Relationship between enzyme properties and disease progression in Canavan disease.

[canavan disease]

Canavan disease (CD ) is a fatal neurological disorder caused by defects in the gene that encodes for a critical metabolic enzyme . The enzyme aspartoacylase catalyzes the deacetylation of N-acetylaspartate to produce acetate required for fatty acid biosynthesis in the brain . The loss of aspartoacylase activity leads to the demyelination and disrupted brain development that is found in CD patients . Sixteen different clinical mutants of aspartoacylase have been cloned , expressed and purified to examine their properties and the relationship between enzyme properties and disease phenotype . In contrast to numerous cell culture studies that reported virtually complete loss of function , each of these purified mutant enzymes was found to have measureable catalytic activity . However , the activities of these mutants are diminished , by as little as three-fold to greater than 100 -fold when compared to the native enzyme . Many of these mutated enzyme forms show decreased thermal stability and an increased propensity for denaturation upon exposure to urea , but only four of the 16 mutants examined showed both diminished thermal and diminished conformational stability . Significantly , each of these lower stability mutants are responsible for the more severe phenotypes of CD , while patients with milder forms of CD have aspartoacylase mutants with generally high catalytic activity and with either good thermal or good conformational stability . These results suggest that the loss of catalytic function and the accumulation of N-acetylaspartate in Canavan disease is at least partially a consequence of the decreased protein stability caused by these mutations .