Mapping an Enzyme Offers Clues to Treating Rare Genetic Disease
New findings could help guide future treatments for the metabolic disorder glutaric aciduria type 1
Structure of the full AASS protein determined by cryo-electron microscopy. Wu, Sci.Adv. 12, eaej2268 (2026)
Researchers at the Icahn School of Medicine at Mount Sinai have mapped an enzyme that could be targeted to develop new treatments for glutaric aciduria type 1 (GA1), a rare genetic disorder that can lead to brain damage, revealing new details about how the enzyme works and how its activity is controlled. The findings were published in the November 13 online issue of Science Advances [www.science.org/doi/10.1126/sciadv.aej2268].
The researchers studied AASS (alpha‑aminoadipic semialdehyde synthase), an enzyme involved in breaking down the amino acid lysine and identified a region that regulates its activity. The findings provide new structural insights that could help guide the development of drugs to inhibit AASS and reduce the buildup of harmful metabolites associated with GA1.
“This is the first detailed picture of the complete AASS enzyme, giving us a much clearer understanding of how its different parts work together,” says senior and co-corresponding author Michael Lazarus, PhD, Associate Professor of Pharmacological Sciences, and Associate Director of the Mount Sinai Center for Therapeutics Discovery, at the Icahn School of Medicine. “We also found that relatively small changes in a flexible region of the protein can have a substantial effect on its activity. That gives us an important new avenue to explore as we work toward potential treatments for GA1.”
GA1 is an inherited metabolic disorder that causes toxic substances to accumulate in the body, which can lead to irreversible brain damage and life-altering neurological complications. “Our investigation of AASS as a potential drug target has revealed multiple ways to alter the enzyme’s activity. A better understanding of how nature uses these mechanisms to control lysine degradation will help with the development of treatments for the disease,” says senior and co-corresponding author Sander Houten, PhD, Professor of Genetics and Genomic Sciences at the Icahn School of Medicine.
To study AASS, the team first developed a method to isolate the complete human enzyme. They then used cryo-electron microscopy, a technique that allows scientists to visualize the structures of biological molecules at high resolution, to map the enzyme in detail.
Biochemical experiments helped the researchers examine how the enzyme functions under different conditions, including in the presence of substances that inhibit or activate it. Computer simulations further revealed how the enzyme’s structure can change and how those movements influence its activity.
The findings point to the importance of a hinge-like region of the enzyme, where seemingly minor structural adjustments can produce substantial changes in function. Understanding this mechanism could help scientists develop inhibitors that act on AASS more effectively, say the investigators. “Our findings show how a relatively small change at a flexible connection point can influence the behavior of a much larger protein,” says Dr. Lazarus.
“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,” added senior and co-corresponding author Robert J. DeVita, PhD, 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.
The researchers note that the findings represent an early step toward developing a therapy, not a treatment or cure for GA1. The experiments were conducted in laboratory settings, and further research, including studies in animals and potentially humans, will be needed to determine whether targeting AASS is safe and effective.
The team’s next step is to use the structural map to identify and develop molecules that inhibit the enzyme. In addition to advancing research into GA1, the findings offer broader insight into how enzymes can be regulated by subtle changes in their structure.
The paper is titled "Structural and biochemical insight into allosteric regulation of the human 2- aminoadipic semialdehyde synthase."
The authors, as listed in the journal, are Ruoxi Wu, Susmita Khamrui, Tetyana Dodatko, Yufei Xiang, Afrooz Golestanian, Ngoc Dung Pham, Kunal Kumar, Yi Shi, Roman Osman, Robert J. DeVita, Sander M. Houten, and Michael B. 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 of the National Institutes of Health under award numbers R01HD112518, R01HD118270, and R35GM124838.
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.
About the Mount Sinai Health System
Mount Sinai Health System is one of the nation’s leading integrated academic health systems and one of the largest in the New York metropolitan area. Its comprehensive system includes seven hospitals, more than 400 outpatient practices, over 600 research and clinical laboratories, the Icahn School of Medicine at Mount Sinai, the Graduate School of Biomedical Sciences, and the Mount Sinai Phillips School of Nursing. Together, the Health System comprises approximately 48,000 employees, more than 9,000 physicians, and 8,600 nurses.
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