Document Detail


Functional studies in fibroblasts of adenylosuccinase-deficient children.
MedLine Citation:
PMID:  8412003     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In fibroblasts of severely retarded (type I) adenylosuccinase (ASase)-deficient children, activities with the two substrates of the enzyme, succinylaminoimidazole carboxamide ribotide (succinyl-AICAR) and adenylosuccinate are decreased in parallel, to about 30% of normal. In a markedly less retarded (type II) patient, ASase activity with adenylosuccinate reaches only 3% of normal, whereas activity with succinyl-AICAR is also about 30% of normal. To assess the functional significance of a partial versus a profound deficiency of ASase, precursor incorporation studies were performed in intact fibroblasts. In cells from controls and from type I patients, incorporation of 0.2 mmol/L [14C]formate into adenine and guanine nucleotides was not accompanied by accumulation of either [14C]succinyl-AICAR or [14C]adenylosuccinate. Similarly, incorporation of 20 mumol/L [14C]hypoxanthine was not accompanied by accumulation of [14C]adenylosuccinate. In contrast, in fibroblasts of the type II patient, in accordance with the profound deficiency of ASase with adenylosuccinate, and with the inhibitory effect of Cl- and nucleotides on the activity with succinyl-AICAR, incorporation of [14C]formate resulted in accumulation of [14C]succinyl-AICAR and [14C]adenylosuccinate, and incorporation of [14C]hypoxanthine in a marked build-up of [14C]adenylosuccinate. That both precursors were still incorporated into the adenine nucleotides of the fibroblasts of the type II patient indicates that adenylate synthesis remains possible even with 3% residual ASase activity, as also shown by their grossly normal ATP concentrations. The results suggest that the pathophysiology of ASase deficiency may be mediated at least in part by accumulation of succinyladenosine and succinyl-AICAriboside.
Authors:
F Van den Bergh; M F Vincent; J Jaeken; G Van den Berghe
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of inherited metabolic disease     Volume:  16     ISSN:  0141-8955     ISO Abbreviation:  J. Inherit. Metab. Dis.     Publication Date:  1993  
Date Detail:
Created Date:  1993-10-25     Completed Date:  1993-10-25     Revised Date:  2007-03-21    
Medline Journal Info:
Nlm Unique ID:  7910918     Medline TA:  J Inherit Metab Dis     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  425-34     Citation Subset:  IM    
Affiliation:
Laboratory of Physiological Chemistry, International Institute of Cellular and Molecular Pathology, Brussels, Belgium.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Monophosphate / analogs & derivatives,  metabolism
Adenosine Triphosphate / metabolism
Adenylosuccinate Lyase / deficiency*
Aminoimidazole Carboxamide / analogs & derivatives,  metabolism
Cells, Cultured
Child
Fibroblasts / enzymology*
Formic Acids / metabolism
Humans
Hypoxanthine
Hypoxanthines / metabolism
Mental Retardation / enzymology
Ribonucleotides / metabolism
Chemical
Reg. No./Substance:
0/Formic Acids; 0/Hypoxanthines; 0/Ribonucleotides; 19240-42-7/adenylosuccinate; 3031-95-6/SAICAR; 360-97-4/Aminoimidazole Carboxamide; 56-65-5/Adenosine Triphosphate; 61-19-8/Adenosine Monophosphate; 64-18-6/formic acid; 68-94-0/Hypoxanthine; EC 4.3.2.2/Adenylosuccinate Lyase

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