Researchers at the Icahn School of Medicine at Mount Sinai have mapped the structure of AASS, an enzyme involved in lysine breakdown, to uncover new targets for treating the rare genetic disorder glutaric aciduria type 1, according to a report by News-Medical.
Published in the November 13 online issue of Science Advances, the investigation provides structural insights that could guide the development of drugs to inhibit alpha-aminoadipic semialdehyde synthase. Glutaric aciduria type 1 (GA1) is an inherited metabolic disorder causing toxic substances to accumulate, potentially leading to irreversible brain damage and life-altering neurological complications.
“This is the first detailed picture of the complete AASS enzyme, giving us a much clearer understanding of how its different parts work together,” Michael Lazarus said. Lazarus is senior and co-corresponding author, Associate Professor of Pharmacological Sciences, and Associate Director of the Mount Sinai Center for Therapeutics Discovery at the Icahn School of Medicine.
- The Target: Scientists mapped the complete human AASS enzyme, which breaks down the amino acid lysine in the body.
- The Mechanism: Small structural changes in a flexible hinge-like region of the protein can significantly alter its activity, offering a potential site for future drug intervention.
- The Caveat: This study is an early laboratory step and does not represent an immediate treatment or cure for patients.
To study the protein, the team developed a method to isolate the complete human enzyme. They then used cryo-electron microscopy to map the structure at high resolution. Biochemical experiments examined how the enzyme functions under different conditions, including in the presence of inhibitors and activators.
Computer simulations further revealed how structural movements influence the enzyme’s activity. The findings point to the importance of a hinge-like region where minor adjustments produce substantial functional changes. Understanding this mechanism could help scientists design more effective inhibitors.
“Our investigation of AASS as a potential drug target has revealed multiple ways to alter the enzyme’s activity,” Sander Houten told News-Medical. Houten is a senior and co-corresponding author and Professor of Genetics and Genomic Sciences at the Icahn School of Medicine.
| Research Parameter | Methodology Used | Primary Objective |
|---|---|---|
| Enzyme Isolation | Novel laboratory extraction | Isolate complete human AASS enzyme |
| Structural Mapping | Cryo-electron microscopy | Visualize biological molecules at high resolution |
| Functional Analysis | Biochemical experiments and computer simulations | Examine enzyme movement and allosteric regulation |
The investigators emphasize that the findings represent an early step toward developing a therapy, rather than a clinical treatment or cure for GA1. The experiments took place in laboratory settings, and further research in animals and humans will be necessary to determine whether targeting AASS is safe and effective.
The team’s next step involves using the structural map to identify and develop molecules that inhibit the enzyme. Beyond advancing GA1 research, the findings offer broader insight into how enzymes can be regulated through subtle structural changes.
“With this new enzyme structural knowledge, we can begin to explore how to design molecules that inhibit AASS and assess whether they could eventually lead to a treatment for GA1,” Robert J. DeVita told News-Medical. DeVita is senior and co-corresponding author, Professor of Pharmacological Sciences, and Director of Medicinal Chemistry in the Marie-Josée and Henry R. Kravis Drug Discovery Institute at the Icahn School of Medicine.
