Adenylosuccinate lyase (ASL) deficiency is a rare metabolic disorder that results in autistic features. It is caused by mutations that decrease activity of the adenylosuccinate lyase enzyme which is essential for nucleotide synthesis. Numerous disease-related ASL mutations have been identified, but their effects are unknown because the instability of human ASL has made experimentation difficult.
Dr. Coleman's lab has recently found a solution for stabilizing human ASL, and her research program is now poised to characterize normal and mutant ASL. Dr. Coleman's fellow will conduct experiments to compare the functions of normal and mutant ASLs. The mutant forms of the enzyme will be engineered to mimic six of those found in human ASL deficiency. The enzymes will be characterized by catalytic activity, binding studies, and biophysical measurements to evaluate their size, shape, and stability. The researchers expect to find that mutant forms of ASL have altered binding sites or structures, both of which would hinder the enzyme's function. The hope is that understanding the differences in function between the various ASL forms can illuminate the biological pathways that, when disrupted, will generate autism.