Mount Sinai Study Maps Enzyme AASS as Possible Target for Rare Brain-Damaging Disorder GA1

Researchers at the Icahn School of Medicine at Mount Sinai have produced the first detailed picture of the complete human version of an enzyme called AASS, a protein that may one day be a target for treating glutaric aciduria type 1, or GA1. The work appeared in the November 13 online issue of Science Advances.

GA1 is a rare inherited metabolic disorder. It causes toxic substances to accumulate in the body, and that buildup can lead to irreversible brain damage and life-altering neurological complications. The enzyme at the center of the new study, alpha-aminoadipic semialdehyde synthase, takes part in the breakdown of the amino acid lysine. The idea behind the research is that if AASS activity can be dialed down, the harmful metabolites associated with GA1 might accumulate less.

To get there, the team first had to develop a method for isolating the whole human enzyme. They then used cryo-electron microscopy, a technique that visualizes biological molecules at high resolution, to map its structure. Biochemical experiments tested how the enzyme behaves under different conditions, including in the presence of substances that inhibit or activate it. Computer simulations added a view of how the structure moves and how those movements shape its activity.

The central finding concerns a hinge-like, flexible region of the protein. Relatively small structural adjustments there can produce substantial changes in how the enzyme works. Michael Lazarus, PhD, associate professor of pharmacological sciences and associate director of the Mount Sinai Center for Therapeutics Discovery, a senior and co-corresponding author, described it this way: a small change at a flexible connection point can influence the behavior of a much larger protein. He called the work the first detailed picture of the complete AASS enzyme, showing how its different parts work together, and said the hinge offers a new avenue toward potential GA1 treatments.

Sander Houten, PhD, professor of genetics and genomic sciences and another senior and co-corresponding author, said the investigation revealed multiple ways to alter the enzyme's activity. Understanding how nature uses these mechanisms to control lysine degradation, he said, will help in developing treatments. Robert J. DeVita, PhD, the third senior and co-corresponding author, is a professor of pharmacological sciences and director of medicinal chemistry in the Marie-Josée and Henry R. Kravis Drug Discovery Institute. He said the structural knowledge lets the team begin exploring how to design molecules that inhibit AASS, and then assess whether they could eventually lead to a treatment.

The researchers are explicit about the limits. This is an early step toward a therapy, not a treatment or a cure. The experiments were carried out in laboratory settings, with no patients involved, and animal studies and potentially human studies will be needed to establish whether targeting AASS is safe and effective.

The paper is titled "Structural and biochemical insight into allosteric regulation of the human 2-aminoadipic semialdehyde synthase." Its authors are Ruoxi Wu, Susmita Khamrui, Tetyana Dodatko, Yufei Xiang, Afrooz Golestanian, Ngoc Dung Pham, Kunal Kumar, Yi Shi, Roman Osman, DeVita, Houten, and Lazarus. The work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of General Medical Sciences, part of the National Institutes of Health, under awards R01HD112518, R01HD118270, and R35GM124838.

The team's next step is to use the structural map to identify and develop molecules that inhibit the enzyme. Beyond GA1, the investigators say the results offer broader insight into how enzymes can be regulated by subtle changes in their structure.