N-acetyl-L-aspartate in the brain. It is believed that controlling N-acetyl-L-aspartate levels is essential for developing and maintaining white matter. It is not known why so much N-acetyl-L-aspartate is produced in the brain nor what its primary function is. However, one hypothesis is that it is potentially used as a chemical reservoir that can be tapped into for acetate for acetyl-CoA synthesis or aspartate for glutamate synthesis. This way, N-acetyl-L-aspartate can be used to transport these precursor molecules and aspartoacylase is used to release them. For example, N-acetyl-L-aspartate produced in neurons can be transported into oligodendrocytes and the acetate released can be used for myelin synthesis. Another hypothesis is that N-acetyl-L-aspartate is essential osmolyte that acts as a molecular water pump that helps maintain a proper fluid balance in the brain. Disease Relevance Mutations that lead to loss of aspartoacylase activity have been identified as the cause of Canavan disease. Canavan disease is a rare autosomal recessive disorder that causes spongy degeneration of the white matter in the brain and severe psychomotor retardation, usually leading to death at a young age. The loss of aspartoacylase activity leads to the buildup of N-acetyl-L-aspartate in the brain and an increase in urine concentration by up to 60 times normal levels. Though the exact mechanism of how loss of aspartoacylase activity leads to Canavan disease is not fully understood, there are two primary competing explanations. The first is that it leads to defective myelin synthesis due to a deficiency of acetyl-CoA derived from the acetate product. Another explanation is that the elevated levels of N-acetyl-l-aspartate interfere with its normal brain osmoregulatory mechanism leading to osmotic disequilibrium. There are over 70 reported mutations of this enzyme, but the most common ones are the amino acid substitutions E285A and A305E. E285A reduces activity of aspartoacylase down to as low as 0.3% of its normal function and is found in 98% of cases with Ashkenazi Jewish ancestry. The mutation A305E is found in about 40% of non-Jewish patients and reduces activity to about 10%. Of these two mutations, a crystal structure of the E285A mutant has been taken, showing that the loss of the hydrogen bonding from glutamate leads to a conformational change that distorts the active site and alters the substrate binding, leading to the much lower catalytic activity. See also Aspartic acid Neurodegeneration Enzyme deficiency Notes References External links EC 3.5.1