Identification of mutations (D128G, H141L) in the liver arginase gene of patients with hyperargininemia

Vockley, Joseph G.; Tabor, David E.; Kern, Rita M.; Goodman, Barbara K.; Wissmann, Paul B.; Kang, Dong-Hee; Grody, Wayne W.; Cederbaum, Stephen D.

doi:10.1002/humu.1380040210

Cited by 36 publications

(22 citation statements)

References 10 publications

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“…Each subunit requires and binds two Mn 2ϩ residues for function, and each monomeric subunit is able to catalyze the hydrolytic reaction independently (12). The location and types of mutations found in human arginase deficiency have been extensively studied and catalogued (1,17,19). As might be expected, all natural missense mutations were found in a highly conserved residue and all but one was found in a conserved region of 5 or more amino acids.…”

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confidence: 90%

Mouse Model for Human Arginase Deficiency

Iyer

Yoo²,

Kern³

et al. 2002

Molecular and Cellular Biology

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Deficiency of liver arginase (AI) causes hyperargininemia (OMIM 207800), a disorder characterized by progressive mental impairment, growth retardation, and spasticity and punctuated by sometimes fatal episodes of hyperammonemia. We constructed a knockout mouse strain carrying a nonfunctional AI gene by homologous recombination. Arginase AI knockout mice completely lacked liver arginase (AI) activity, exhibited severe symptoms of hyperammonemia, and died between postnatal days 10 and 14. During hyperammonemic crisis, plasma ammonia levels of these mice increased >10-fold compared to those for normal animals. Livers of AI-deficient animals showed hepatocyte abnormalities, including cell swelling and inclusions. Plasma amino acid analysis showed the mean arginine level in knockouts to be approximately fourfold greater than that for the wild type and threefold greater than that for heterozygotes; the mean proline level was approximately one-third and the ornithine level was one-half of the proline and ornithine levels, respectively, for wild-type or heterozygote mice-understandable biochemical consequences of arginase deficiency. Glutamic acid, citrulline, and histidine levels were about 1.5-fold higher than those seen in the phenotypically normal animals. Concentrations of the branched-chain amino acids valine, isoleucine, and leucine were 0.4 to 0.5 times the concentrations seen in phenotypically normal animals. In summary, the AI-deficient mouse duplicates several pathobiological aspects of the human condition and should prove to be a useful model for further study of the disease mechanism(s) and to explore treatment options, such as pharmaceutical administration of sodium phenylbutyrate and/or ornithine and development of gene therapy protocols.Arginase (EC 3.5.3.1) is the fifth and final enzyme of the urea cycle, the major pathway for the detoxification of ammonia in mammals. There are at least two forms of arginase in mammals, AI and AII, located in the cytoplasm and mitochondrion, respectively. The principal ureagenic enzyme activity (AI) is most abundant in normal mammalian liver and acts in coordination with the other enzymes of the urea cycle to sequester and eliminate excess nitrogen from the body (7). The second form (AII) is found in many organs, with the highest levels found in kidney and prostate and lower levels in macrophages, lactating mammary glands, and brain, often in the absence of the other urea cycle enzymes (7,18). In humans, deficiency of the liver isoform (AI) causes hyperargininemia (OMIM 207800; Online Mendelian Inheritance in Man [http:// www.ncbi.nlm.nih.gov/entrez/query.fcgi?dbϭOMIM]), a metabolic disorder characterized by neurological impairment, with deterioration of the cortex and pyramidal tracts and progressive dementia, spasticity, and growth retardation and punctuated by infrequently fatal episodes of hyperammonemia (7

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confidence: 90%

Mouse Model for Human Arginase Deficiency

Iyer

Yoo²,

Kern³

et al. 2002

Molecular and Cellular Biology

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151

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“…Nonsense mutations have been reported in a minority of patients, with missense mutations being more prevalent [Uchino et al, 1995;Vockley et al, 1994]. Many of these missense mutations occur in highly conserved regions of the gene .…”

Section: Molecular Characteristicsmentioning

confidence: 99%

Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency

Scaglia

Lee²

2006

American J of Med Genetics Pt C

103

160

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The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Urea cycle disorders are a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia and hyperglutaminemia. Deficiencies of all of the enzymes of the cycle have been described and although each specific disorder results in the accumulation of different precursors, hyperammonemia and hyperglutaminemia are common biochemical hallmarks of these disorders. Arginase is the enzyme involved in the last step of the urea cycle. It catalyzes the conversion of arginine to urea and ornithine. The latter reenters the mitochondrion to continue the cycle. Hyperargininemia is an autosomal recessive disorder caused by a defect in the arginase I enzyme. Unlike other urea cycle disorders, this condition is not generally associated with a hyperammonemic encephalopathy in the neonatal period. It typically presents later in childhood between 2 and 4 years of age with predominantly neurological features. If untreated, it progresses with gradual developmental regression. A favorable outcome can be achieved if dietary treatment and alternative pathway therapy are instituted early in the disease course. With this approach, further neurological deterioration is prevented and partial recovery of skills ensues. Early diagnosis of this disorder through newborn screening programs may lead to a better outcome. This review article summarizes the clinical characterization of this disorder; as well as its biochemical, enzymatic, and molecular features. Treatment, prenatal diagnosis and diagnosis through newborn screening are also discussed.

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“…In this connection, the D128G variant of human liver arginase was described as inactive [16,17], although the possible influence of structural changes accompanying the mutation were not examined. Since this aspartate is conserved among all sequenced arginases and agmatinases [4][5][6][7], a critical role for the equivalent residue in agmatinase (Asp153), may be reasonably expected.…”

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Insights into the reaction mechanism of Escherichia coli agmatinase by site‐directed mutagenesis and molecular modelling

Salas

Rodrı́guez

López

et al. 2002

European Journal of Biochemistry

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Upon mutation of Asp153 by asparagine, the catalytic activity of agmatinase (agmatine ureohydrolase, EC 3.5.3.11) from Escherichia coli was reduced to about 5% of wild-type activity. Tryptophan emission fluorescence (k max ¼ 340 nm), and CD spectra were nearly identical for wildtype and D153N agmatinases. The K m value for agmatine (1.6 ± 0.1 mM), as well as the K i for putrescine inhibition (12 ± 2 mM) and the interaction of the enzyme with the required metal ion, were also not altered by mutation. Threedimensional models, generated by homology modelling techniques, indicated that the side chains of Asp153 and Asn153 can perfectly fit in essentially the same position in the active site of E. coli agmatinase. Asp153 is suggested to be involved, by hydrogen bond formation, in the stabilization and orientation of a metal-bound hydroxide for optimal attack on the guanidinium carbon of agmatine. Thus, the disruption of this hydrogen bond is the likely cause of the greately decreased catalytic efficiency of the D153N variant.Keywords: agmatinase; Asp153; site-directed mutagenesis; homology-modelling; E. coli.Agmatinase (agmatine ureohydrolase, EC 3.5.3.11) catalyses the hydrolysis of agmatine to putrescine and urea [1]. Agmatine, which results from decarboxylation of arginine by arginine decarboxylase [2], is a metabolic intermediate in the biosynthesis of putrescine and higher polyamines [1] and may have important regulatory roles in mammals [3][4][5].Agmatinases from Escherichia coli and human tissues, and putative agmatinases from Synechocystic sp. Schizosaccharomyces pombe and Bacillus subtilis, have been cloned and the deduced amino acid sequences indicate their homology to all sequenced arginases [4][5][6][7]; all these enzymes catalyse an hydrolytic reaction with production of urea. The question arises therefore as to whether a similar or identical mechanism is involved in catalysis by these enzymes, which apparently evolved from a single primordial protein [6,7]. In this context, both enzymes exhibit an absolute requirement for Mn 2+ for catalytic activity [8,9]; the well established requirement of a binuclear metal cluster for full catalytic activity of arginase [8] is probably also valid for agmatinase [9]. This is reinforced by the fact that residues known to be metal ligands in arginase are strictly conserved in the sequence of agmatinase [7]. Moreover, a critical role for one conserved histidine residue (His163 in the sequence of E. coli agmatinase) has been shown by chemical modification and site-directed mutagenesis of human and rat liver arginases [10,11] and E. coli agmatinase [12]; similar information was deduced from X-ray crystallographic data for arginase from Bacillus caldovelox [13].Based on the crystal structure of rat liver arginase, it was suggested that arginine hydrolysis involves the participation of a metal-bound hydroxide, which is stabilized for optimal nucleophilic attack at the substrate, by donating an hydrogen bond to Asp128 [8,14,15]. In this connection, the D128G variant of human...

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Identification of mutations (D128G, H141L) in the liver arginase gene of patients with hyperargininemia

Cited by 36 publications

References 10 publications

Mouse Model for Human Arginase Deficiency

Mouse Model for Human Arginase Deficiency

Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency

Insights into the reaction mechanism of Escherichia coli agmatinase by site‐directed mutagenesis and molecular modelling

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