Structural and biochemical insight into allosteric regulation of the human 2-aminoadipic semialdehyde synthase

Multiple clinically relevant inborn errors of metabolism occur in lysine degradation, yet the regulation of this biochemical pathway remains poorly understood. The initial rate-limiting step of lysine catabolism is catalyzed by the bifunctional enzyme 2-aminoadipic semialdehyde synthase (AASS). Here, we report the cryo-EM structure of the full-length 400-kilodalton tetrameric AASS enzyme complex with substrates and products bound to both the lysine-2-oxoglutarate (LOR) and saccharopine dehydrogenase (SDH) catalytic domains. We also identified allosteric compounds that modulate the activity of AASS by reacting with cysteine-414 and shifting the pH optimum for biochemical activity. The mutagenesis of this allosteric Cys 414 has marked effects on the enzyme’s conformation and activity despite being more than 12 angstrom from the active site. We find that small changes near the hinge of an enzyme can have large effects on its catalytic properties. Last, targeting allosteric cysteines may be a general strategy for modulating enzyme activity by altering the dynamics of the enzyme.