Alkyl‐dihydroxyacetone phosphate synthase and dihydroxyacetone phosphate acyltransferase form a protein complex in peroxisomes

Biermann, Jan; Just, Wilhelm W.; Wanders, R. J. A.; Bosch, H. van den

doi:10.1046/j.1432-1327.1999.00295.x

Cited by 34 publications

(22 citation statements)

References 40 publications

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“…Interestingly, both FAR1 and FAR2 are highly expressed in brain where large quantities of ether lipids are synthesized. Both GNPAT and AGPS are localized exclusively into peroxisomes, and together constitute a complex within this organelle (Biermann et al 1999). The last contribution of peroxisomes for the biosynthesis of plasmalogens is the reduction of the ketone group at the sn-2 position of the 1-alkyl-DHAP, generated by acyl/alkyl-DHAP reductase, to 1-0-alkyl-2-hydroxy-sn-glycerophosphate (GPA).…”

Section: Biosynthesis Of Plasmalogensmentioning

confidence: 99%

“…Mislocalization of either these enzymes to the cytosol, causes their inactivation and an impairment in the biosynthesis of plasmalogens (Brites et al 2004). Additionally, the mistargeting of AGPS from peroxisomes to the cytosol or non-sense mutations that cause protein instability and degradation, affect GNPAT activity and levels (Biermann et al 1999;de Vet and van den Bosch 2000;Itzkovitz et al 2012). As such, the function of the GNPAT/AGPS complex is seen as an important event to allow efficient and optimal activity to produce plasmalogens (Razeto et al 2007).…”

Section: Biosynthesis Of Plasmalogensmentioning

confidence: 99%

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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%

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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“…In most animal tissues, DHAPAT is found in a membrane-bound fraction (15,20) and localized in the luminal side of peroxisomes (15,21). This enzyme was also found to be part of a heterotrimeric complex that includes the 1-alkyl-DHAP synthase (22,23). Alterations in DHAPAT function have been associated with various human diseases such as neonatal adrenoleukodystrophy, infantile Refsum, disease, hyperpipecolic academia, and rhizomelic chondrodyplasia punctata (24 -26).…”

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confidence: 99%

Leishmania major Expresses a Single Dihydroxyacetone Phosphate Acyltransferase Localized in the Glycosome, Important for Rapid Growth and Survival at High Cell Density and Essential for Virulence

Zufferey

Mamoun

2006

Journal of Biological Chemistry

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Despite major advances in the understanding of pathogenesis of the human protozoan parasite Leishmania major, little is known about the enzymes and the primary precursors involved in the initial steps of synthesis of its major glycerolipids including those involved in virulence. We have previously demonstrated that the initial step of acylation of the precursor glycerol 3-phosphate is not essential for the synthesis of ester and ether phospholipids in this parasite. Here we show that Leishmania expresses a single acyltransferase with high specificity for the precursor dihydroxyacetone phosphate and shows the best activity in the presence of palmitoylCoA. We have identified and characterized the LmDAT gene encoding this activity. LmDAT complements the lethality resulting from the loss of both dihydroxyacetone phosphate and glycerol-3-phosphate acyltransferase activities in yeast. Recombinant LmDAT exhibits biochemical properties similar to those of the native enzyme of the promastigote stage parasites. We show that LmDAT is a glycosomal enzyme and its loss in a ⌬lmdat/⌬lmdat null mutant results in complete abrogation of the parasite dihydroxyacetone phosphate acyltransferase activity. Furthermore, lack of LmDAT causes a major alteration in parasite division during the logarithmic phase of growth, an accelerated cell death during stationary phase, and loss of virulence. Together, our results demonstrate that LmDAT is the only dihydroxyacetone phosphate acyltransferase of the L. major localized in the peroxisome, important for growth and survival and essential for virulence.Worldwide, protozoan parasites of the genus Leishmania cause a large spectrum of important human diseases collectively named leishmaniasis. These parasites develop within the digestive tract of the sand fly vector as flagellated, mobile promastigotes and differentiate into and multiply as non-motile amastigotes within the phagolysosomal compartment of vertebrate host macrophages.Glycerolipids constitute 70% of total lipids in the protozoan parasite Leishmania (1-3). They are classified into ester and ether lipids depending on the substitution at position 1 of the glycerol backbone. Ester lipids harbor an acyl group, whereas ether lipids carry a fatty alcohol moiety. Lipids of Leishmania parasites have been a focus of extensive studies because some of their derivatives, such as lipophosphoglycan and glycosylphosphatidylinositol-anchored protease gp63, were shown to be important for parasite virulence and development (for review, see . Lipids are also essential cell constituents and, therefore, must be constantly synthesized to allow multiplication of the parasite. This suggests that the pathways leading to their synthesis are essential for parasite proliferation and pathogenesis and, thus, offer a reasonable target for rational design of new anti-leishmanial drugs. In fact, a lipidbased drug, miltefosine, is a potent antileishmanial compound that inhibits parasite growth in vitro and in vivo and is currently used for treatment of visceral and muc...

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“…Although not an integral membrane protein, the enzyme appears to be tightly bound to the inner aspect of the peroxisomal membrane (19,20). Alkyl-DHAP synthase is present in a heterotrimeric complex with DHAP acyltransferase, the enzyme that provides the substrate for alkyl-DHAP synthase (21,22).…”

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confidence: 99%

Alkyl-dihydroxyacetonephosphate Synthase

Vet¹,

Hilkes²,

Fraaije³

et al. 2000

Journal of Biological Chemistry

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Alkyl-dihydroxyacetonephosphate synthase is a peroxisomal enzyme involved in ether lipid synthesis. It catalyzes the exchange of the acyl chain in acyl-dihydroxyacetonephosphate for a long chain fatty alcohol, yielding the first ether linked intermediate, i.e. alkyldihydroxyacetonephosphate, in the pathway of ether lipid biosynthesis. Although this reaction is not a net redox reaction, the amino acid sequence of the enzyme suggested the presence of a flavin adenine dinucleotide (FAD)-binding domain. In this study we show that alkyldihydroxyacetonephosphate synthase contains an essential FAD molecule as cofactor, which is evidenced by fluorescence properties, UV-visible absorption spectra and the observation that the enzyme activity is dependent on the presence of this cofactor in a coupled in vitro transcription/translation assay. Furthermore, we could demonstrate that the FAD cofactor directly participates in catalysis. Upon incubation of the enzyme with the substrate palmitoyl-dihydroxyacetonephosphate, the flavin moiety is reduced, indicating that in this initial step the substrate is oxidized. Stopped flow experiments show that the reduction of the flavin moiety is a monophasic process yielding a oxygen stable, reduced enzyme species. Upon addition of hexadecanol to the reduced enzyme species, the flavin moiety is efficiently reoxidized. A hypothetical reaction mechanism is proposed that is consistent with the data in this paper and with previous studies.

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Alkyl‐dihydroxyacetone phosphate synthase and dihydroxyacetone phosphate acyltransferase form a protein complex in peroxisomes

Cited by 34 publications

References 40 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

Leishmania major Expresses a Single Dihydroxyacetone Phosphate Acyltransferase Localized in the Glycosome, Important for Rapid Growth and Survival at High Cell Density and Essential for Virulence

Alkyl-dihydroxyacetonephosphate Synthase

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