB, Moser HW. Disorders of peroxisomal biogenesis. In Scriver CR, Beaudel AL, Sly WS, Valle D, eds. The MetaboUc and Molecular Basis of Inherited Disease. 7th ed. Chapter 71 McGraw-Hill, New York, 1994, Vol. B, pp. 2287-2324. 

Moser HW. Genotype-phenotype correlations in disorders of peroxisome biogenesis. Mol Genet Metab 1999 68(2) 316-327. 

Evidence in favor of peroxisomal involvement in cholesterol biosynthesis is the following. The molecular cloning of cDNAs encoding many of these enzymes revealed peroxisomal targeting sequences (W.J. Kovacs, 2003). The availability of specific antibodies allowed immunocytochemical localization to peroxisomes [4] (W.J. Kovacs, 2006). Fibroblasts from individuals with peroxisome biogenesis disorders showed reduced enzymatic activities of cholesterol biosynthetic enzymes, reduced rates of cholesterol synthesis, and lower cholesterol content [4]. Together these data suggest that peroxisomes may play a role in all steps in the cholesterol biosynthetic pathway, except the conversion of famesyl-PP to squalene. The latter reaction is catalyzed by squalene synthase, which is found. solely in the ER. 

A number of inherited deficiencies of peroxisomal enzymes have been described. Zellweger s syndrome, which results from defective peroxisomal biogenesis, leads to complex developmental and metabolic phenotypes affecting principally the liver and the brain. One of the metabolic characteristics of these diseases is an elevation of C26 0, and C26 1 fatty acid levels in plasma. Refsum s disease is caused by a deficiency in a single peroxisomal enzyme, the phytanoyl CoA hydroxylase that carries out a-oxidation of phytanic acid. Symptoms include retinitis pigmentosa, cerebellar ataxia, and chronic polyneuropathy. Because phytanic acid is obtained solely from the diet, placing patients on a low-phytanic acid diet has resulted in marked improvement. 

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