Mount Sinai Maps AASS Enzyme, GA1 Target Emerges

A team at the Icahn School of Medicine at Mount Sinai has mapped the full structure of AASS, an enzyme that sits at the top of the pathway the body uses to break down the amino acid lysine. The structure, determined by cryo-electron microscopy, appeared in the November 13 online issue of Science Advances. It shows a control region nobody had seen in full before, and that region is the part a drug would aim at.

The paper, by Ruoxi Wu and colleagues, is titled "Structural and biochemical insight into allosteric regulation of the human 2-aminoadipic semialdehyde synthase." AASS is a bifunctional enzyme, two working parts in one protein. Its LOR domain runs the first step of lysine breakdown and its SDH domain runs the second. The team identified a hinge-like region that regulates the enzyme's activity, the allosteric switch in the paper's title.

The disease on the other side of the pathway is glutaric aciduria type 1, or GA1. It's an inherited metabolic disorder caused by a deficiency in a different enzyme, GCDH, that works further down the same pathway. When GCDH fails, toxic substances build up, and the buildup can cause irreversible brain damage and severe neurological complications, often in infancy.

The treatment logic follows from the plumbing. If a drug slows AASS at the top of the pathway, less material flows down toward the blocked step, and less of the toxic product accumulates. That approach is called substrate reduction, and AASS is a plausible place to try it because people born with a deficient AASS enzyme show a biochemical abnormality, hyperlysinemia, that usually carries no clinical symptoms. Turning the enzyme down doesn't obviously break anything else.

The senior author is Michael B. Lazarus, an associate professor of pharmacological sciences at Mount Sinai and associate director of its Center for Therapeutics Discovery. The work drew support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of General Medical Sciences, both part of the National Institutes of Health.

The team is plain about the distance left. The findings are an early step toward a therapy, not a treatment or a cure, and the experiments were done in laboratory settings. Animal studies, and then human ones, would have to show that targeting AASS is safe and that it works. What changed this week is narrower and real: the target now has a complete shape.

The target has supporting evidence from animal work published earlier this year. In a study in Scientific Reports, mice bred to lack the GCDH enzyme, the standard GA1 model, were also bred to lack AASS. Those double-knockout mice were clinically indistinguishable from normal mice and showed a marked reduction of glutaric acid, and they didn't develop the severe disease pattern that a high-lysine diet triggers in GA1 model mice. Removing the top of the pathway protected the brain downstream.

A structure changes what chemists can do next. With the full protein mapped, including the regulatory hinge, screening can move from guesswork to design: compounds can be modeled against the switch itself, tested for whether they close it, and refined against the structure. That's the standard path from a cryo-EM map to a drug candidate, and it's measured in years. For families living with GA1, who currently manage the disorder with diet and emergency protocols rather than a medicine aimed at its cause, the map is the first piece of the path that exists.