Nucleotide sequence of human alkyl-dihydroxyacetonephosphate synthase cDNA reveals the presence of a peroxisomal targeting signal 2

Vet, Edwin C.J.M. de; Broek, Bas T.E van den; Bosch, H. van den

doi:10.1016/s0005-2760(97)00014-3

Cited by 55 publications

(16 citation statements)

References 14 publications

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“…The correct localization of GNPAT and AGPS is achieved by the presence of peroxisomal targeting signals (PTS). GNPAT has a PTS1 signal, following a PEX5-dependent import into peroxisomes, and AGPS has a PTS2 signal and follows a PEX7-dependent import (de Vet et al 1997;Thai et al 1997). Mislocalization of either these enzymes to the cytosol, causes their inactivation and an impairment in the biosynthesis of plasmalogens (Brites et al 2004).…”

Section: Biosynthesis Of Plasmalogensmentioning

confidence: 99%

Plasmalogens and fatty alcohols in rhizomelic chondrodysplasia punctata and Sjögren‐Larsson syndrome

Malheiro¹,

Silva²,

Brites³

2014

J of Inher Metab Disea

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Plasmalogens are a special class of ether-phospholipids, best recognized by their vinyl-ether bond at the sn-1 position of the glycerobackbone and by the observation that their deficiency causes rhizomelic chondrodysplasia punctata (RCDP). The complex plasmalogen biosynthetic pathway involves multiple enzymatic steps carried-out in peroxisomes and in the endoplasmic reticulum. The rate limiting step in the biosynthesis of plasmalogens resides in the formation of the fatty alcohol responsible for the formation of an intermediate with an alkyl-linked moiety. The regulation in the biosynthesis of plasmalogens also takes place at this step using a feedback mechanism to stimulate or inhibit the biosynthesis. As such, fatty alcohols play a relevant role in the formation of ether-phospholipids. These advances in our understanding of complex lipid biosynthesis brought two seemingly distinct disorders into the spotlight. Sjögren-Larsson syndrome (SLS) is caused by defects in the microsomal fatty aldehyde dehydrogenase (FALDH) leading to the accumulation of fatty alcohols and fatty aldehydes. In RCDP cells, the defect in plasmalogens is thought to generate a feedback signal to increase their biosynthesis, through the activity of fatty acid reductases to produce fatty alcohols. However, the enzymatic defects in either glyceronephosphate O-acyltransferase (GNPAT) or alkylglycerone phosphate synthase (AGPS) disrupt the biosynthesis and result in the accumulation of the fatty alcohols. A detailed characterization on the processes and enzymes that govern these intricate biosynthetic pathways, as well as, the metabolic characterization of defects along the pathway should increase our understanding of the causes and mechanisms behind these disorders.

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Section: Biosynthesis Of Plasmalogensmentioning

confidence: 99%

Plasmalogens and fatty alcohols in rhizomelic chondrodysplasia punctata and Sjögren‐Larsson syndrome

Malheiro¹,

Silva²,

Brites³

2014

J of Inher Metab Disea

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“…Even more remarkable is the absence of the entire PTS2 pathway in Caenorhabditis elegans (77). Proteins that contain a PTS2 in other organisms, like thiolase (3,4,78,79), alkyldihydroxyacetonephosphate synthase (80), and phytanoyl-CoA hydroxylase (81) are equipped with a PTS1 in C. elegans. Whether the identified PTS3 pathway is only present in some yeast species or whether it is a more general peroxisomal import pathway, conserved among different proteins and different organisms, remains to be investigated.…”

Section: Figmentioning

confidence: 99%

Saccharomyces cerevisiae Acyl-CoA Oxidase Follows a Novel, Non-PTS1, Import Pathway into Peroxisomes That Is Dependent on Pex5p

Klein

Berg

Bottger

et al. 2002

Journal of Biological Chemistry

127

139

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The peroxisomal protein acyl-CoA oxidase (Pox1p) of Saccharomyces cerevisiae lacks either of the two well characterized peroxisomal targeting sequences known as PTS1 and PTS2. Here we demonstrate that peroxisomal import of Pox1p is nevertheless dependent on binding to Pex5p, the PTS1 import receptor. The interaction between Pex5p and Pox1p, however, involves novel contact sites in both proteins. The interaction region in Pex5p is located in a defined area of the amino-terminal part of the protein outside of the tetratricopeptide repeat domain involved in PTS1 recognition; the interaction site in Pox1p is located internally and not at the carboxyl terminus where a PTS1 is normally found. By making use of pex5 mutants that are either specifically disturbed in binding of PTS1 proteins or in binding of Pox1p, we demonstrate the existence of two independent, Pex5p-mediated import pathways into peroxisomes in yeast as follows: a classical PTS1 pathway and a novel, non-PTS1 pathway for Pox1p.

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“…RNAi experiments with dsRNA to ADHAPS, which catalyzes the second step in plasmalogen biosynthesis, showed a substantial delay in the development of the nematode. Likewise, in humans, inborn defects in ADHAPS cause abnormal psychomotor development and result in a lethal peroxisomal disorder, RCDP type 3 (7,9). Surprisingly, the phenotypes of worms treated with dsRNA to inactivate the processes of acyl-CoA synthetase-mediated activation of fatty acids, ␣-and ␤-oxidation of fatty acids, and intraperoxisomal decomposition of harmful hydrogen peroxide were close to that of control worms (Fig.…”

Section: Peroxisomal Metabolic Functions and Peroxins Influence The Dmentioning

confidence: 99%

RNA interference of peroxisome-related genes inC. elegans: a new model for human peroxisomal disorders

Petriv

Pilgrim

Rachubinski

et al. 2002

Physiological Genomics

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RNA-mediated interference (RNAi) for the posttranscriptional silencing of genes was used to evaluate the importance of various peroxisomal enzymes and peroxins for the development of Caenorhabditis elegans and to compare the roles of these proteins in the nematode to their roles in yeasts and humans. The nematode counterparts of the human ATP-binding cassette half-transporters, the enzymes alkyldihydroxyacetonephosphate synthase and Δ3,5-Δ 2,4-dienoyl-CoA isomerase, the receptors for peroxisomal membrane and matrix proteins (Pex19p and Pex5p), and components of the docking and translocation machineries for matrix proteins (Pex13p and Pex12p) are essential for the development of C. elegans. Unexpectedly, RNAi silencing of the acyl-CoA synthetase-mediated activation of fatty acids, the α- and β-oxidation of fatty acids, the intraperoxisomal decomposition of hydrogen peroxide, and the peroxins Pex1p, Pex2p, and Pex6p had no apparent effect on C. elegans development. The described analysis of functional gene knockouts through RNAi provides a basis for the use of C. elegans as a valuable model system with which to study the molecular and physiological defects underlying the human peroxisomal disorders.

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Nucleotide sequence of human alkyl-dihydroxyacetonephosphate synthase cDNA reveals the presence of a peroxisomal targeting signal 2

Cited by 55 publications

References 14 publications

Plasmalogens and fatty alcohols in rhizomelic chondrodysplasia punctata and Sjögren‐Larsson syndrome

Plasmalogens and fatty alcohols in rhizomelic chondrodysplasia punctata and Sjögren‐Larsson syndrome

Saccharomyces cerevisiae Acyl-CoA Oxidase Follows a Novel, Non-PTS1, Import Pathway into Peroxisomes That Is Dependent on Pex5p

RNA interference of peroxisome-related genes inC. elegans: a new model for human peroxisomal disorders

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