Intragenic complementation and the structure and function of argininosuccinate lyase

Yu, Bing; Howell, P. Lynne

doi:10.1007/pl00000646

Cited by 32 publications

(25 citation statements)

References 113 publications

(135 reference statements)

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“…Complementation coefficients were calculated for complexes equilibrated at both 25 and 501C and for each of the substrates separately. The complementation coefficients obtained for complexes equilibrated at 251C, which showed the effects of complementation on the catalytic properties of the enzyme, revealed three heteromeric complexes with a positive complementation effect higher than 25% (as defined in [Yu and Howell, 2000]): p.Tyr114His/p.Glu376Asp (CC 5 1.25 and 0.98 for S-AMP and SAICAR, respectively), p.Tyr114His/p.Arg396His (CC 5 1.84 and 1.59 for S-AMP and SAICAR, respectively), and p.Tyr114His/ p.Arg190Gln (CC 5 1.30 and 1.18 for S-AMP and SAICAR, respectively). A negative complementation effect was seen in the case of the p.Arg396Cys/p.Arg194Cys complex (CC 5 0.74 and 1.00 for S-AMP and SAICAR, respectively).…”

Section: Functional-structural Correlation Of Heteromeric Complexesmentioning

confidence: 99%

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Biochemical and structural analysis of 14 mutant adsl enzyme complexes and correlation to phenotypic heterogeneity of adenylosuccinate lyase deficiency

et al. 2010

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Adenylosuccinate lyase (ADSL) deficiency is neurometabolic disease characterized by accumulation of dephosphorylated enzyme substrates SAICA-riboside (SAICAr) and succinyladenosine (S-Ado) in body fluids of affected individuals. The phenotypic severity differs considerably among patients: neonatal fatal, severe childhood, and moderate phenotypic forms correlating with different values for the ratio between S-Ado and SAICAr concentrations in cerebrospinal fluid have been distinguished. To reveal the biochemical and structural basis for this phenotypic heterogeneity, we expressed and characterized 19 ADSL mutant proteins identified in 16 patients representing clinically distinct subgroups. Respecting compound heterozygosity and considering the homotetrameric structure of ADSL, we used intersubunit complementation and prepared and characterized genotype-specific heteromeric mutant ADSL complexes. We correlated clinical phenotypes with biochemical properties of the mutant proteins and predicted structural impacts of the mutations. We found that phenotypic severity in ADSL deficiency is correlated with residual enzymatic activity and structural stability of the corresponding mutant ADSL complexes and does not seem to result from genotype-specific disproportional catalytic activities toward one of the enzyme substrates. This suggests that the S-Ado/SAICAr ratio is probably not predictive of phenotype severity; rather, it may be secondary to the degree of the patient's development (i.e., to the age of the patient at the time of sample collection).

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Section: Functional-structural Correlation Of Heteromeric Complexesmentioning

confidence: 99%

“…The process of random oligomerization can be tested in vitro using intersubunit complementation in which the individual subunits are either mixed or preferably coexpressed together before further characterization [Brosius and Colman, 2002;Lee et al, 1999;Yu and Howell, 2000].…”

Section: Introductionmentioning

confidence: 99%

Biochemical and structural analysis of 14 mutant adsl enzyme complexes and correlation to phenotypic heterogeneity of adenylosuccinate lyase deficiency

et al. 2010

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“…Argininosuccinate lyase (ASL, EC 4.3.2.1) also named argininosuccinase catalyzes the reversible reaction of argininosuccinate to arginine and fumarate (8)(9)(10)(11). It is an important enzyme in the urea cycle in liver.…”

Section: Introductionmentioning

confidence: 99%

Study of serum argininosuccinate lyase determination for diagnosis of liver diseases

Feng

Chen

Wen

et al. 2008

Clinical Laboratory Analysis

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The objectives of this research were to establish an automatic analysis method for the determination of serum argininosuccinate lyase (ASL) and to investigate the value of serum ASL test in the diagnosis of various liver disorders. According to the chemical reaction catalyzed by ASL, an enzyme-coupled reaction system was designed, and a methodology evaluation of this method was performed. A total of 291 patients with various liver diseases, 247 patients with nonliver disease and 32 healthy controls, were recruited, their serum levels of ASL and traditional hepatopathy markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and total bilirubin (TBil), were all determined, and their diagnostic values in liver diseases were analyzed and compared. Liver biopsy and the score of histopathological inflammation grading were performed in 31 patients with hepatopathy to explore the correlation between serum ASL level and hepatic histopathological change. A continuous monitoring assay method of serum ASL activity was established, which could be performed with automatic biochemistry analyzer. Methodological evaluation exhibited that the precision of this method was good indicated by the 4.0% intraassay coefficient of variation (CV), and 5.9% interassay CV. The mean recovery was 100.5%, linear range was from 0 to 167.7 U/L, and the lowest detection limit was approximately 0 U/L. All of the tested hepatopathy markers listed above were significantly increased in the liver disease group. However, levels of traditional markers of hepatopathy were all significantly increased at different degrees (all P<0.001) in patients with nonliver diseases; in contrast, there were no significantly increased ASL levels in all non-hepatopathy groups (P=0.335). The receiver operating characteristic (ROC) curve showed that the sensitivity and specificity of ASL were 100% and 91.1% (cutoff value=8 U/L), respectively, in the assessment of liver diseases. In contrast, ALT levels were 97.6% and 24.7%, and AST levels were 83.8% and 28.3% (both cutoff values=40.0 U/L), respectively. A positive correlation (r=0.417, P=0.019) was observed between serum ASL levels (86.9+/-26.5) and scores of histopathological inflammation grading (SHIG) (9.83+/-3.36). The sensitivity and specificity of ALS is much higher than that of ALT and AST for the diagnosis of liver diseases. ASL may be a more valuable marker for estimating hepatopathy.

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“…The ASL subunits consist of 463 amino acids with a predicted molecular weight of about 52 kDa (O'Brien et al 1986). ASL belongs to a superfamily of enzymes that have homologous parts and catalyse similar cleavages (Yu and Howell 2000).…”

Section: Introductionmentioning

confidence: 99%

Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene

et al. 2002

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Argininosuccinic aciduria is an urea cycle disorder caused by argininosuccinate lyase (ASL) deficiency and is inherited as an autosomal-recessive trait. To date, mutation analysis has been limited because of incomplete sequence information about the human ASL gene. As a consequence, only 12 different mutations in 12 patients have been reported, so far. This study aimed at the completion of the structure and the sequence of the human ASL gene, the development of a genomic DNA-based system for mutation analysis and, finally, the characterisation of the molecular genetic background of ASL deficiency in 27 unrelated patients. This report provides transcript variants, the complete sequence of the human ASL gene and a complete ASL homologue on chromosome 22. The homologue was formerly thought to be a pseudogene but was found, in this study, to be correlated with an immunoglobulin-lambda-like mRNA. On the basis of the novel sequence data, a polymerase reaction chain system for mutation-screening in all 16 coding exons of the ASL gene was established and applied to the analysis of the ASL-deficient patients. We found mutations in all of the 54 investigated alleles and identified 23 (19 novel) different mutations. Some mutational hot-spots were identified (mainly in exons 4, 5, and 7) as were several predominant mutations: IVS5+1G-->A (15 alleles), c.532G-->A (7), c.346C-->T (6), c.1153C-->T (4). This study introduces a system for mutation analysis in the ASL gene, thereby elucidating the genetic background of ASL deficiency, which was found to be associated with considerable allelic heterogeneity.

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Intragenic complementation and the structure and function of argininosuccinate lyase

Cited by 32 publications

References 113 publications

Biochemical and structural analysis of 14 mutant adsl enzyme complexes and correlation to phenotypic heterogeneity of adenylosuccinate lyase deficiency

Biochemical and structural analysis of 14 mutant adsl enzyme complexes and correlation to phenotypic heterogeneity of adenylosuccinate lyase deficiency

Study of serum argininosuccinate lyase determination for diagnosis of liver diseases

Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene

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