Human dihydroxyacetonephosphate acyltransferase deficiency: A new peroxisomal disorder

Wanders, R. J. A.; Schumacher, H.; Heikoop, Judith C.; Schutgens, R. B. H.; Tager, J. M.

doi:10.1007/bf02435984

Cited by 127 publications

(65 citation statements)

References 6 publications

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“…To examine whether ACBD5 deficiency influences other lipid metabolic processes involving peroxisomal enzymes, we also analyzed the levels of plasmenylethanolamine (PlsEtn), which harbors a vinyl ether-linked long-chain fatty alcohol at its sn-1 position, and phospholipids containing DHA (C22:6n-3). The biosynthesis of PlsEtn is initiated in peroxisomes (25,26), whereas the biosynthesis of DHA from dietary linolenic acid (C18:3n-3) is completed by peroxisomal ␤-oxidation (27). Apparently, neither the level of PlsEtn nor that of DHA-containing phospholipids was affected in ⌬ACBD5 fibroblasts (Fig.…”

Section: Acbd5 Is a Peroxisomal Tail-anchored Protein Exposing Itsmentioning

confidence: 99%

Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal β-Oxidation of Very-long-chain Fatty Acids

Yagita

Shinohara

Abe

et al. 2017

Journal of Biological Chemistry

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Edited by Dennis R. VoelkerAcyl-CoA binding domain-containing 5 (ACBD5) is a peroxisomal protein that carries an acyl-CoA binding domain (ACBD) at its N-terminal region. The recent identification of a mutation in the ACBD5 gene in patients with a syndromic form of retinal dystrophy highlights the physiological importance of ACBD5 in humans. However, the underlying pathogenic mechanisms and the precise function of ACBD5 remain unclear. We herein report that ACBD5 is a peroxisomal tail-anchored membrane protein exposing its ACBD to the cytosol. Using patient-derived fibroblasts and ACBD5 knock-out HeLa cells generated via genome editing, we demonstrate that ACBD5 deficiency causes a moderate but significant defect in peroxisomal ␤-oxidation of very-long-chain fatty acids (VLCFAs) and elevates the level of cellular phospholipids containing VLCFAs without affecting peroxisome biogenesis, including the import of membrane and matrix proteins. Both the N-terminal ACBD and peroxisomal localization of ACBD5 are prerequisite for efficient VLCFA ␤-oxidation in peroxisomes. Furthermore, ACBD5 preferentially binds very-long-chain fatty acyl-CoAs (VLC-CoAs). Together, these results suggest a direct role of ACBD5 in peroxisomal VLCFA ␤-oxidation. Based on our findings, we propose that ACBD5 captures VLC-CoAs on the cytosolic side of the peroxisomal membrane so that the transport of VLC-CoAs into peroxisomes and subsequent ␤-oxidation thereof can proceed efficiently. Our study reclassifies ACBD5-related phenotype as a novel peroxisomal disorder.

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Section: Acbd5 Is a Peroxisomal Tail-anchored Protein Exposing Itsmentioning

confidence: 99%

Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal β-Oxidation of Very-long-chain Fatty Acids

Yagita

Shinohara

Abe

et al. 2017

Journal of Biological Chemistry

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“…Because of the combined loss of peroxisomal function and plasmalogen deficiency, it has not been possible to determine which clinical manifestations are due to a plasmalogen deficit. Patients with a defect in ether lipid biosynthesis and normal peroxisome function have also been described [6,8].…”

Section: Introductionmentioning

confidence: 99%

Plasmalogens as endogenous antioxidants: somatic cell mutants reveal the importance of the vinyl ether

Zoeller

Lake

Nagan

et al. 1999

Biochemical Journal

178

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Exposure of plasmalogen-deficient variants of the murine cell line RAW 264.7 to short-term (0-100 min) treatment with electron transport inhibitors antimycin A or cyanide (chemical hypoxia) resulted in a more rapid loss of viability than in the parent strain. Results suggested that plasmalogen-deficient cells were more sensitive to reactive oxygen species (ROS) generated during chemical hypoxia ; the mutants could be rescued from chemical hypoxia by using the antioxidant Trolox, an α-tocopherol analogue, and they were more sensitive to ROS generation by plumbagin or by rose bengal treatment coupled with irradiation. In addition, the use of buffers containing #H # O greatly enhanced the cytotoxic effect of chemical hypoxia, suggesting the involvement of singlet oxygen. We used the unique enzymic deficiencies displayed by the mutants to differentially restore either plasmenylethanolamine (the major plasma-

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“…Patients with RCDP types 2 and 3 have craniofacial dysmorphism, cataract, severe psychomotor retardation, as well as rhizomelia and chondrodysplasia punctata ( 3,(10)(11)(12). It is tempting to speculate that the lack of a particular 1-alkyl-2-acyl GPI-AP is responsible for some of these abnormalities.…”

Section: Discussionmentioning

confidence: 99%

“…RCDP type 1 is caused by mutation in PEX7 that is essential for transferring the minor group of enzymes bearing a PTS2, such as 3-ketoacyl-CoA thiolase of fatty-acid ␤ -oxidation pathway, alkyl-dihydroxyacetone phosphate synthase (alkyl-DHAP synthase), which is required for synthesis of alkyl-phospholipids, and phytanoyl-CoA 2-hydroxylase, which is required for degradation of phytanic acid ( 3 ). Specifi c defects in DHAPacyltransferase (DHAP-AT) and alkyl-DHAP synthase (also called alkylglycerone phosphate synthase), the fi rst two enzymes in the alkyl-phospholipid biosynthetic pathway, cause disorders similar to RCDP type 1, termed RCDP type 2 and type 3, respectively (10)(11)(12), indicating that the major symptoms of RCDP are due to defective biosynthesis of plasmalogens and/or other alkyl-phospholipids, such as platelet activating factor.…”

mentioning

confidence: 99%

Defective lipid remodeling of GPI anchors in peroxisomal disorders, Zellweger syndrome, and rhizomelic chondrodysplasia punctata

Kanzawa

Shimozawa

Wanders

et al. 2012

Journal of Lipid Research

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Human dihydroxyacetonephosphate acyltransferase deficiency: A new peroxisomal disorder

Cited by 127 publications

References 6 publications

Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal β-Oxidation of Very-long-chain Fatty Acids

Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal β-Oxidation of Very-long-chain Fatty Acids

Plasmalogens as endogenous antioxidants: somatic cell mutants reveal the importance of the vinyl ether

Defective lipid remodeling of GPI anchors in peroxisomal disorders, Zellweger syndrome, and rhizomelic chondrodysplasia punctata

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