Characterization of the gene encoding human peroxisomal 3-oxoacyl-CoA thiolase (ACAA). No large DNA rearrangement in a thiolase-deficient patient

Bout, A.; Franse, Maartje M.; Collins, Janna C.; Blonden, Lou; Tager, J. M.; Benne, Rob

doi:10.1016/0167-4781(91)90035-k

Cited by 31 publications

(14 citation statements)

References 29 publications

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“…A patient suffering from a single enzyme defect in the peroxisomal /3-oxidation did not display a detectable DNA rearrangement of the human peroxisomal 03-ketothiolase gene in genomic DNA (9). This patient had more serious clinical symptoms than our patients which may be due to the peroxisomal thiolase involvement in the ,/-oxidation of di-and trihydroxycoprostanoic acids as well as of VLCFA. Recently, a rearrangement altering the color pigment genes in a patient with X-linked adrenoleukodystrophy was shown to include two deletions apparently separated by a large inversion on chromosome Xq28 (25).…”

Section: Resultsmentioning

confidence: 51%

Large deletion of the peroxisomal acyl-CoA oxidase gene in pseudoneonatal adrenoleukodystrophy.

Fournier¹,

Saudubray²,

Bénichou³

et al. 1994

J. Clin. Invest.

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We have cloned the cDN} encodiig human peroxisomal acyl-CoA oxidase, the first enzyme in the peroxisomal 13-oxidation of very long cha in fatty acids. Its nucleotv e sequence was foundl to be h ighly homologous (85' to the rat cDNA countei part.An 88% homology betveen rat and h was found in the COOH-terminal end of the cDNA w ch includes the Ser-Lys-Leu peroxisomal targeting signal common to many peroxisomal proteins. The gene spans 30-40 kb and is poorly polymorphic. Southern blot analyses were performed in two previously reported siblings with an isolated peroxisomal acyl-CoA oxidase deficiency (pseudoneonatal adrenoleukodystrophy). A deletion of at least 17 kb, starting downstream from exon 2 and extending beyond the 3' end of the gene, was observed in the two patients. These observations provide a molecular basis for the observed acyl-CoA oxidase deficiency in our family. In addition, our study will enable the characterization of the genetic defect in unrelated families with suspected acyl-CoA oxidase disorders. (J. Clin. Invest. 1994. 94:526-531.)

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Section: Resultsmentioning

confidence: 51%

Large deletion of the peroxisomal acyl-CoA oxidase gene in pseudoneonatal adrenoleukodystrophy.

Fournier¹,

Saudubray²,

Bénichou³

et al. 1994

J. Clin. Invest.

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“…Of those, five were part of peroxisomal beta-oxidation of long chain unsaturated fatty acids (Figure 7). These blocked reactions were all catalysed by 3-ketoacyl coenzyme A thiolase (EC 2.3.1.16), an enzyme responsible for the last step of the four recurring steps of fatty acid β-oxidation [49]. The SMILEY solutions successfully coupled the root no-production metabolites of these reactions, involving 3-oxo fatty acid coenzyme A derivatives, to their corresponding fatty acid in three resolving reactions.…”

Section: Resultsmentioning

confidence: 99%

The human metabolic reconstruction Recon 1 directs hypotheses of novel human metabolic functions

2011

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BackgroundMetabolic network reconstructions formalize our knowledge of metabolism. Gaps in these networks pinpoint regions of metabolism where biological components and functions are "missing." At the same time, a major challenge in the post genomic era involves characterisation of missing biological components to complete genome annotation.ResultsWe used the human metabolic network reconstruction RECON 1 and established constraint-based modelling tools to uncover novel functions associated with human metabolism. Flux variability analysis identified 175 gaps in RECON 1 in the form of blocked reactions. These gaps were unevenly distributed within metabolic pathways but primarily found in the cytosol and often caused by compounds whose metabolic fate, rather than production, is unknown. Using a published algorithm, we computed gap-filling solutions comprised of non-organism specific metabolic reactions capable of bridging the identified gaps. These candidate solutions were found to be dependent upon the reaction environment of the blocked reaction. Importantly, we showed that automatically generated solutions could produce biologically realistic hypotheses of novel human metabolic reactions such as of the fate of iduronic acid following glycan degradation and of N-acetylglutamate in amino acid metabolism.ConclusionsThe results demonstrate how metabolic models can be utilised to direct hypotheses of novel metabolic functions in human metabolism; a process that we find is heavily reliant upon manual curation and biochemical insight. The effectiveness of a systems approach for novel biochemical pathway discovery in mammals is demonstrated and steps required to tailor future gap filling algorithms to mammalian metabolic networks are proposed.

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“…More than one cap site is commonly found in such genes. Multiple GC boxes are frequently found in eukaryotic promoters and are a characteristic feature of the mammalian peroxisomal genes, such as those encoding rat ACOX (7), PBE (22), thiolase A (19), as well as human catalase (18) and human thiolase (23). The GC box probably represents a common transcription signal for the genes of the 3-oxidation enzymes including human ACOX.…”

Section: Resultsmentioning

confidence: 99%

Isolation of the human peroxisomal acyl-CoA oxidase gene: organization, promoter analysis, and chromosomal localization.

Varanasi

Chu

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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Peroxisomal acyl-CoA oxidase (ACOX; EC 1.3.3.6) is the first enzyme of the fatty acid 1-oxidation pathway, which catalyzes the desaturation of acyl-CoAs to 2-tnns-enoyl-CoAs, and it donates electrons directly to molecular oxygen, thereby producing H202. The discovery of carcinogenic peroxisome proliferators, which markedly increase the levels ofthis H202-producing ACOX in rat and mouse liver, generated interest in peroxisomal «-oxidation system genes. The present study deals with the structural organization of human ACOX gene. This gene spans :33 kb and consists of 14 exons and 13 introns. Primer-extension analysis revealed three principal cap sites, which were mapped at 50, 52, and 53 nt upstream of the initiator methionine codon. The 5' flanking region of the ACOX gene was sequenced up to 500 bp ups ofthe cap sites. This promoter region is G+C-rich and contains three copies of the "GC box" hexanucleofides. Multiple GC boxes are a characteristic feature of the rat ACOX and functional protein genes ofthe 1oxidation system. A+T-rich TATA-boxilike sequences, TTTATTT and TTATY, have also been identified in this human ACOX gene, but typical CCAAT motifs are absent. This ACOX gene has been mapped to chromosome 17q25 by in situ hybridization, using a biotinlabeled probe.Peroxisomes are cellular organelles that are present in virtually all eukaryotic cells. These organelles contain hydrogen peroxide-producing flavin oxidases together with catalase, which decomposes hydrogen peroxide (1). At present >50 enzymes have been found in mammalian peroxisomes, and more than half of these play a role in lipid metabolism (1

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Characterization of the gene encoding human peroxisomal 3-oxoacyl-CoA thiolase (ACAA). No large DNA rearrangement in a thiolase-deficient patient

Cited by 31 publications

References 29 publications

Large deletion of the peroxisomal acyl-CoA oxidase gene in pseudoneonatal adrenoleukodystrophy.

Large deletion of the peroxisomal acyl-CoA oxidase gene in pseudoneonatal adrenoleukodystrophy.

The human metabolic reconstruction Recon 1 directs hypotheses of novel human metabolic functions

Isolation of the human peroxisomal acyl-CoA oxidase gene: organization, promoter analysis, and chromosomal localization.

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