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Biochemical‐structural‐phenotypic correlation of adenylosuccinate lyase deficiency based on analysis of mutant enzyme complexes
Author(s) -
Zikanova Marie,
Skopova Vaclava,
Hnizda Ales,
Krijt Jakub,
Kmoch Stanislav
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.889.7
Subject(s) - mutant , phenotype , biology , genotype , enzyme , genetics , mutation , biochemistry , hypoxanthine guanine phosphoribosyltransferase , microbiology and biotechnology , gene
Adenylosuccinate lyase (ADSL) deficiency is disorder of purine metabolism affecting mainly central nervous system. Three forms differing in severity of symptoms and correlating negatively with ratios of accumulating SAdo/SAICAr in body fluids were established. This diversity is not clear and may result from a genotype specific and thus structural related nonparallel loss of activity towards one of the substrates. To test this we selected 16 patients with individual disease causing genotypes and cloned, expressed, purified and characterized individual mutant proteins and co‐expressed genotype specific mutant proteins. We also located mutations in the structural model of ADSL. We found that phenotypic severity (eg. SAdo/SAICAr ratio) generally does not result from disproportional enzyme activities of mutant protein complexes but it correlates rather with their residual enzymatic activities and structural stability. We conclude that SAdo/SAICAr ratio value is probably not predictive of phenotype severity but rather it corresponds to degree of patient's development and brain maturation. This work was supported by CR grants CSF 301070600 and MSM 20620806.