Northwestern Chemistry welcomes Koon Mook Kang from the Silverman Group, hosted by the Graduate Liaison Committee.
Selective Inactivation of GABA Aminotransferase by Targeting Conformational Flexibility of a Reactive Intermediate.
Abstract: Selective targeting of homologous PLP-dependent enzymes, such as GABA aminotransferase (GABA-AT) and ornithine aminotransferase (OAT), is notoriously challenging. While mechanism-based inactivators are the only available therapeutic option targeting GABA-AT, their off-target activity against OAT hinders clinical translation. To address this problem, we investigated and reported the OAT-specific inactivation mechanism of CPP-115, a GABA-AT inactivator designed in the Silverman group that is being taken by a child with infantile spasms, by integrating conventional biochemical experiments, X-ray crystallography at different mechanistic stages, and computational simulations of a key intermediate. Based on the finding that conformational flexibility of the reactive intermediate is required for the OAT-specific mechanism, we designed and synthesized a proof-of-concept molecule that restricts this conformational flexibility, achieving the highest reported GABA-AT selectivity over OAT (>200-fold). Moreover, this molecule demonstrated therapeutic efficacy in pain animal models, bringing GABA-AT-targeted therapies closer to safe clinical use.
Jolly Patro
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