Cloning and sequence analysis of cDNA for human argininosuccinate lyase.

O’Brien, William E.; McInnes, Roderick R.; Kalumuck, Karen; Adcock, Mark

doi:10.1073/pnas.83.19.7211

Cited by 79 publications

(65 citation statements)

References 35 publications

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“…hASL Complements S. cerevisiae ARG4 null Strain-The amino acid sequence of ASL is highly conserved throughout evolution; the human protein shares 56% of identity with the yeast polypeptide encoded by ARG4 gene (15). We checked whether the hASL gene could complement our haploid yeast null mutant ⌬ARG4, a derivative of the BY4741 strain that harbors a deletion of the ARG4 gene and consequently is auxotrophic for arginine ( Table 2).…”

Section: Resultsmentioning

confidence: 99%

Functional Complementation in Yeast Allows Molecular Characterization of Missense Argininosuccinate Lyase Mutations

Trevisson

Burlina

Doimo

et al. 2009

Journal of Biological Chemistry

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Deficiency of argininosuccinate lyase (ASL) causes argininosuccinic aciduria, an urea cycle defect that may present with a severe neonatal onset form or with a late onset phenotype. To date phenotype-genotype correlations are still not clear because biochemical assays of ASL activity correlate poorly with clinical severity in patients. We employed a yeast-based functional complementation assay to assess the pathogenicity of 12 missense ASL mutations, to establish genotype-phenotype correlations, and to screen for intragenic complementation. Rather than determining ASL enzyme activity directly, we have measured the growth rate in arginine-free medium of a yeast ASL null strain transformed with individual mutant ASL alleles. Individual haploid strains were also mated to obtain diploid, "compound heterozygous" yeast. We show that the late onset phenotypes arise in patients because they harbor individual alleles retaining high residual enzymatic activity or because of intragenic complementation among different mutated alleles. In these cases complementation occurs because in the hybrid tetrameric enzyme at least one active site without mutations can be formed or because the differently mutated alleles can stabilize each other, resulting in partial recovery of enzymatic activity. Functional complementation in yeast is simple and reproducible and allows the analysis of large numbers of mutant alleles. Moreover, it can be easily adapted for the analysis of mutations in other genes involved in urea cycle disorders.

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Section: Resultsmentioning

confidence: 99%

Functional Complementation in Yeast Allows Molecular Characterization of Missense Argininosuccinate Lyase Mutations

Trevisson

Burlina

Doimo

et al. 2009

Journal of Biological Chemistry

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“…tSequence from the amino acid sequence deduced from cDNA for human argininosuccinase (18). tSequence from the amino acid sequence deduced from the yeast (Saccharomyces cerevisiae) argininosuccinase gene ARG4 (19).…”

Section: Methodsmentioning

confidence: 99%

Reaction of argininosuccinase with bromomesaconic acid: role of an essential lysine in the active site.

Lusty¹,

Ratner²

1987

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

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We have undertaken studies on bovine liver argininosuccinase (L-argininosuccinate arginine-lyase, EC 4.3.2.1) with the active site-directed reagent bromo[U-14C]mesaconic acid, an analogue of fumaric acid. Reactivity, measured by enzyme inactivation, followed pseudo-first-order kinetics, and the rate increased with reagent concentration. Argininosuccinate completely protected the enzyme against inactivation, but neither arginine nor fumarate was protective. A plot of the degree of inactivation as a function of alkyl groups incorporated was extrapolated to 4 mol per mol of enzyme, or 1 mol per active site. After large-scale alkylation of the enzyme (and digestion with trypsin), two "4C-labeled tryptic peptides were isolated. These were chemically sequenced by the Edman method. The amino acid sequences proved to be identical with regions of the deduced amino acid sequences of argininosuccinases from human and yeast sources [O'

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“…It is the second most common urea cycle disorder after OTC deficiency, with a frequency of approximately 1 in 70,000 live births in the United States, and the gene is located on chromosome 7 [31,76,77]. Patients typically present early in life with hyperammonemia, elevated plasma citrulline, and measurable argininosuccinic acid in plasma and urine, and the hyperammonemic episodes are less frequent and less severe than in many of the other urea cycle disorders [1].…”

Section: Argininosuccinate Lyasementioning

confidence: 99%

Contrasting features of urea cycle disorders in human patients and knockout mouse models

Deignan

Cederbaum

Grody

2008

Molecular Genetics and Metabolism

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The urea cycle exists for the removal of excess nitrogen from the body. Six separate enzymes comprise the urea cycle, and a deficiency in any one of them causes a urea cycle disorder (UCD) in humans. Arginase is the only urea cycle enzyme with an alternate isoform, though no known human disorder currently exists due to a deficiency in the second isoform. While all of the UCDs usually present with hyperammonemia in the first few days to months of life, most disorders are distinguished by a characteristic profile of plasma amino acid alterations that can be utilized for diagnosis. While enzyme assay is possible, an analysis of the underlying mutation is preferable for an accurate diagnosis. Mouse models for each of the urea cycle disorders exist (with the exception of NAGS deficiency), and for almost all of them, their clinical and biochemical phenotypes rather closely resemble the phenotypes seen in human patients. Consequently, all of the current mouse models are highly useful for future research into novel pharmacological and dietary treatments and gene therapy protocols for the management of urea cycle disorders.

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Cloning and sequence analysis of cDNA for human argininosuccinate lyase.

Cited by 79 publications

References 35 publications

Functional Complementation in Yeast Allows Molecular Characterization of Missense Argininosuccinate Lyase Mutations

Functional Complementation in Yeast Allows Molecular Characterization of Missense Argininosuccinate Lyase Mutations

Reaction of argininosuccinase with bromomesaconic acid: role of an essential lysine in the active site.

Contrasting features of urea cycle disorders in human patients and knockout mouse models

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